bluuebunny/crossref_metadata_2025 huggingface dataset:
An observation of polymorphism in pentamidine isethionate
Authors: Steele G
Published: April 2011

Two forms of pentamidine isethionate have been identified from two commercial samples of the compound. The lower melting form was produced by freeze drying and has a melting point of 133.4°C whilst the higher melting form has a melting point of 192°C. Powder x-ray diffraction studies showed that each modification was crystalline and the infra-red spectra showed differences that could be attributed to polymorphism. It was noted that when the freeze dried material was exposed to the atmosphere it converted to the higher melting form and was hygroscopic. Examination of this compound in a formal polymorphism screen was advocated.
Resistance of myenteric neurons in the rat's colon to depletion by 1,8-dihydroxyanthraquinone
Authors: Heinicke E A , Kiernan J A
Published: April 2011

Earlier reports have suggested that anthraquinone purgatives in excessive amounts cause degeneration of neurons in the nteric nervous system. Danthron (1,8-dihydroxyanthraquinone) was administered to rats in their drinking water for four months. The effects of the drug on the total number of neurons and on the immunoreactivity of eight putative neurotransmitters in the myenteric plexus of the colon have been assessed. No differences were found between the treated animals and their controls, indicating that the drug does not kill myenteric neurons. These results agree with recent observations on the effects of senna in rats and mice, and do not support earlier claims that myenteric neurons are killed by anthraquinone purgatives.
Arecoline, but not haloperidol, induces changes in the permeability of the blood-brain barrier in the rat
Authors: Saija A , Princi P , De Pasquale R , Costa G
Published: April 2011

The aim of the present study was to investigate the existence of alterations of the blood-brain barrier (BBB) permeability in rats injected with centrally acting drugs, by calculating a unidirectional blood-to-brain transfer constant (Ki) for the circulating tracer [14C]-α-aminoisobutyric acid. The intraperitoneal (i.p.) injection of the dopaminergic antagonist haloperidol (1 mg kg−1) did not modify the regional BBB permeability. When the cholinomimetic agent arecoline hydrobromide (6.25 mg kg−1) was injected i.p. into methylatropine-pretreated rats, it induced a significant decrease of Kj values within the frontal cortex, parietal cortex, striatum and brain-stem. Our findings emphasize two concepts: (1) centrally acting drugs, such as arecoline, can induce changes in the BBB permeability, through several mechanisms; (2) there is no predictable correlation of drug stimulation of specific brain neuronal pathways and changes in the permeability of the BBB.
Serum protein binding of noscapine: Influence of a reversible hydrolysis
Authors: Karlsson Mats O , Dahlström Bengt
Published: April 2011

The binding of the antitussive drug noscapine to human serum, pure albumin and α1-acid glycoprotein has been investigated by ultrafiltration and equilibrium dialysis, using radiolabelled noscapine. The binding in serum pooled from volunteers was 93 ± 0.2% (at 100 ng mL−1). After incubation for 24 h the binding decreased to about 85% (ultrafiltration 87.0 ± 1.0%; equilibrium dialysis 84.3 ± 1.2%), because of the conversion of noscapine to noscapinic acid. Only unbound drug underwent this hydrolysis, and as noscapine is extensively bound in healthy volunteers, this elimination process is probably unimportant. The major binding protein of noscapine was albumin (K = 3060 M−1, n = 5.62), but the binding to ai-acid glycoprotein was also substantial (K = 31500 M−1, n = 1.73). The interindividual variation in binding was low and binding was linear at the concentrations observed after therapeutic doses (0–500 ng mL−1).
Design of a polyvinyl alcohol hydrogel containing phospholipid as controlled-release vehicle for rectal administration of (±)-propranolol HCl
Authors: Morimoto Kazuhiro , Fukanoki Shinichi , Hatakeyama Yoko , Nagayasu Atsushi , Morisaka Katsuaki , Hyuhyon Suong , Ikada Yoshito
Published: April 2011

Polyvinyl alcohol hydrogels which contained phospholipid, egg yolk lecithin or hydrogenated soya lecithin were designed as a transrectal delivery system for propranolol hydrochloride. The hydrogel preparations containing phospholipid were prepared by a low-temperature crystallization method. The release profile of propranolol from hydrogel preparations containing phospholipid complied with Fickian diffusion (Higuchi model). The release of propranolol from the hydrogel preparation decreased with higher contents of phospholipid (∼ 2% w/w). In rats plasma concentrations of propranolol after rectal administration of hydrogel preparations containing phospholipid (1 and 2% w/w) were prolonged compared with those of rats receiving preparations without phospholipid.
Effect of naproxen sodium on the net synthesis of glycosaminoglycans and protein by normal canine articular cartilage in-vitro
Authors: Brandt Kenneth D , Albrecht Marjorie
Published: April 2011

The effects of the non-steroidal anti-inflammatory drug, naproxen sodium, on the metabolism of normal canine articular cartilage has been examined. At a concentration approaching that achieved in synovial fluid of patients treated with the drug (i.e. 30 μg mL−1) naproxen sodium had no significant effect on net synthesis of either glycosaminoglycans or protein in organ cultures of femoral condylar cartilage, nor did it increase the proportion of newly synthesized glycosaminoglycans recovered from the culture medium, suggesting that it had no direct effect on the integrity of the extracellular matrix.
Effect of Compression Speed on the Tensile Strength of Tablets of Binary Mixtures Containing Aspirin
Authors: Cook Graham D , Summers Malcolm P
Published: April 2011

Mixtures of aspirin with sodium chloride, sucrose, Starch 1500 or Emcompress have been compressed to two maximum upper punch pressures at two compression speeds. Non-linear relationships between tensile strength and composition, and tablet porosity and composition were found in all cases. Tablets of the individual materials compressed at fast speed showed either little change or a reduction in tensile strength when compared with those compressed at slow speed. For mixtures of aspirin with Starch 1500, tablets compressed at fast speed were weaker and more porous than those compressed at slow speed. However, some mixtures of aspirin with sodium chloride, sucrose or Emcompress gave tablets with greater tensile strength and lower porosity when prepared at fast compression speed compared with tablets prepared at slow speed. This behaviour was attributed to the modification of the consolidation behaviour of the aspirin by the second material.
The interaction of orally administered iron with levodopa and methyldopa therapy
Authors: Greene R J , Hall A D , Hider R C
Published: April 2011

The ability of methyldopa and levodopa to interact with both ferrous and ferric iron under a variety of conditions likely to be encountered physiologically has been examined. Spectrophotometric studies of ferrous sulphate in the presence of methyldopa indicate that no complexation occurs below pH 2, whilst between pH 4–9, a variety of iron-methyldopa complexes is formed. The formation of these complexes is fast at high pH (pH 9: t 1/2 < 5 s), whilst the rate slows as the pH is lowered (pH 4: t 1/2 > 30 min). These complexes are characteristic of iron-catecholate species, indicating that in the presence of methyldopa (and levodopa) ferrous iron undergoes autoxidation to the ferric form. The tight binding of ferric iron to methyldopa is predicted to alter the biodistribution characteristics of the complex with respect to the unchelated components. Furthermore, under the acid conditions of the stomach, redox cycling can occur. This will result in both catechol oxidation and production of the toxic hydroxyl radical. The findings suggest that care should be exercised when simultaneous administration of either methyldopa or levodopa with ferrous sulphate is indicated.
A single injection of a biodegradable microsphere formulation of the ACTH-(4–9) analogue ORG 2766 accelerates functional recovery after brain damage
Authors: Wolterink Gerrit , Bouwman Theo R M , Eenink Mart J D , De Nijs Henrik , van Ree Jan M
Published: April 2011

The functional recovery from impaired motor activity induced by 6-hydroxydopamine lesions in rat nucleus accumbens was accelerated by subcutaneous treatment with the ACTH-(4–9) analogue Met/O2/-Glu-His-Phe-D-Lys-Phe (ORG 2766). Treatment was effective after daily injections of ORG 2766 dissolved in saline during the first 6 days following the lesion (ED50: 28.5 ng kg−1 day−1) or after a single injection of the peptide in a biodegradable microsphere formulation administered after the lesion (ED50:8.9 ng kg−1 day−1). This study shows that a single injection of a microsphere preparation can replace multiple injections with ORG 2766 in order to facilitate functional recovery after brain damage.
Diffusion coefficient in native mucus gel of rat small intestine
Authors: Winne Dietrich , Verheyen Walter
Published: April 2011

The diffusion coefficients of [3H] water, urea, benzoic acid, antipyrine, aminopyrine, α-methyl-glucoside, L-phenylalanine and of hydrogen ions were measured at 38 °C in native mucus gel from rat small intestine. The diffusion in the gel was reduced to 37–53% (for hydrogen ions to 7%) compared with buffer solution. In addition, the buffering capacity of the gel retarded the permeation of hydrogen ions before a steady state flux was attained. A model calculation revealed that in the preparation a gel layer of 80 μm thickness represents 23% of the total permeation resistance for substances with high epithelial permeability. The aqueous part of the pre-epithelial diffusion resistance amounts to 77% of the total resistance.
Antinociceptive and anti-inflammatory activity of a novel quipazine derivative (AAL-13): a selective inhibitor of 5-hydroxytryptamine reuptake
Authors: El-Mahdy Samiha A M , Alhaider A A , Mahgoub Afaf A
Published: April 2011

The anti-inflammatory and antinociceptive activities of a novel quipazine derivative 2(4-(3-chloropropyl)piperazinyl) quinoline (AAL-13), a selective inhibitor of 5-hydroxytryptamine (5-HT) reuptake, has been examined. Anti-inflammatory activity was assessed by measuring the inhibition of a cotton pellet granuloma and of carrageenan-induced paw oedema in rats, and of cantharidin-induced topical inflammation in the mouse ear. Antinociceptive activity was studied by using the modified Randall-Selitto method. Indomethacin was used as a reference. AAL-13 slightly inhibited granuloma formation (13%, P < 0.02) at 100 mg kg−1 day−1 for 7 days, whereas half that dose had no significant effect. There was significant inhibition of carrageenan-induced rat paw oedema (35%, P < 0.05 and 103%, P < 0.001) 3 h after single doses of AAL-13 (50 and 100 mg kg−1 p.o., respectively). Three hours after i.p. injection, the oedema inhibition was 58% (P < 0.05) and 86% (P < 0.001) for doses of 25 and 50 mg kg−1, respectively. In comparison, indomethacin (3, 6 and 12 mg kg−1 p.o.) inhibited oedema by 59% (P < 0.02), 65% (P < 0.01) and 63% (P < 0.02), respectively. Intraperitoneally, only the 12 mg kg−1 dose produced significant inhibition (82%, 3 h after carrageenan injection, P < 0.05). AAL-13 (1.5 mg/ear) had a significant anti-inflammatory effect on the mouse ear (52%, inhibition, P < 0.05), while indomethacin (3 mg/ear) gave 43% inhibition (P < 0.05). AAL-13 raised the pain threshold and analgesic index in both inflamed and non-inflamed rat paw similarly, while indomethacin (2–3 mg kg−1) was more active in the inflamed paw. However, the larger dose of indomethacin (12 mg kg−1) did raise the threshold in non-inflamed limbs. AAL-13 (up to 100 mg kg−1 daily for 7 days) was devoid of any ulcerogenic effect on the stomach, while indomethacin was lethal in doses greater than 3 mg kg−1 daily. We postulated that the anti-inflammatory and antinociceptive activity of AAL-13 might be due to its ability to block 5-HT and noradrenaline reuptake.
Evaluation of Protein Binding Effect on Local Disposition of Oxacillin in Rat Liver by a Two-compartment Dispersion Model
Authors: Yano Yoshitaka , Yamaoka Kiyoshi , Minamide Toshiomi , Nakagawa Terumichi , Tanaka Hisashi
Published: April 2011

The effect of protein binding upon the hepatic uptake of oxacillin was evaluated in the rat isolated perfused liver, based on the two-compartment dispersion model by means of the fast inverse Laplace transform (FILT). The perfusion experiment was carried out using the perfusates without and with bovine serum albumin (BSA, 40 g L−1). Oxacillin was injected as a pulse through the portal vein, and the outflow concentration-time course of oxacillin was fitted to the dispersion model using the non-linear least squares program MULTI(FILT). The partition ratio (k'), which is the measure of the extent of the reversible distribution into the hepatic tissue, was 0.163 ± 0.041 (s.d.) in the presence of BSA, and 0.095 ± 0.018 in the absence of BSA, which suggests interaction of the albumin-bound drug with the hepatic tissue. The elimination rate constant (ke) from the perfusate in the absence of BSA was 8.0 ± 0.55 min−1 and that in the presence of BSA was 3.3 ± 1.4 min−1 while the unbound fraction of the drug in the presence of 40 gL−1 BSA was 0.282. The hepatic elimination rate of oxacillin was not proportional to the unbound concentration of drug suggesting hepatic uptake of the bound fraction.
The effects of oral administration of (—)-menthol on nasal resistance to airflow and nasal sensation of airflow in subjects suffering from nasal congestion associated with the common cold
Authors: Eccles Ronald , Jawad Moutaz S , Morris Sara
Published: April 2011

The effects of oral administration of a lozenge containing 11 mg (—)-menthol on nasal resistance to airflow (NAR) and nasal sensation of airflow in 62 subjects suffering from nasal congestion associated with naturally acquired common cold infection have been studied. NAR was measured by posterior rhinomanometry and nasal sensation of airflow by means of a visual analogue scale (VAS). The effects of the lozenge were compared with a candy placebo lozenge in a double blind randomized trial. NAR showed a significant increase (P < 0.05) in both the menthol and placebo groups over the 2 h experiment with no difference between the groups at any time. The VAS scores showed significant changes of subjective improvement in nasal sensation of airflow (P < 0.001) in the menthol-treated group 10 min after dosing whereas the placebo group showed no change. It is concluded that dosing with 11 mg menthol in subjects with common cold has no effect on NAR as measured by posterior rhinomanometry but causes a marked change in nasal sensation of airflow with a subjective sensation of nasal decongestion.
Polyphloretin phosphate (PPP) antagonists of prostaglandin action also inhibit prostaglandin biosynthesis in-vitro
Authors: Curtis-Prior P B , Oblin A R , Bennett A , Parkinson N A , Orloff A M
Published: April 2011

Several polyphloretin phosphate (PPP) fractions (low mol. wt LC1259; high mol. wt LC1261; crude mixture, LC101) were confirmed in their established property as antagonists of the pharmacological actions of prostaglandins in a preparation of guinea-pig isolated ileum stimulated by prostaglandin (PG)E2. Further samples of the same material were then compared in-vitro with indomethacin in their ability to inhibit prostaglandin biosynthesis from arachidonic acid by a microsomal enzyme preparation. All three PPP fractions potently inhibited prostaglandin generation, with the rank order of potency LC1259 = LC101 = indomethacin > LC1261. The oral LD50 in mice was 25 mg kg−1 for indomethacin and > 1 g kg−1 for LC101. PPP fractions (especially LC101) may therefore have therapeutic potential as anti-inflammatory agents.
AHR-15010—A Novel Anti-arthritic Agent
Authors: Nolan J C , Walsh D A , Lo Y , Gathright C E , Radvany C H , Foxwell M , Whitman L , Graff G , Sancilio L F
Published: April 2011

AHR-15010 (3-(2-methoxyphenoxy)-1,2-propanediol bissulphamate ester) is a compound of novel structure that displays anti-arthritic activity in adjuvant arthritis in rats. When given orally from days 18 through day 50, (excluding weekends) after adjuvant injection, AHR-15010, at doses of 3.16 to 100 mg kg−1, produced significant anti-inflammatory activity and reduced the severity of the hind paw joint lesions as monitored by X-ray analysis. AHR-15010, however, has no acute anti-inflammatory activity in the Evans Blue-carrageenan pleural effusion assay in rats, has no analgesic activity in mice, and has no activity in a classic, delayed-type, hypersensitivity assay in mice or in a cotton pellet granuloma test in rats. These data, in conjunction with biochemical data showing that AHR-15010 has no prostaglandin synthetase inhibiting activity, suggest that AHR-15010 is an anti-arthritic with a unique mechanism of action. AHR-15010 is a carbonic anhydrase inhibitor. Data are presented that suggest that AHR-15010 and acetazolamide, a prototype carbonic anhydrase inhibitor, may present novel approaches to the treatment of arthritis.
Desipramine and nortriptyline antagonize apomorphine and reserpine hypothermia by a different mechanism
Authors: Volterra G , Borsini F , Lecci A , Meli A
Published: April 2011

The reversal of hypothermia, induced by reserpine or by a high (16 mg) dose of apomorphine, in male Swiss mice, does not seem to utilize a common mechanism. Desipramine (20 mg kg−1 i.p., 60 min) or nortriptyline (8 mg kg−1 i.p., 60 min) increased temperature in both reserpine (2.5 mg kg−1 s.c, 18–19 h) and apomorphine (16 mg kg−1 s.c, 30 min) treated mice. In apomorphine-treated animals the effect of both drugs was reversed by the mixed dopaminergic D1- D2-antagonist haloperidol (1 mg kg− i.p 90 min), the D1-receptor blocking drug SCH 23390 (0.05 mg kg−1 s.c, 30 min), the ?1-adrenoceptor blocking drugs prazosin (3 mg kgsp>−1 s.c., 90 min) and phenoxybenzamine (20 mg kg−1 i.p., 65 min), the ?-adrenoceptor blocking drug (±)-propranolol (10 mg kg−1 i.p., 120 min), and the opioid antagonist naloxone (2 mg kg−1 i.p., 15 min). In contrast the selective D2-antagonist (±)-sulpiride (100 mg kg−1 i.p., 90 min), and the ?2-antagonist yohimbine (2 mg kg−1 i.p., 75 min), failed to effect the reversal of apomorphine hypothermia brought about by desipramine or nortriptyline. Their temperature effects in reserpinized mice were not modified by any of the antagonists tested.
Study on the histamine-like activity of guanfacine
Authors: Martinez-Mir M I , Doñate F , Estañ L , Morales-Olivas F J , Rubio E
Published: April 2011

The effects of guanfacine have been studied on guinea-pig isolated atria and diethylstilboestrol-treated rat isolated uterus to determine whether it possesses histamine-like activity. Guanfacine produced a concentration-dependent negative chronotropic effect which was not modified by ranitidine (0.1 μM). In rat isolated uterus contracted by KCl, clonidine (5–5000 μM) produced concentration-dependent relaxation which was blocked by ranitidine (0.1 μM), but guanfacine only produced relaxation at high concentrations (100–1000 μM), and this was not affected by ranitidine (0.1 μM). It is concluded that guanfacine, unlike clonidine, does not produce effects due to activation of H2-receptors in either guinea-pig atria or rat uterus.
A Simple Method for the Preparation of Liposomes for Pharmaceutical Applications: Characterization of the Liposomes
Authors: Perrett Stephen , Golding Michael , Williams W Patrick
Published: April 2011

A new method for the preparation of liposomes is described that avoids the use of pharmaceutically unacceptable solvents and energy-expensive procedures such as sonication. The method is based on the initial formation of a proliposome mixture containing lipid, ethanol and water, which is converted to lipsomes by a simple dilution step. Measurements using 6-carboxyfluorescein as a marker indicate that water-soluble drugs can be trapped with extremely high efficiency (65–80% depending on lipid composition). The structural organization of the proliposome mixture and the final liposomes were characterized using electron microscopy and 31P-NMR.
Distribution of Subcutaneously Administered Inulin between Blood and Peripheral Lymph in the Rabbit
Authors: Lamka J , Krejčová V , Vondráčková Z , Gallová Š , Květina J
Published: April 2011

In experiments on rabbit peripheral lymph, the contribution of the blood and lymphatic system to the whole-body distribution of inulin after subcutaneous administration has been investigated and the effects of hyaluronidase and of thermal stimulus at the administration site examined. Inulin concentrations in lymph exceeded plasma concentrations by more than 100-fold. At the end of the experiment (90 min) the amount of drug in the total lymph collected was about one-seventh the amount found in urine. The blood system, as a result of higher circulation at the administration site distributes inulin from the subcutis more rapidly than does lymph. Hyaluronidase did not influence inulin concentrations in blood and lymph but thermal stimulus significantly decreased both concentration and total distribution. The decrease resulted from a developed oedema and vasoconstriction in the skin and subcutis of the cannulated extremity.
Thixotropic phenomenon in flocculated aqueous dispersions of acrylate methacrylate copolymers
Authors: Okor R S
Published: April 2011

Aqueous gels of two analogous, water-insoluble copolymers A and B have been formed by addition of excess water to concentrated ethanol solutions of the polymers. A and B differed only in their content of cationic groups in a ratio 2:1 (A: B). The gels were converted permanently to fluids (i.e. gel-sol transformation) at high shear rates. Stability of the resulting polymer dispersions depended on the presence and mutual repulsion of the polymer cations. Polymer B dispersions were less stable to the flocculating effect of an electrolyte (sodium chloride). At certain critical concentrations, 0.2 M NaCl (for polymer A), or 0.1 M NaCl (for polymer B) the electrolyte flocculated the otherwise stable dispersions to a gel structure. The electrolyte-flocculated gels were readily redispersed to fluids by shaking but reverted to gels on standing (thixotropic). In contrast the original coacervated gels (without electrolyte) could not be redispersed easily with manual shaking. Lower polymer-polymer interaction in the thixotropic system relates possibly to increases in particle size and irregularity of particle shape during flocculation.
A new method for assessment of drug absorption from muscle: application of a local perfusion system
Authors: Nara Eiji , Hatono Tetsuya , Hashida Mitsuru , Sezaki Hitoshi
Published: April 2011

Drug absorption from muscle has been examined using the rabbit hind leg, isolated by cannulating the femoral artery and vein, and perfused with or without bovine serum albumin (BSA) using a single-pass technique. A model compound, [14C]sucrose, was injected into the musculus gastrocnemius, and its appearance in the venous outflow was monitored and kinetically analysed by statistical moment theory. The fraction absorbed and mean arrival time in the venous outflow were calculated to be 103% and 50.5 min, respectively, in the BSA-containing system. The results of perfusion experiments without BSA were not significantly different, suggesting possible use of the simpler BSA-free perfusion system to obtain information on the muscular absorption of drugs.
Chronic D1-receptor blockade: effects on D2-receptor agonist-induced yawning in rats
Authors: Hietala Jarmo , Lappalainen Jaakko , Syvälahti Erkka
Published: April 2011

The effects of chronic treatment with the selective D1 dopamine receptor antagonist SCH 23390 (0.25 mg kg−1 s.c. twice daily for 18 days, 4 days withdrawal on yawning induced by the D2-receptor agonist quinpirole has been investigated. Low doses of quinpirole (20 and 50 μg kg−1 s.c.) induced dose-related yawning behaviour in rats. The yawning response to quinpirole was not significantly different in the presence or absence of SCH 23390 pretreatment. However, chronic treatment with SCH 23390 alone significantly suppressed yawning behaviour. The results suggest that chronic D1-receptor blockade with SCH 23390 does not alter the function of the D2-receptor population mediating yawning behaviour. However, after withdrawal it may result in behavioural activation as seen by suppression of yawning behaviour in the present study.
First-derivative spectrophotometric determination of salbutamol in pharmaceutical preparations
Authors: Hackmann E R M , Benetton S A , Santoro M I R M
Published: April 2011

The development of a first-order derivative spectrophotometric assay of salbutamol as a single-component and in combination with beclomethasone dipropionate in pharmaceutical formulations is described. The method eliminates the interference of tablet excipients and allows the determination of both components without their previous separation. The precision of the method for the assay of salbutamol in tablets was 1.0% with an average recovery of 98.8%. In the assay of the two-component preparation, the precision was 1.1%, with average recoveries for salbutamol of 99.3% and for beclomethasone dipropionate of 99.4%.
Intestinal Absorption of Drugs. The Influence of Mixed Micelles on on the Disappearance Kinetics of Drugs from the Small Intestine of the Rat
Authors: Poelma F G J , Breäs R , Tukker J J , Crommelin D J A
Published: April 2011

The solubilization of the hydrophilic drugs paracetamol and theophylline, and the lipophilic drugs dantrolene, griseofulvin and ketoconazole has been determined in mixed micellar aqueous dispersions composed of 10 mM taurocholate + 5 mM oleic acid. The solubilization of dantrolene and paracetamol has also been determined in aqueous (mixed) micellar dispersions of 1 g L−1 lysophosphatidyl-choline (LPC), or taurocholate/LPC. The influence of these (mixed) micelles on the absorption of the model drugs from solution was studied in the rat chronically isolated internal loop. Absorption kinetics of the drugs were evaluated on the basis of the disappearance rate of the drug dissolved in the perfusion medium in this loop. Absorption experiments with taurocholate/oleic acid in the perfusate resulted in a reduction of the disappearance rate for the lipophilic drugs and the hydrophilic drug theophylline. This could partly be ascribed to the decreased fraction of drug free in solution as a result of its micellar solubilization for dantrolene, griseofulvin and ketoconazole, but the decrease in the disappearance rate of theophylline was unexpected. Taurocholate/oleic acid, LPC and taurocholate/LPC micelles had no effect on the disappearance of paracetamol. The disappearance rate of dantrolene in the presence of LPC alone was not altered, in spite of the decreased fraction of the drug free in solution owing to its micellar solubilization. In contrast, taurocholate/LPC micelles caused a reduction in the rate of disappearance of dantrolene, as expected according to the phase-separation model. In-vitro, taurocholate and taurocholate/LPC reduced the molecular cohesion of porcine intestinal mucus, whereas LPC alone did not exhibit an effect on the gel structure of mucus. It is concluded that the transfer of solutes across the pre-epithelial aqueous diffusion layer (including the mucus) and the epithelium is unaltered by (mixed) micelles at concentrations in the physiological range.
Non-synaptic Cholinergic Modulation of Neurogenic Twitches of the Guinea-pig Ileum
Authors: Kadlec O , Hynie S , Mas̆ek K , S̆eferna I , S̆evc̆ík J
Published: April 2011

The effect of cholinergic and anticholinergic compounds on conduction of neuronal excitation has been studied in myenteric plexus-longitudinal muscle strips from the guinea-pig ileum. A preparation in a special triple bath was drawn through two rubber membranes dividing the strip into three segments. Neurogenic stimulation of the oral segment set up nerve action potentials propagating aborally across the middle segment (10 mm) so that the aboral segment might be also invaded, eventually. Drugs were added to the middle segment to affect neuronal propagation (non-synaptic effects) which was monitored by twitch height of the aboral segment. The application of acetylcholine to the middle segment augmented aboral twitches. The effects of nicotine, pilocarpine and oxotremorine were selectively blocked by (+)-tubocurarine, pirenzepine and atropine, respectively. The effect of acetylcholine was suppressed by pirenzepine and atropine and mimicked by doubling of KC1 concentration. The effect of acetylcholine may be thus explained by the facilitated propagation of nerve action potentials in partially depolarized cholinergic terminals via stimulation of muscarinic receptors. The adenylate cyclase system is not directly involved in the mechanism of muscarinic facilitation of neuronal propagation in the terminals; however, it may participate in the modulation of a final common effector mechanism.
Inhibitory Effect of 2-Hydroxypropyl-β-cyclodextrin on Crystal-growth of Nifedipine During Storage: Superior Dissolution and Oral Bioavailability Compared with Polyvinylpyrrolidone K-30
Authors: Uekama Kaneto , Ikegami Kengo , Wang Zheng , Horiuchi Yasuhide , Hirayama Fumitoshi
Published: April 2011

To prevent the crystal-growth of nifedipine during storage, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) was employed as a hydrophilic drug carrier and compared with polyvinylpyrrolidone K-30 (PVP). Amorphous nifedipine powders were prepared by spray-drying with HP-β-CyD or PVP, and their crystal-growing behaviour at accelerated storage conditions were examined by X-ray diffraction analysis and microscopy. Although PVP initially retarded the crystallization of nifedipine, it failed to control the increase of crystal size after prolonged storage at 60°C., 75% r.h., resulting in a remarkable decrease in dissolution rate in water. In sharp contrast, a relatively fine and uniform size of nifedipine crystals was maintained in the HP-β-CyD system even after accelerated storage conditions. The enhanced dissolution observed for all the HP-β-CyD systems in a dissolution medium containing 0·1% non-ionic surfactant HCO-60 were clearly reflected in the in-vivo absorption of nifedipine following oral administration to dogs. These results suggest that HP-β-CyD is particularly useful in solving problems encountered on storage of amorphous nifedipine in solid dosage forms.
Stomach outline visualization in gastrointestinal transit studies using scintigraphy
Authors: Course N J , Newton J M , Short M D
Published: April 2011

A major disadvantage of gamma scintigraphy in gastrointestinal transit studies is the inability to provide adequate delineation of anatomical details. As an aid to the important requirement of outlining the stomach to ensure accurate quantification of the time at which material empties from this organ, a new technique is described, using short half-life 81mKr gas to provide clearer identification of the stomach outline and position.
Different Sites of Action for α2-Adrenoceptor Antagonists in the Modulation of Noradrenaline Release and Contraction Response in the Vas Deferens of the Rat
Authors: Harsing L G , Vizi E S
Published: April 2011

Rat vas deferens was prepared, loaded with [3H]noradrenaline, and superfused to measure the release of tritium in resting conditions and in response to electrical field stimulation. The α2-adrenoceptor antagonists yohimbine, CH-38083 (7,8-(methylenedioxi)-14α-hydroxyalloberbane HCl), and idazoxan increased the electrically induced release of tritium in a concentration-dependent manner, whereas noradrenaline and the α2-adrenoceptor agonist xylazine exerted opposite effects. The inhibitory effect of noradrenaline on electrically induced tritium release was antagonized by yohimbine, CH-38083, and idazoxan. Of the α2-adrenoceptor antagonists tested, yohimbine and CH-38083 reversed the xylazine-induced inhibition of tritium release, and idazoxan was found to be completely ineffective against xylazine. Idazoxan, yohimbine and CH-38083 antagonized the inhibitory effect of xylazine on electrical stimulation-induced contractions of the vas deferens, as was evidenced by the apparent pA2 values. We conclude from the present experiments that noradrenaline and xylazine inhibit noradrenaline release by acting on distinct prejunctional α2-adrenoceptors and that the receptor subtype that responds to xylazine is insensitive to idazoxan. In addition, inhibition by xylazine of contractility but not of noradrenaline release was antagonized by idazoxan, suggesting that besides noradrenergic neurotransmission, other motor transmitter systems (purinergic) may also be involved in the inhibition by α2-adrenoceptor antagonists of mechanical responses in the rat vas deferens.
Renal clearance–lipophilicity relationships of some organic acids in rabbits, rats and mice
Authors: Lázníček Milan
Published: April 2011

The effect of lipophilicity on the renal clearance for a group of weak organic acids (benzoic, phenylacetic and hippuric acid derivatives) was studied in rabbits, rats and mice. These compounds are eliminated in the kidney by glomerular filtration and undergo both tubular secretion and tubular reabsorption. For quantification of the effect of lipophilicity, an equation

log(ERPF/CLR − 1) = a + b log D

was employed, where CLR represents renal clearance of the parent drug, ERPF is effective renal plasma flow, D is the partition coefficient of the acids between octanol and water, and a and b are constants. In interspecies comparison, the values of parameters a and b are similar indicating no significant interspecies differences in this route of elimination.
Haemolytic action of N-alkylpolymethylenediamines
Authors: Miyamoto Etsuko , Murata Yoshifumi , Kawashima Susumu , Ueda Michihiro
Published: April 2011

The haemolytic action of various N-alkyl derivatives (lauryl; C12H25-, myristyl; C14H29-, palmityl; C16H33-) of 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, 1,6-diaminohexane, 1,7-diaminoheptane, 1,8-diaminooctane was examined using rabbit red blood cells. The activities of the various derivatives were compared with those of antiplaque agents commonly used as mouthwashes; cetylpyridinium chloride (CP) and chlorhexidine acetate (CH). The haemolytic activities of these agents were dependent on the length of the N-alkyl chain, whereas the number of methylene groups between the nitrogen atoms had little effect. The order of potency was CP, N-palmityl derivatives, N-myristyl derivatives > N-lauryl derivatives > CH which was similar to the order of the antiplaque effect evaluated in-vitro.
Effects of morphine: an electrophysiological study on guinea-pig papillary muscle
Authors: Alarcón S , Hernández J , Laorden M L
Published: April 2011

Intracellular microelectrodes were used to study the electrophysiological effects of morphine on guinea-pig papillary muscle. Morphine (5 × 10−4  m) caused a significant decrease in the maximum rate of depolarization. At high concentrations (5 × 10−3  m) morphine induced a decrease in the action potential amplitude and a prolongation of the action potential duration. The administration of naloxone (10−7  m) partially antagonized the cardiac electrophysiological effects of morphine. These results suggest that the electrophysiological effects of morphine may be due to an interaction with opioid receptors.
Bile Salt- and Lysophosphatidylcholine-induced Membrane Damage in Human Erythrocytes
Authors: Martin Gary P , El-Hariri Linda M , Marriott Christopher
Published: April 2011

The interaction of bile salts and lysophosphatidylcholine (LPC) with membranes has implications both in understanding the aetiology of a number of gastrointestinal disorders, including gastritis, gastric ulcers and colonic cancer, and in enhancing drug absorption by various epithelia. The membrane toxicity of nine bile salts (the sodium (S) salts of chenodeoxycholate (CDC), deoxycholate (DC) and cholate (C) and their glycine (G) and taurine (T) conjugates) and LPC was determined using erythrocyte haemolysis as a model parameter. Washed human erythrocytes were incubated for 15–60 min at 20°C with media buffered at pH 8, 7 and 6. Bile salt toxicity was shown to be a function of type, concentration, pH and contact time with the membrane. At pH 7 toxicity decreased in the order LPC > unconjugated dihydroxy salts (SDC and SCDC) > conjugated deoxycholates (SGDC and STDC) > conjugated chenodeoxycholates (SGCDC and STCDC) > unconjugated trihydroxy salt (SC) > conjugated trihydroxy salts (SGC and STC). Incubation with equimolar combinations of bile salts (SDC + SCDC; STCDC + SGDC; SDC + STDC) indicated that the resultant damage was an additive function of the damage induced by the individual bile salts.
Adsorption of Paracetamol and Chloroquine Phosphate by Some Antacids
Authors: Iwuagwu M A , Aloko K S
Published: April 2011

The adsorption of paracetamol and chloroquine phosphate onto some antacids with adsorptive properties, has been studied. Dissolution of the drugs from commercial tablets was significantly retarded in the presence of the antacids. The adsorption and retardation of dissolution of both drugs by the adsorbent antacids studied followed the rank order magnesium trisilicate > magnesium oxide > aluminium hydroxide > edible clay. The concomitant administration of the drugs and antacid formulations containing any of these should be discouraged.
Effect of compressional forces on piroxicam polymorphs
Authors: Ghan G A , Lalla J K
Published: April 2011

The effect of compressional force on the polymorphic transition in piroxicam has been examined, using pure polymorph, by differential scanning calorimetery, powder X-ray diffractometry and by determination of dissolution rates from tablets of the individual polymorphs. The needle shaped polymorph was found to undergo transition to the cubic polymorph during compression.
Improvement of Intestinal Absorption of Thyrotropin-releasing Hormone by Chemical Modification with Lauric Acid
Authors: Yamada Keigo , Murakami Masahiro , Yamamoto Akira , Takada Kanji , Muranishi Shozo
Published: April 2011

Intestinal absorption of 125I-labelled lauryl thyrotropin-releasing hormone (Lau-TRH), a novel lipophilic derivative of TRH, was examined by rat in-situ closed intestinal loops. At a dose of 1 μmol per rat into the small intestine, a significant increase in percent of dose in plasma radioactivity of Lau-TRH was observed in comparison with that of TRH. A dose-dependent decrease in percent of dose in plasma radioactivity of TRH was noted, suggesting a saturable process of TRH transport. In contrast, the percent of dose in plasma radioactivity of Lau-TRH increased with increasing dose of Lau-TRH. The stability of TRH and Lau-TRH was studied in plasma and rat small intestinal homogenates. Lau-TRH was more stable than TRH in rat plasma. These results suggest that chemical modification of TRH with lauric acid may not only increase the lipophilicity of TRH but also reduce the degradation of TRH, resulting in the increased plasma radioactivity of TRH. On the other hand, Lau-TRH was gradually converted to TRH in the intestinal mucosal homogenate. These findings indicate that chemical modification of TRH with lauric acid might be a useful approach for improving the intestinal absorption of this peptide.
Relationship Between Paracetamol Plasma Levels and its Analgesic Effect in the Rat
Authors: Granados-Soto Vinicio , Flores-Murrieta Francisco J , López-Muñoz Francisco J , Salazar Luis A , Villarreal Julian E , Castañeda-Hernández Gilberto
Published: April 2011

The relationship between plasma levels of paracetamol and its analgesic effect was studied in the rat using a model of pain-induced functional impairment (PIFI). Female Wistar rats received an intraarticular injection of 30% uric acid in the knee of the right hind limb, inducing its dysfunction. Animals then received oral paracetamol at doses of 178, 316 or 562 mg kg−1and the recovery of functionality over time was considered as an expression of analgesia. Paracetamol plasma levels were determined by HPLC. Results showed that there is a direct relationship between paracetamol plasma levels and its analgesic effect that follows a sigmoidal model according to the Hill equation. The PIFI model appears to be a useful tool to establish pharmacokinetic/pharmacodynamic relationships for non-narcotic analgesics.
Single- and Multiple-dose Pharmacokinetics of Nefiracetam, a New Nootropic Agent, in Healthy Volunteers
Authors: Fujimaki Y , Sudo K , Hakusui H , Tachizawa H , Murasaki M
Published: April 2011

The pharmacokinetic profile of nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-l-pyrrolidinyl)acetamide), a new nootropic agent, was studied in healthy Japanese male volunteers. Nefiracetam was administered orally at doses of 10–200 mg in the single-dose studies, and at doses of 200 mg three times a day for seven days in the multiple-dose study. An HPLC method was used to determine the concentrations of nefiracetam in serum, urine and faecal samples. Linear kinetic behaviour was obtained after single oral administration. Serum concentrations of nefiracetam reached maximum values (Cmax) within 2 h for all dosage groups, and declined monophasically after Cmax with half-lives of 3–5 h. The area under the concentration-time curve (ALTC∞) and Cmax were linearly related to the dose. The apparent clearance (CL) values were 94·4–140·3 mL min−1. Urinary excretion of nefiracetam was independent of the administered dose, and less than 10% of the dose was recovered in urine as the unchanged form within 24 h after administration. Renal clearance (CLR) did not change significantly as dose increased from 10 to 1200 mg. Faecal excretion of nefiracetam was less than 0·1% of the dose up to 24 h after a 300 mg oral dose. Food intake delayed the absorption of nefiracetam but did not significantly modify its pharmacokinetics. No clinically significant accumulation of nefiracetam in the body was observed during and after multiple doses.
Dissolution and absorption of caffeine from guarana
Authors: Bempong Daniel K , Houghton Peter J
Published: April 2011

The rate of release of caffeine from capsules of guarana was compared with that from capsules containing an equivalent amount of caffeine using the British Pharmacopoeia dissolution test apparatus. Determinations were carried out in media of pH 2 and 6·8 and caffeine concentrations in the dissolution fluid were determined by HPLC. No significant differences in release rates were found between the two preparations at either pH. The rate of absorption of caffeine across rat intestine using the everted gut was also compared for a guarana suspension and a solution containing an equivalent amount of caffeine. Experiments were carried out using fluids of pH 4·0 and 7·4. No significant differences in absorption between the two preparations were observed. These results show that the release and uptake of caffeine from guarana is the same as for preparations containing free caffeine.
The influence of β-cyclodextrin on the solubility and dissolution rate of paracetamol solid dispersions
Authors: Tasić LJ M , Jovanović M D , Djurić Z R
Published: April 2011

The effect of cyclodextrin (β-CD) on the solubility and dissolution rate of various paracetamol dispersion powders (1:1 w/w), and tablets was studied. Lower solubility was exhibited by a spray dried solid dispersion made from paracetamol-Ethocel-Macrogol 6000 (95:2:3). The improvement in solubility was influenced by complexation with β-CD and the crystalline nature of the powder products made by different procedures. The difference in crystallinity was confirmed by X-ray powder diffraction patterns. The dissolution rate of paracetamol from tablets made from the solid dispersions was satisfactory compared with paracetamol alone. The differences between the dissolution rate from the examined paracetamol tablets resulted from the different solubility of each powder and from the structural changes of particles which influenced the consolidation of the tablet mass.
Salivary excretion of mexiletine after bolus intravenous administration in rats
Authors: Nagasako Sadao , Hayashibara Masakazu , Katagiri Yoshihiro , Iwamoto Kikuo
Published: April 2011

Salivary excretion of mexiletine was investigated following bolus intravenous administration (10 mg kg−1) in rats. Parotid and mandibular saliva was collected separately by stimulating salivation with constant rate infusion of pilocarpine (3 mg kg−1 h−1). The mexiletine levels in blood plasma and parotid and mandibular saliva declined biexponentially with time in almost parallel fashion. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva. Significant correlations were observed when all data relating mexiletine concentration in plasma and saliva were included (P < 0·001). The saliva/plasma drug concentration ratios (S/P ratios) did not vary to a large extent (0·56 ± 0·10 for parotid saliva, 0·21 ± 0·06 for mandibular saliva), but there was a consistent tendency for the higher plasma drug levels in the distribution phase to produce relatively high S/P ratios for both parotid and mandibular saliva. Moreover, the plasma mexiletine levels calculated by the equation of Matin et al (1974) employing the observed values for the saliva drug level, saliva pH and free fraction of mexiletine in plasma were significantly higher than the observed drug levels. Therefore, it is suggested that the salivary excretion of mexiletine could not be explained quantitatively by simple, passive secretion based on pH-partition theory.
Torasemide, but not frusemide, increases intracellular cAMP and cGMP content in the aorta of the renal hypertensive rat
Authors: Yamanaga Katsumi , Uchida Takeshi , Kido Hideaki , Hayashi Kazutaka , Watanabe Masahiro
Published: April 2011

Repeated oral administration of the novel loop diuretic torasemide (3 mg kg−1) and frusemide (30 mg kg−1) for 7 days, elicited a significant fall in the systolic blood pressure in the one-kidney, one-clip Goldblatt renal hypertensive rat (RHR). The hypotensive action was greater in the torasemide group than in the frusemide group. Furthermore torasemide increased intracellular cAMP and cGMP content in aorta of RHR. Frusemide caused no effect. It is hypothesized that the increase in adenosine- or guanosine-nucleotides is involved in the antihypertensive action of torasemide, but not in that of frusemide.
Locomotor effects of nitrous oxide in mice: requirement of newly-synthesized and main intraneuronal storage pools of dopamine
Authors: Dorris Roy L , Truong Vi
Published: April 2011

Nitrous oxide increases locomotor activity in mice. Other locomotor stimulants are thought to act via central dopaminergic mechanisms and can be divided into two groups as determined by their antagonism by tyrosine hydroxylase inhibitors or by reserpine pretreatment. The purpose of the present study was to determine if nitrous oxide fits one or the other of the groups. Mice were acclimatized for 1 h to exposure chambers (4 L filtration flasks), in air, delivered at 4 L min−1 and then exposed to N2O:O2 (50:50), also delivered at 4 L min−1. Locomotor activity was evaluated at 10 min intervals throughout the experiment. Racemic α-methyltyrosine methyl ester HCl (200 mg kg−1), administered at the beginning of acclimatization, almost totally eliminated the nitrous oxide effect but not that of methylphenidate HCl (20 mg kg−1). Reserpine pretreatment (5 mg kg−1 18 h) totally eliminated the nitrous oxide effect but not that of amphetamine (5 mg kg−1). The results suggest that nitrous oxide requires both the newly synthesized and the main storage pools of dopamine and do not allow assignment of the agent, specifically, to either of the groups.