bluuebunny/crossref_metadata_2025 huggingface dataset:
Physicochemical interactions of praziquantel, oxamniquine and tablet excipients
Authors: Prankerd Richard J , Ahmed Sayed M
Published: April 2011

A differential scanning calorimetry and infrared spectrophotometry study of potential interactions between oxamniquine and praziquantel, two synergistic anti-parasitic drugs, indicated that they did not interact on fusion. Mixtures of the two drugs with each of nine common pharmaceutical excipients (Ac-Di-Sol, Avicel, Crospovidone, calcium phosphate, magnesium stearate, starch, lactose, PEG 6000, stearic acid) appeared to interact only with stearic acid. These results suggested that a combination solid dosage form was feasible.
Physicochemical properties of oxamniquine indicate a new polymorphic form
Authors: Prankerd Richard J , Ahmed Sayed M
Published: April 2011

New dissolution rate, chemical stability and thermal analysis data are reported for an anti-schistosomal drug, oxamniquine. A slow dissolution rate (40–70% in 1 h) was found, which may contribute to its erratic clinical response. The drug was found to be chemically stable in water for at least 21 days at 37°C. Dissolution rate and thermal analysis evidence is presented for a previously unreported polymorph (Form III). This form appears to be intermediate in physical stability between the known Forms I and II.
The use of albumin microspheres in the treatment of carrageenan-induced inflammation in the rat
Authors: Lewis D A , Field W N , Hayes K , Alpar H O
Published: April 2011

Free hydrocortisone, hydrocortisone incorporated into microspheres and empty microspheres have been administered orally to rats with carrageenan-induced hindpaw inflammation. Hydrocortisone administered in particles was effective at a lower dose than free steroid in reducing inflammation. Inflammatory exudates were able to release steroid from the microspheres by proteolytic degradation.
Amorphism and Physicochemical Stability of Spray-dried Frusemide
Authors: Matsuda Yoshihisa , Otsuka Makoto , Onoe Mika , Tatsumi Etsuko
Published: April 2011

The physicochemical properties of amorphous forms of frusemide, prepared by spray-drying at 50 or 150°C, and their hygroscopic stability at temperatures of 25 and 40°C, and at 0 and 75% relative humidity were investigated. The glass transition temperature of the amorphous form A was 44·2°C as measured by differential scanning calorimetry, while that of the amorphous form B was 54·4°C. The activation energies for glass transition and crystallization processes were calculated from the differential scanning calorimetry thermograms of amorphous forms A and B, respectively. Stability determined by X-ray diffraction at 0% relative humidity, 25 and 40°C suggested that form B was more stable than form A. However, the stability of form A at 75% relative humidity and 25 and 40°C was similar to that of form B.
Pig Ear Skin as an In-vitro Model for Human Skin Permeability
Authors: Dick Ian P , Scott Robert C
Published: April 2011

Pig skin has been shown to have similar histological and physiological properties to human skin and has been suggested as a good model for human skin permeability. In this series of experiments, the in-vitro permeability of pig ear skin was compared with human (abdominal) skin and rat (dorsal) skin using both hydrophilic (water, mannitol, paraquat) and lipophilic (aldrin, carbaryl, fluazifop-butyl) penetrants. Pig skin was found to have a closer permeability character than rat skin to human skin, particularly for lipophilic penetrants. Electrical conductivity measurements across pig skin membranes showed that skin conductivity could be a useful method for assessing the integrity of membranes, particularly when used in conjunction with water permeability assessments.
The Mitigating Effects of Phosphatidylcholines on Bile Salt- and Lysophosphatidylcholine-induced Membrane Damage
Authors: El-Hariri Linda M , Marriott Christopher , Martin Gary P
Published: April 2011

The effects, at pH 7·0, of a series of 0·2 Mm phosphatidylcholines (PC), namely dicaproyl-PC (DCPC), didecanoyl-PC (DDPC), dilauroyl-PC (DLaPC), dimyristoyl-PC (DMPC), dipalmitoyl-PC (DPPC), dioleoyl-PC (DOPC) and dilinoleoyl-PC (DLPC) and a series of 0·2 Mm fatty acid salts (namely sodium myristate, palmitate, stearate, oleate and linoleate) upon the erythrocyte haemolysis induced by 2 Mm sodium taurodeoxycholate (STDC) were determined. The influence of egg PC and dihexadecyl phosphate (DHDP) concentration upon the haemolysis induced by 1·4 Mm sodium deoxycholate (SDC), 2 Mm STDC and 0·1 Mm lysophosphatidylcholine (LPC) were also established. A bile salt: egg PC mole ratio of 0·5 virtually abolished the haemolysis induced by SDC and STDC, whereas the same ratio of LPC: egg PC only reduced haemolysis from 65 to 40% (maximum haemolysis). DHDP had no effect on the haemolytic action of SDC or STDC. The salts of the fatty acids were non-haemolytic, and when mixed with STDC did not affect the level of haemolysis induced by the bile salt. In contrast, DDPC and DLaPC enhanced the haemolysis of STDC and DCPC had no effect, whereas DMPC, DPPC, DSPC, DOPC, DLPC and egg PC all reduced haemolysis. Maximum reduction was determined for DMPC and egg PC. The mixed micelle preparation temperature (either room or 60°C) and temperature of incubation (either 20°C for 30 min or 37°C for 5 min) had only minor effects on the net haemolysis induced by STDC. These findings may be of significance in understanding the aetiology of certain gastrointestinal diseases and in determining whether mixed bile salt micelles have a role as drug penetration enhancers.
Effects of Isosorbide-5-mononitrate and Isosorbide-2-mononitrate on the Contractile and Electrical Activity and on the Content of Cyclic Nucleotides in Isolated Heart Muscles of the Guinea-pig and Dog
Authors: Atanassova R , Spassov G , Balansky R , Boev K
Published: April 2011

Isosorbide-5-mononitrate and isosorbide-2-mononitrate, the metabolites of isosorbide dinitrate, were studied for their effects on the contractile and electrical activity and on the content of cyclic nucleotides in isolated heart muscles of guinea-pig and dog. Isosorbide-5-mononitrate at all concentrations tested and isosorbide-2-mononitrate at low concentrations did not produce significant changes in the mechanical activity of guinea-pig heart preparations. Isosorbide-2-mononitrate in concentrations above 10−4  m inhibited the contractility and shortened the action potential of guinea-pig and dog heart muscle. Neither mononitrate had an effect on cAMP concentration but both induced a significant elevation of cGMP content in guinea-pig heart tissue, the effect of isosorbide-2-mononitrate being greater.
Correlation of extrusion forces, raw materials and sphere characteristics
Authors: Baert L , Fanara D , Remon J P , Massart D
Published: April 2011

This communication reports on the correlation between extrusion forces and sphere characteristics. Dicalcium phosphate dihydrate, α-lactose monohydrate and anhydrous β-lactose were models for respectively an insoluble, a medium soluble and a highly soluble drug and were used to produce spheres. Phase diagrams for ternary mixtures consisting of microcrystalline cellulose, water and a third excipient were constructed. The region where good spheres were obtained correlated well with the area of extrusion forces between 630 and 1260 N. This correlation was seen for the insoluble, the medium and the highly soluble products.
Effects of senna and its active compounds rhein and rhein-anthrone on PAF formation by rat colon
Authors: Mascolo N , Autore G , Izzo A A , Biondi A , Capasso F
Published: April 2011

A single or a prolonged oral administration of senna (60 mg kg−1) to rats did not increase either colonic PAF (platelet activating factor) content or intraluminal release of acid phosphatase. A similar result was observed in the colonic tissue of rats perfused in-vitro with rhein (1–300 μg mL−1) or rhein-anthrone (1–300 μg mL−1). A single or prolonged administration of castor oil (2 mL) to rats increased both colonic PAF content and intraluminal release of acid phosphatase. Colonic tissue of rats perfused in-vitro with calcium ionophore A23187 (1 and 10 μg mL−1) formed large amounts of PAF and acid phosphatase. Since PAF can mediate intestinal damage and acid phosphatase is a marker of cellular injury, we conclude that senna and its derivatives, rhein and rheinanthrone, are well tolerated in rats.
Further studies on the anti-nociceptive effect of vasopressin
Authors: Ramaswamy S , Shewade D G , Tyagi M G , Bapna J S
Published: April 2011

The possible interactions of pathways which mediate anti-nociception when stimulated by (α2-adrenoceptor agonists and arginine vasopressin (AVP) were investigated. Yohimbine, an α2-antagonist, failed to modify the anti-nociceptive response of AVP. However, clonidine pretreatment, in sub-effective and effective doses, potentiated the anti-nociceptive response of a sub-effective dose of AVP. This potentiation was attenuated by yohimbine and completely anatagonized by naloxone. These studies suggest that pathways related to the opioidergic system and those stimulated by α2-agonists may be utilized by AVP in eliciting the anti-nociceptive response.
Effects of benzodiazepine administration on A1 adenosine receptor binding in-vivo and ex-vivo
Authors: Kaplan Gary B , Cotreau Monette M , Greenblatt David J
Published: April 2011

The adenosine receptor has been implicated in the central mechanism of action of benzodiazepines. The specific binding of an A1-selective adenosine antagonist radioligand, [3H]8-cyclopentyl-1,3-dipropylxanthine, was measured in-vivo in mice treated with alprazolam (2 mg kg−1, i.p.), lorazepam (2 mg kg−1, i.p.) and vehicle. Binding studies were performed in-vivo and ex-vivo in mice receiving continuous infusion of alprazolam (2 mg kg−1 day−1), lorazepam (2 mg kg−1 day−1) and vehicle by mini-osmotic pumps for 6 days. Continuous infusion of alprazolam and lorazepam significantly decreased specific binding by 34 and 53%, respectively, compared with vehicle treatment (P < 0·01). Single doses of alprazolam and lorazepam induced a similar trend in specific binding in-vivo (P = 0·07). There were no alterations in A1 -receptor density (Bmax) or affinity (Kd) in cortex, hippocampus or brainstem in ex-vivo studies. Benzodiazepine treatment may diminish A1- receptor binding in-vivo by inhibiting adenosine uptake or by direct occupancy of the A1 adenosine receptor recognition site.
Non-Michaelis–Menten Type Hepatic Uptake of Liposomes in the Rat
Authors: Harashima Hideyoshi , Kume Yoshihiro , Yamane Chizu , Kiwada Hiroshi
Published: April 2011

The objective of this study was to verify the methodology for measuring uptake clearance of liposomes and to characterize kinetically the saturable hepatic uptake of liposomes through phagocytosis. The correction of vascular space was important in the evaluationof hepatic uptake. The efflux of liposomes from liver was shown to be negligible, by a repeated dose study, and thus, hepatic clearance can be obtained by the hepatic uptake divided by the area under the blood concentration-time curve (AUC). The determinant parameter which describes the saturability of uptake clearance of liposomes, independent of infusion rate, was investigated, using the data of an in-vivo constant infusion study, where infusion rate-dependent saturable hepatic clearance was observed. The mean blood concentration failed to obtain an infusion rate-independent function. On the other hand, the AUC could explain the saturability of hepatic clearance for every infusion rate by a unique relationship. The hepatic uptake amount could also explain this saturability, independent of infusion rate. These kinetic characteristics are inconsistent with Michaelis–Menten type kinetics, therefore a new model is required to describe the saturable hepatic clearance in the disposition of liposomes.
A Novel Prodrug of Salicylic Acid, Salicylic Acid-glycylglycine Conjugate, Utilizing the Hydrolysis in Rabbit Intestinal Microorganisms
Authors: Nakamura Junzo , Asai Kumiko , Nishida Koyo , Sasaki Hitoshi
Published: April 2011

The hydrolysis of salicylic acid-glycylglycine conjugate (salicyl-glycylglycine) following oral, intravenous, intracaecal and rectal administration (434, 72, 36 and 36 μmol kg−1, respectively: equivalent to salicylic acid) was examined in rabbits to develop a novel prodrug of salicylic acid. Salicylic acid was detected in the blood 2 h after oral administration of salicyl-glycylglycine and it reached a maximum level (55·6 μg mL−1) at 15 h, whereas a small amount of salicyl-glycylglycine was found in the blood. In contrast, unchanged salicyl-glycylglycine was found mainly in the blood following its intravenous administration, suggesting the involvement of presystemic deconjugation in the hydrolysis of salicyl-glycylglycine. Immediate and very extensive salicyclic acid formation in the caecum was observed following intracaecal administration of salicyl-glycylglycine, suggesting that the intestinal microorganisms were responsible for the biotransformation of this compound. In-vitro incubation of salicyl-glycylglycine with caecal content showed that salicyl-glycylglycine was hydrolysed efficiently in the caecum. Consequently, the blood concentration of salicylic acid was prolonged extensively following rectal administration of salicylglycylglycine, indicating the usefulness of salicyl-glycylglycine as a prodrug of salicylic acid.
α1-Adrenoceptor Subtypes in Bovine Prostate
Authors: Maruyama Keiko , Tsuchihashi Hiroshi , Baba Shoko , Mano Fumie , Nagatomo Takafumi
Published: April 2011

The object of this study was to examine the existence and characteristics of α1-adrenoceptor subtypes in the bovine prostate using the radioligand binding assay method. [3H]Prazosin was used as the radioligand and its binding sites in bovine prostate were classified into two subtypes. One subtype showed a high affinity (α1High, Kd: 101·1 Pm and Bmax: 11·8 fmol (mg protein)−1) and the other had a low affinity (α1Low, Kd: 3371·4 Pm and Bmax: 50·5 fmol (mg protein)−1). Although the same pKi values of clorethylclonidine, p-aminoclonidine, benoxathian and dibenamine to both α1High and α1  Low binding sites in bovine prostate tissue were observed, other α1 antagonists used in this study had different pKi values for the two α1-adrenoceptor subtypes. The existence and binding characteristics of α1-adrenoceptor subtypes in bovine prostate were clarified. It is possible that agents selective for one site may contribute to the development of better drugs for the treatment of bladder outlet obstructions of men with benign prostatic hyperplasia.
Inhibitory Effects of Tiamulin on Contractile and Electrical Responses in Isolated Thoracic Aorta and Cardiac Muscle of Guinea-pigs
Authors: Nakajyo Shinjiro , Hara Yutaka , Hirano Shin-Ichi , Agata Naoki , Shimizu Kazumasa , Urakawa Norimoto
Published: April 2011

The inhibitory effect of tiamulin, an antibiotic produced by Pleurotus mutilis, on contractile and electrical responses in isolated thoracic aorta and cardiac muscle of guinea-pigs was studied. In the thoracic aorta, tiamulin with an IC50 of 9·7 × 10−6  m inhibited sustained contractions induced by isosmotically added 60 Mm KCl. The inhibitory effect of tiamulin on a Ca2+-induced contraction in a depolarized muscle was competitively antagonized by raising external Ca2+ concentration. Bay K 8644 (10−7  m) antagonized tiamulin's inhibition of the Ca2+ -induced contraction. Tiamulin (2×10−5  m) decreased the elevated cytoplasmic Ca2+ level measured by the fura 2 AM method in the depolarized muscle. In high K+-isoprenaline-treated left atria, tiamulin (2 × 10−5–2 × 10−4  m) produced negative inotropic effects. On the other hand in the membrane action potential of papillary muscles, tiamulin (2 × 10−6–2 × 10−4  m) produced decreases in action potential and durations and 2 × 10−4  m tiamulin depressed the slow response action potential in depolarized muscles. Tiamulin produced prolongations of the PR interval in ECG, negative chrono- and inotropic effects, and an increase in perfusion flow in guinea-pig isolated and perfused hearts. These effects of tiamulin on the aorta or cardiac muscle were similar to those of verapamil and nifedipine. These results suggest that both the inhibitory action of tiamulin on the high K+-induced contraction in the aorta and the negative inotropic effect of tiamulin on the cardiac muscle are due to an inhibition of Ca2+ entry through the voltage-dependent Ca2+ channels of cells of both these muscles.
Feverfew Extracts and Parthenolide Irreversibly Inhibit Vascular Responses of the Rabbit Aorta
Authors: Barsby R W J , Salan U , Knight D W , Hoult J R S
Published: April 2011

Samples prepared from chloroform extracts of fresh leaves of feverfew (Tanacetum parthenium) strongly inhibited responses of rabbit aortic rings to phenylephrine, 5-hydroxytryptamine, thromboxane mimetic U46619 (9,11-dideoxy-11α,9α-epoxy-methano-PGF2α), and angiotensin II, but the inhibition to contractions induced by potassium depolarization was much less. The inhibition was concentration- and time-dependent, non-competitive, and irreversible, and also occurred in endothelium-denuded preparations. The feverfew extracts also caused a progressive loss of tone of pre-contracted aortic rings and appeared to impair the ability of acetylcholine to induce endothelium-dependent relaxations of the tissue. These effects were mimicked by a purified preparation of an α-methylenebutyrolactone, parthenolide, obtained from the extract. Our results demonstrate a nonspecific and potentially toxic response to feverfew on the vasculature.
Nicotinate Esters: Their Binding to and Hydrolysis by Human Serum Albumin
Authors: Steiner Alain , Mayer Joachim M , Testa Bernard
Published: April 2011

Nicotinate esters were studied for their binding to, and hydrolysis by, human serum albumin. Some esters (ethyl, isopropyl, t-butyl, cyclohexyl, benzyl) were bound but not hydrolysed, while others (2-chloroethyl, 2-butoxyethyl) displayed the opposite behaviour; 1-carbamoylethyl ester was neither bound nor readily hydrolysed. Only p-methoxyphenyl nicotinate was both a ligand and a substrate, and its rate constants of binding and hydrolysis were calculated in a stepwise procedure using a kinetic model.
Phenobarbitone Population Pharmacokinetics from Routine Clinical Data: Role of Patient Characteristics for Estimating Dosing Regimens
Authors: Yukawa Eiji , Higuchi Shun , Aoyama Toshinobu
Published: April 2011

Routine clinical pharmacokinetic data collected from patients receiving phenobarbitone have been analysed to evaluate the role of patient characteristics for estimating dosing regimens. The data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The pharmacokinetic model of phenobarbitone was described using a one-compartment steady-state model. The effect of a variety of developmental and demographic factors on clearance was investigated. NONMEM estimates indicated a nonlinear function of total body weight as the optimum adjustment of phenobarbitone clearance. Concomitant administration of phenobarbitone and other antiepileptic drugs showed a decrease of phenobarbitone clearance in young children. The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the steady-state concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring.
Digoxin Population Pharmacokinetics from Routine Clinical Data: Role of Patient Characteristics for Estimating Dosing Regimens
Authors: Yukawa Eiji , Mine Hisanori , Higuchi Shun , Aoyama Toshinobu
Published: April 2011

Routine clinical pharmacokinetic data collected from patients receiving digoxin have been analysed to evaluate the role of patient characteristics for estimating dosing regimens. The data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The pharmacokinetic model of digoxin was described using a one-compartment steady-state model. The effect of a variety of developmental and demographic factors on clearance was investigated. NONMEM estimates indicate that digoxin clearance was influenced by the demographic variables of age, total body weight, serum creatinine and sex. The interindividual variability in digoxin clearance was modelled with additive error with an estimated standard deviation of 46·15 L day−1 and the intraindividual variability, or residual error was 0·209 ng mL−1. The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the steady-state concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring.
PAF formation by human gastrointestinal mucosa/submucosa in-vitro: release by ricinoleic acid, and inhibition by 5-aminosalicylic acid
Authors: Capasso F , Tavares I A , Bennett A
Published: April 2011

Human isolated gastrointestinal mucosa/submucosa incubated with ricinoleic acid (12·5–100 μg mL−1) or the calcium ionophore A23187 (10 μg mL−1) released platelet-activating factor (PAF) as determined by a scintillation proximity assay after extraction and purification. 5-Aminosalicylic acid (25–100 μg mL−1) inhibited PAF release by ricinoleic acid in a concentration-dependent manner, and 50 μg mL−1 reduced the effect of A23187. We suggest that PAF may play a role in the taxation and mucosal damage by ricinoleic acid released from castor oil.
Nifedipine-morphine interaction: a further investigation on nociception and locomotor activity in mice
Authors: Pavone Flaminia , Battaglia Mario , Sansone Mario
Published: April 2011

Nociception and locomotor activity were tested in mice (C57BL/6 and DBA/2 strains), receiving the dihydropyridine calcium-channel blocker nifedipine, alone or combined with morphine. The calcium antagonist did not change the reaction time to thermal stimulation (tail-flick test), when administered alone, but combinations of nifedipine and morphine prolonged tail-flick latencies less than did the opiate alone. Nifedipine decreased locomotion in both strains, reduced the hypermotility induced by morphine in C57 mice, and enhanced the locomotor depression induced by the opiate in DBA mice. A comparison of the effects of nifedipine with those of the non-calcium antagonist vasodilator, hydralazine, suggests that the interactions with morphine were not exclusively related to neuronal changes produced by calcium channel blockade, but also to haemodynamic factors. In fact, except for the lack of interference with morphine-induced hypermotility in C57 mice, hydralazine, given alone or in combination with morphine, produced effects similar to those of nifedipine.
Stimulation of postsynaptic 5-HT1A receptors is responsible for the anticonflict effect of ipsapirone in rats
Authors: Przegaliṅski E , Chojnacka-Wojcik E , Filip M
Published: April 2011

Ipsapirone (1·25–10 mg kg−1), a non-benzodiazepine anxiolytic drug with high affinity for 5-hydroxytryptamine1A (5-HT1A) receptors, increased dose-dependently the number of punished licks in the drinking conflict test (Vogel test) in rats. The anticonflict effect of the drug administered at a dose of 5 mg kg−1 was not modified in animals with lesions of 5-HT neurones, produced by p-chloroamphetamine (PCA, 2× 10 mg kg−1). The anticonflict effect of ipsapirone in PCA-pretreated rats was antagonized by the 5-HT1A receptor and α1-adrenoceptor antagonist NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimmido)]butylpiperazine hydrobromide; 0·5–1 mg kg−1), but not by the selective α1-adrenoceptor blocker prazosin (0·5 mg kg−1). Neither NAN-190 nor prazosin affected the punished response in PCA-pretreated rats. The present results indicate that the anticonflict effect of ipsapirone depends on stimulation of postsynaptic 5-HT1A receptors.
BQ-153, a novel endothelin (ET)A antagonist, attenuates the renal vascular effects of endothelin-1
Authors: Cirino M , Motz C , Maw J , Ford-Hutchinson A W , Yano M
Published: April 2011

Endothelin (ET)-l, leukotriene D4 and the thromboxane analogue, U-44069, were all shown to produce dose-dependent reductions in renal blood flow after direct injection into the renal artery of anaesthetized pigs. The effects of ET-1 differed from the other two mediators in that ET-1 caused a transient vasodilator followed by a prolonged vasoconstrictor response. The pressor response was not mediated by the secondary release of either leukotriene D4 or thromboxane A2 as evidenced by the lack of effect of appropriate receptor antagonist MK571 (3-{-2(7-chloro-2 quinolinyl) ethenyl}phenyl{3-(dimethylamino-3-oxopropyl)thio}methyl thio propionic acid) and L-670,596 respectively. This response, however, could be inhibited in a dose-dependent fashion by the selective ETA antagonist, BQ-153 (cyclo-d-sulphalanine-l-Pro-d-Val-l-Leu-d-Trp-). Following blockade by BQ-153 the vasodilator response was unaffected and a residual pressor response remained, suggesting that either or both of these effects were mediated either through an ETB or a novel, as yet undefined, endothelin receptor.
Comparison of Nebuliser Efficiency for Aerosolizing Pentamidine
Authors: Smith Don , Erskine David , Steele Janice , Hills Denise , Gazzard Brian
Published: April 2011

Inhaled pentamidine has become an important method of treatment and prophylaxis for Pneumocystis carinii pneumonia and we have compared nebuliser efficiency in terms of drug output and droplet sizes in four brands of jet nebuliser (Acorn-22, Inspiron, Cirrus, Respirgard II) and one brand of ultrasonic nebuliser (Fisoneb), at 2 pentamidine concentrations and 3 flow rates, using a laser particle sizer. Droplet size (which varied from 1·2 to 4·7 μm mass median diameter) was dependent in all cases, except with the Respirgard II system, on the flow rate of the gas driving the equipment and the concentration of pentamidine used. Drug output varied significantly between nebuliser brands and for a 300 mg dose of pentamidine was: 61% for the Acorn-22, 62% for the Inspiron, 49% for the Fisoneb and 43% for the Respirgard II. Both droplet size and drug output are important in determining nebuliser efficiency.
The Effect of Dinoprost on Transport of Water and Imipramine Through Rat Small Intestinal Membranes
Authors: Arimori Kazuhiko , Deshimaru Megumi , Nakano Masahiro
Published: April 2011

The relation between transmucosal fluid movement and its effect on absorption and exsorption of imipramine was studied with the in-situ single-pass perfusion technique in rats. Dinoprost (prostaglandin F2α, PGF2α) caused a dose-related inhibition of both absorption and secretion of water across the intestinal membrane. When PGF2α was infused at a rate of 5 μmol kg−1 h−1, the absorption rate of water decreased from 51·7 to 21·5 mL h−1 and the secretion rate decreased from 48·9 to 26·8 mL h−1. Net water flux changed from net water absorption (0·9 mL h−1)tonet water secretion (5·33 mL h−1) by infusion of PGF2α. However, absorption and exsorption of imipramine were little affected by infusion of PGF2α. The absorption rates of imipramine were 3·03 and 2·36 mg h−1 in the absence and presence of PGF2α, respectively. Furthermore, the average amounts of imipramine exsorbed into the intestinal lumen in 2 h were 7·82 and 8·10% in the absence and presence of PGF2α, respectively. Infusion of PGF2α, also enhanced motility of the small intestine compared with the control. From these results, it appears that PGF2α has no effect on the absorption and exsorption of imipramine across the intestinal membrane although it is reasonable to use PGF2α in the case of patients with overdoses of drugs which decrease gastrointestinal motility.
α2-Adrenoceptor Changes During Cerebral Ageing. The Effect of Ginkgo biloba Extract
Authors: Huguet François , Tarrade Thierry
Published: April 2011

[3H]Rauwolscine binding to α2-adrenoceptors in cerebral cortex and hippocampus membranes of young (4 months) and aged (24 months) Wistar rats has been investigated. In aged rats, Bmax values of [3H]rauwolscine binding were significantly reduced (25–32%) in the cerebral cortex and hippocampus, as compared with the number of α2-adrenoceptors found in young rats. Chronic treatment with Ginkgo biloba extract did not alter [3H]rauwolscine binding in the hippocampus of young rats, but significantly increased (28%) the [3H]rauwolscine binding density in aged rats. These data confirm the previously described age-related noradrenergic alteration and suggest that noradrenergic activity in aged rats is more susceptible to Ginkgo biloba extract treatment.
Method for Analysis, and Distribution Profile, of Covalently-linked Ferritin-daunorubicin Conjugate in the Blood of Trypanosome-infected Mice
Authors: Brown J E , Patterson L H , Williamson J , Brown J R
Published: April 2011

Daunorubicin is a highly potent trypanocide in-vitro but is inactive in-vivo. When daunorubicin is conjugated to bovine serum albumin or horse spleen ferritin using Schiffs base linkages, the complex is trypanocidal in-vitro and in-vivo. We have developed novel analytical methods, using HPLC with fluorimetric detection, for the quantitation of daunorubicin and doxorubicin in biological samples, either as unconjugated drug, or when covalently linked to macromolecules or particles. Ferritin-daunorubicin conjugate (25 mg kg−1) was administered intraperitoneally to mice infected with monomorphic Trypanosoma brucei rhodesiense; peak plasma levels occurred after 1·5 h, and were 5 times higher than those resulting from administration of an equivalent amount of unconjugated daunorubicin. Plasma levels then declined rapidly (t½ for 1–6 h period was 0·58 and 0·86 h respectively for conjugated and unconjugated daunorubicin). However, higher plasma levels were seen 24 h after treatment, suggesting the distribution profile of daunorubicin when conjugated to ferritin is multiphasic with resultant high levels of daunorubicin obtained for a prolonged time period.
Potassium markedly potentiates the effect of veratridine on dopamine release from rat superfused striatal ribbons
Authors: Olivier Valérie , Miquet Jean-Marie , Aubeneau Michel , Blanchard Jean-Charles , Doble Adam , Boireau Alain
Published: April 2011

The effects of veratridine-induced depolarization on [3H]dopamine ([3H]DA) release in the presence of a physiological (5 Mm) or a depolarizing (25 Mm) concentration of K+ were studied in-vitro in rat superfused striatal ribbons. A combination of the two depolarizing agents induced a marked potentiation in the overflow of [3H]DA, giving an overall 3- to 5-fold increase in veratridine activity. This potentiation was completely antagonized by tetrodotoxin (100 Nm). These studies indicated that K+-induced depolarization can increase the potency of veratridine in releasing dopamine from terminals.
Similar central actions of intravenous methohexitone suspension and solution in the rabbit
Authors: Viernstein H , Stumpf C
Published: April 2011

The central actions of solutions of methohexitone sodium and suspensions of methohexitone given intravenously in equimolar doses have been compared. The administrations induced identical anaesthesia. Because, in general, drugs acting upon the central nervous system are poorly soluble in water, this finding should be useful for routine pharmacological investigations as it avoids the use of organic solvents which may themselves affect the central nervous system.
Partition and distribution coefficients of aryloxypropanolamine β-adrenoceptor antagonists
Authors: Recanatini M
Published: April 2011

n-Octanol/water partition and distribution coefficients of fifteen β-blockers have been measured and the relationships between log P (neutral species), log Pi (fully ionized species) and log D7·4 have been examined. A strict correlation exists among these three parameters, suggesting that the ionization exerts similar effects on the partition behaviour of these drugs.
An In-vitro and In-vivo Correlative Approach to the Evaluation of Ester Prodrugs to Improve Oral Delivery of Propranolol
Authors: Shameem Mohammed , Imai Teruko , Otagiri Masaki
Published: April 2011

A series of ester prodrugs of propranolol was synthesized by incorporating substituents (straight alkyl, branched alkyl, acyloxyalkyl and cycloalkyl) into the β-hydroxy function of propranolol with the aim of protecting the drug against first-pass metabolism following oral administration. The in-vitro hydrolysis rates of the prodrugs were, in increasing order, liver homogenate ≫ plasma > buffers. The pH-rate profile of the prodrugs showed maximum stability around pH 4·0; the hydrolysis rates were drastically increased over pH 6·8. QSAR analysis revealed hydrophobic (π) and electronic (σ) effects of the substituents play the main roles for prodrug hydrolysis in buffers and plasma, while hydrolysis in liver homogenate could not be well explained by any of these parameters. Four prodrugs (O-acetyl-, O-butyryl-, O-isovaleryl- and O-cyclopropanoyl-propranolol) were selected for oral administration based on their hydrolysis in-vitro. Following oral administration of prodrugs to beagle dogs the absolute bioavailabilities (F) of propranolol were about 2–4-fold that after an equivalent dose of propranolol. The prodrugs were rapidly absorbed and regenerated propranolol to attain peak plasma levels at 0–0·5 h. Intact prodrug levels were also observed, which varied depending on their respective stabilities in in-vitro media. A linear relationship between F of propranolol and log P was obtained. F further appeared to be parabolically dependent on the observed hydrolysis rates of prodrugs in liver homogenate suggesting optimal design manipulation. The overall in-vitro and in-vivo results showed that lipophilic prodrugs having higher chemical and enzymatic stability in buffers and plasma, but susceptible to hydrolysis in the liver homogenate, to be the most promising prodrugs for improving oral bioavailability of propranolol.
A Modification of the Extended Hildebrand Approach to Predict the Solubility of Structurally Related Drugs in Solvent Mixtures
Authors: Bustamante Pilar , Escalera Begoña , Martin Alfred , Selles Eugenio
Published: April 2011

A modification of the extended Hildebrand equation is proposed to estimate the solubility of an organic drug in solvent mixtures. The equation accurately reproduces the solubility of four sulphonamides in dioxane-water mixtures without requiring the heat of fusion of the solute. A single equation is obtained for predicting the solubility of related drugs using the solubilities of the drugs in the pure solvents, dioxane and water, and solute-solvent interaction terms consisting of the solubility parameter, δ2, of the solute and the solubility parameter, δ1, and basic partial solubility parameter, δ1b, of the solvent mixture. By this procedure a single equation was obtained to estimate the solubilities of three xanthines in dioxane-water and another equation to obtain the solubilities of four sulphonamides. The equation obtained for sulphonamides is able to predict the experimental solubilities of two parent compounds, sulphasomidine and sulphathiazole, and the solubilities of a drug of different structure, p-hydroxybenzoic acid. This suggests that the intermolecular solute-solvent interaction of sulphonamides and p-hydroxybenzoic acid are similar. The results indicate that the solubility behaviour of drugs having different structures may be modelled using a common equation provided that they show similar solute-solvent interactions.
Stereochemical Aspects of the Molecular Pharmaceutics of Ibuprofen
Authors: Romero A J , Rhodes C T
Published: April 2011

Thermal analysis, thermodynamics of solution and molecular modelling of (+)-ibuprofen and (+)-ibuprofen gave information on how heterochiral or homochiral interactions would affect the processing of ibuprofen. The study confirmed that (±)-ibuprofen exists as a true racemate with a 10% eutectic pure enantiomer composition. Both the racemate and the (+)-isomer crystal unit cells include four molecules and crystallize in the P21/c and P21 space groups, respectively. Thus the intermolecular forces were different in each crystal. As a consequence the (+)-enantiomer lattice was more fragile but only slightly more soluble than the racemate in aqueous media. The solid-state structure contributions to solubility were different for the two crystals (ΔH(+) = 51·1 and ΔH(±) = 32–2 kJ mol−1) but the standard free energies of the solutions were comparable for both compounds.
A Comparative Study of the Toxicity of Chemically Reactive Xenobiotics Towards Adherent Cell Cultures: Selective Attenuation of Menadione Toxicity by Buthionine Sulphoximine Pretreatment
Authors: Riley R J , Spielberg S P , Leeder J S
Published: April 2011

Metabolic activation to reactive intermediates is a prerequisite for many forms of chemically-induced toxicity. Hepa lclc-9 cells were exposed to varying concentrations of several reactive metabolites implicated in adverse drug reactions and the toxicity of the compounds assessed using applied fluorescence technology. Cytotoxicity was assessed using the fluorescence of 2′, 7′-bis-(2-carboxyethyl)-5-(6)-carboxyfluorescein as an index of cell viability. The role of glutathione in cellular defence against these chemicals was investigated by pretreating the target cells overnight with buthionine sulphoximine, a specific inhibitor of glutathione synthesis. Depletion of intracellular glutathione augmented the toxicity of N-acetyl-p-benzoquinone imine (1·5–3-fold at 100 and 10 μm). Toxicity produced by the hydroxylamine of sulphamethoxazole (500 μm) was dependent entirely on pretreatment of the cells with buthionine sulphoximine (% cell death = 33 ± 16 compared with 0 ± 4 in untreated cells, P < 0·05). By contrast, the lethal effects of the model quinone, menadione, were attenuated markedly following glutathione depletion. The data obtained suggest that this assay, previously used with suspension cultures, may be useful in the rapid in-vitro screening of putative reactive intermediates. Moreover, the application of such methodology should prove beneficial for the elucidation of cellular mechanisms of defence and detoxification.
Effects of Isoquinolinesulphonamide Compounds on Multidrug-resistant P388 Cells
Authors: Nakamura Shigeo , Wakusawa Shinya , Tajima Kazuo , Miyamoto Ken-Ichi , Hagiwara Masatoshi , Hidaka Hiroyoshi
Published: April 2011

The effects of eight isoquinolinesulphonamide compounds on resistance to vinblastine in adriamycin-resistant mouse leukaemia cells (P388/ADR) which overexpress the relative molecular weight (Mr) 140 kDa P-glycoprotein in the plasma membrane were investigated. N-[2-(Methylamino)ethyl]-5-isoquinolinesulphonamide (H-8) and N-(2-aminoethyl)-5-isoquinolinesulphonamide (H-9) did not reverse vinblastine resistance. N-[2-[N-[3-(4-Chlorophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulphonamide (H-86) and N-[2-[N-[3-(4-chlorophenyl)-1-methyl-2-propenyl]amino]ethyl]-5-isoquinolinesulphonamide (H-87) caused accumulation of intracellular vinblastine and inhibition of vinblastine efflux from the cells and reversed the resistance. Addition of an aminoethyl group to the nitrogen atom of the sulphonamide group (W-66) or a formyl group at the terminal amino group (H-85) of H-86 reduced those activities. Conversion of the chlorophenyl group of H-87 to pyridinyl (H-31) or furanyl (H-34) markedly decreased activities against the drug resistance. The activity against vinblastine accumulation closely correlated with the apparent partition coefficient of compounds. These compounds dose-dependently inhibited photoaffinity labelling of a photosensitive analogue of vinblastine, N-(p-azido-(3-[125I])salicyl)-N′-β-aminoethylvindesine ([125I]NASV), and there was a good correlation between inhibition of [125I]NASV-photolabelling and hydrophobicity. Although these isoquinolinesulphonamides inhibited protein kinase A with different magnitudes, this activity did not correlate with the effect on the drug resistance. These results indicate that isoquinolinesulphonamide compounds with a hydrophobic group interact with antitumour drugs on P-glycoprotein and reverse multidrug resistance without involvement of their activity on protein kinase A.
Effect of Molsidomine and Linsidomine on the Human Isolated Bronchus and the Guinea-pig Isolated Trachea
Authors: Zhang Yong , Palette-Pays Catherine , Naline Emmanuel , Varoquaux Odile , Advenier Charles
Published: April 2011

The effects of molsidomine and its metabolite linsidomine were studied on the guinea-pig isolated trachea and on the human isolated bronchus. These effects were compared with those of nitrate derivatives (sodium nitroprusside, isosorbide dinitrate), theophylline, zardaverine and isoprenaline. Linsidomine exerted a relaxant effect similar to that of sodium nitroprusside on the two types of preparations precontracted with acetylcholine, histamine or potassium chloride. Molsidomine was about one-hundredth as potent as linsidomine, and less efficacious. The effects of the two substances were not modified by removal of the human bronchial epithelium. The concentration-response curves of linsidomine and sodium nitroprusside were significantly shifted to the right by methylene blue (3 × 10−5  m) but the effects of isoprenaline were unmodified. The effects of linsidomine and sodium nitroprusside were potentiated specifically by zaprinast (10−6-10−5  m), an inhibitor of type Ia or V phosphodiesterases, whereas the effects of isoprenaline were potentiated by zardaverine (10−9-10−8  m), an inhibitor of class III and IV phosphodiesterases. The effects of all three substances (linsidomine, isoprenaline and sodium nitroprusside) were potentiated equally by theophylline (10−5-10−4  m), a nonspecific inhibitor of phosphodiesterases. It is concluded that linsidomine is a potent relaxant of the smooth muscle of the guinea-pig isolated trachea and human isolated bronchus. In terms of potency and efficacy, its effect is much superior to that of the parent compound molsidomine. It is suggested that linsidomine acts, like nitrate derivatives, through the guanylate cyclase-cGMP system.
Differential Vasorelaxant Effects of K+-Channel Openers and Ca2+-Channel Blockers on Canine Isolated Arteries
Authors: Iwamoto T , Nishimura N , Morita T , Sukamoto T
Published: April 2011

The vasorelaxant effects of the K+-channel openers, pinacidil and cromakalim, were compared with those of the Ca2+-channel blockers, verapamil and KB-2796 (1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride), in canine isolated coronary, renal, basilar and mesenteric arteries precontracted with U46619, a thromboxane A2 mimetic. The relaxation induced by pinacidil and cromakalim was greater in coronary than in other arteries, the magnitude of relaxation being in the order of coronary > renal > basilar > mesenteric arteries. The relaxant responses to both drugs were inhibited by glibenclamide, a blocker of ATP-sensitive K+ channels. The relaxation induced by verapamil and KB-2796, in contrast, was greater in basilar than in other arteries, the magnitude of relaxation being in the order of basilar > coronary > renal and mesenteric arteries. In fura-2-loaded, U46619-stimulated arteries, pinacidil and cromakalim produced a greater reduction in intracellular Ca2+ concentration and muscle tension in coronary than in mesenteric arteries, while verapamil and KB-2796 reduced these values more potently in basilar than in mesenteric arteries. These results suggest that K+-channel openers exhibit a vasorelaxant selectivity for coronary arteries, whereas Ca2+-channel blockers exhibit such selectivity for cerebral arteries. The selective vasorelaxant action induced by these drugs appears to correspond, in part, to their effects on the concentration of intracellular Ca2+.
Effect of Glutathione on Canine Myocardial Ischaemia Without Reperfusion
Authors: Such Luis , Alberola Antonio , Gil Francisco , Bendala Elena , Viña José , Morcillo Esteban J
Published: April 2011

The present study was to evaluate the effect of exogenous glutathione on myocardial damage resulting from permanent (no reperfusion) coronary ligation (3 or 6 h) in anaesthetized dogs. Haemodynamics, infarct size and myocardial glutathione content were determined. Erythrocyte superoxide dismutase (SOD) activity was also determined in coronary venous blood samples. Glutathione was administered by the intraperitoneal route, 100 mg kg−1 as initial dose given 5 min before coronary ligation, and successive doses of 25 mg kg−1 every 40 min throughout the study period. Saline-treated dogs showed myocardial infarction, a decrease in myocardial glutathione content, and a transient increase in SOD activity. Three hours occlusion in glutathione-treated dogs resulted in a small reduction of infarct size, and no changes in myocardial glutathione content and SOD activity. By contrast, administration of glutathione failed to reduce infarct size and failed to prevent myocardial glutathione decrease in dogs subjected to 6 h occlusion. These results indicate that exogenous glutathione is of minor beneficial effect for myocardial damage resulting from permanent coronary occlusion and suggest that endogenous glutathione has a limited role in protecting against myocardial ischaemia without reperfusion.
Suppressive Effect of Recombinant TNF-gelatin Conjugate on Murine Tumour Growth In-vivo
Authors: Tabata Yasuhiko , Uno Kazuko , Ikada Yoshito , Muramatsu Shigeru
Published: April 2011

A recombinant human tumour necrosis factor α (TNF) was conjugated to gelatin by means of carbodiimide to improve the in-vivo stability of TNF. About 55% of TNF activity was retained after gelatin conjugation as judged by the cytotoxicity assay using L-M cells in-vitro. Intraperitoneal injection of the TNF-gelatin conjugate significantly suppressed the in-vivo growth of murine Meth A fibrosarcoma cells (SS2 cells) in mouse peritoneum, in comparison with that of free TNF at the same dosage (P < 0·05). After intraperitoneal injection, TNF activity of the conjugate was detected in both the serum and the peritoneal cavity of mice for a longer period than was free TNF, irrespective of the presence of SS2 cells. Chromatographic studies of the conjugate demonstrated that the increase in the apparent molecular weight of TNF was consistent with gelatin conjugation. It is likely that this leads to a prolonged retention of TNF activity in-vivo. In addition, the TNF-gelatin conjugate suppressed the in-vitro growth of SS2 cells to the same extent as free TNF. Thus, it is possible that the longer retention period of the conjugate brought about an increase in the chance of contact between TNF and SS2 cells, resulting in the enhanced suppressive effect of TNF on in-vivo tumour cell growth. Gelatin conjugation is an effective method for increasing the in-vivo antitumour activity of TNF.
Relaxation by Calcium Antagonists of Potassium-contracted Trachea from Normal and Sensitized Guinea-pigs: Influence of Epithelium and the Surface of Drug Entry
Authors: Roman M , Pascual R , Iriarte C F , Villanueva M M , Ortiz J L , Cortijo J , Morcillo E
Published: April 2011

A technique by which drug access was restricted to either the mucosal or the adventitial surface of tracheal rings, isolated from normal (unsensitized) or sensitized guinea-pigs, was used to study the role of the epithelium in the relaxation produced by calcium antagonists (verapamil, nifedipine, cinnarizine and flunarizine) of K+-induced contraction. In trachea from normal guinea-pigs, the relaxation to verapamil for unrestricted or mucosal drug entry was reduced in the absence of epithelium, whereas the relaxation produced by nifedipine, cinnarizine or flunarizine was unchanged. In sensitized trachea, the relaxation elicited by the calcium antagonists tested was similar in intact and epithelium-denuded tracheal rings irrespective of the surface of drug entry. These results confirm that the epithelium influences the relaxation to verapamil. This modulatory effect is absent in sensitized trachea and is not shared by other calcium antagonists.