bluuebunny/crossref_metadata_2025 huggingface dataset:
Algorithms for Skin Permeability Using Hydrogen Bond Descriptors: the Problem of Steroids
Authors: Abraham Michael H , Martins Filomena , Mitchell Robert C
Published: April 2011

Several algorithms that use hydrogen bond descriptors have been published for the permeation of compounds from aqueous solution through human stratum corneum. In the present work, all the skin permeability coefficients, Kp in cm s−, used in these algorithms for non-steroids have been correlated through the Abraham equation to give a new algorithm:

where n is the number of solutes, r is the correlation coefficient, s.d. is the standard deviation, and F is the F-statistic. The solute descriptors are: R2 an excess molar refraction, the dipolarity/polarizability, the overall or effective hydrogen-bond acidity and basicity, and VX the McGowan characteristic volume. Equation 1 is a reasonably good predictor of log Kp values for steroids as given by Johnson et al., but not for those given by Scheuplein.
In-vitro Permeability of the Human Nail and of a Keratin Membrane from Bovine Hooves: Prediction of the Penetration Rate of Antimycotics through the Nail Plate and their Efficacy
Authors: Mertin Dirk , Lippold Bernhard C
Published: April 2011

In contrast to the partition coefficient octanol/water the molecular size of penetrating drugs has a noticeable influence on the permeability of the human nail plate and a keratin membrane from bovine hooves. The relationship between permeability and molecular weight is founded on well-established theories. The correlation between the permeability of the nail plate and that of the hoof membrane allows a prediction of the nail permeability after determination of the drug penetration through the hoof membrane.

The maximum flux of ten antimycotics (amorolfine, bifonazole, ciclopirox, clotrimazole, econazole, griseofulvin, ketoconazole, naftifine, nystatin and tolnaftate) through the nail plate was predicted on the basis of their penetration rates through the hoof membrane and their water solubilities. An efficacy coefficient against onychomycoses was calculated from the maximum flux and the minimum inhibitory concentration.

Accordingly, amorolfine, ciclopirox, econazole and naftifine are expected to be especially effective against dermatophytes, whereas in the case of an infection with yeasts only, amorolfine and ciclopirox are promising.
Liver and Gastrointestinal First-pass Effects of Azosemide in Rats
Authors: Kim Jonghan , Kim So H , Lee Myung G
Published: April 2011

Since considerable first-pass effects of azosemide have been reported after oral administration of the drug to rats and man, first-pass effects of azosemide were evaluated after intravenous, intraportal and oral administration, and intraduodenal instillation of the drug, to rats.

The total body clearances of azosemide after intravenous (5 mg kg−) and intraportal (5 and 10 mg kg−) administration of the drug to rats were considerably smaller than the cardiac output of rats suggesting that the lung or heart first-pass effect (or both) of azosemide after oral administration of the drug to rats was negligible. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) after intraportal administration (5 mg kg−) of the drug was significantly lower than that after intravenous administration (5 mg kg−) of the drug (1000 vs 1270 μg min mL−) suggesting that the liver first-pass effect of azosemide was approximately 20% in rats. The AUC from time 0 to 8 h (AUC0–8 h) after oral administration (5 mg kg−) of the drug was considerably smaller than that after intraportal administration (5 mg kg−) of the drug (271 vs 1580 μg min mL−) suggesting that there are considerable gastrointestinal first-pass effects of azosemide after oral administration of azosemide to rats. Although the AUC0–8 h after oral administration (5 mg kg−) of azosemide was approximately 15% lower than that after intraduodenal instillation (5 mg kg−) of the drug (271 vs 320 μg min mL−), the difference was not significant, suggesting that the gastric first-pass effect of azosemide was not considerable in rats. Azosemide was stable in human gastric juices and pH solutions ranging from 2 to 13. Almost complete absorption of azosemide from whole gastrointestinal tract was observed after oral administration of the drug to rats.

The above data indicated that most of the orally administered azosemide disappeared (mainly due to metabolism) following intestinal first-pass in rats.
Pharmacological and Pharmacokinetic Characteristics of YM435, a Novel Dopamine DA1-Receptor Agonist, in Anaesthetized Dogs
Authors: Yatsu Takeyuki , Miyamoto Ikuo , Kaneko-Takanuki Fumiyo , Watanabe Takashi , Takenaka Toichi
Published: April 2011

Time-course of plasma concentration of unchanged drug of the dopamine DA1-receptor agonist (–)-(S)-4-(3,4-dihydroxyphenyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride hydrate (YM435), and its effects on blood pressure and renal blood flow were investigated in anaesthetized dogs.

Continuous intravenous infusion of YM435 (0.1–3 μg kg− min−) rapidly increased renal blood flow and lowered blood pressure in a dose-dependent manner. These effects remained generally stable throughout the infusion period. Following the start of infusion, plasma concentration of unchanged drug also rose rapidly and dose-dependently and remained virtually constant throughout the infusion period. A significant correlation was observed between log YM435 plasma concentration and the increase in renal blood flow (r = 0.93, P < 0.0001) and between the former and the reduction in blood pressure (r = 0.93, p < 0.0001).

The present results indicate that YM435 produces renal vasodilatation and lowering of blood pressure in a dose-dependent manner and with rapid onset following continuous intravenous infusion, and that these effects are generally stable throughout the period of infusion. These haemodynamic effects of YM435 were in good agreement with the time-course of plasma concentration of unchanged drug.
Influence of Age on Cardiovascular Effects of Increased Dietary Sodium and Angiotensin-converting Enzyme Inhibiton in Normotensive Wistar Rats
Authors: Teräväinen Terttu-Liisa , Mervaala Eero Ma , Laakso Juha , Paakkari Ilari , Vapaatalo Heikki , Karppanen Heikki
Published: April 2011

Recent studies have shown that increased intake of dietary sodium chloride produces blood pressure-independent increase in cardiac and renal mass even in young normotensive rats. With advancing age the harmful cardiovascular effects of increased dietary sodium are not so well known. In the present study the influence of advancing age on the cardiovascular effects of increased intake of sodium (control diet, 0.3% and high-sodium diet, 2.6% sodium in the chow) were examined in young and aged (3 and 18 months old, respectively, at the beginning of the experiment) male normotensive Wistar rats in a six-week study. Moreover, the potential role of renin-angiotensin system in ageing during normal and a high-sodium intake was studied using a pharmacological tool, angiotensin converting enzyme (ACE) inhibitor ramipril.

Ageing did not significantly modify basal systolic blood pressure measured by the tail cuff method. A high intake of sodium chloride increased blood pressure significantly only in aged rats, while in young rats it increased renal weight. Left ventricular weight was not affected by high-sodium diet in either age group. The ACE inhibition during control diet lowered blood pressure and decreased left ventricular weight in young rats only and these effects were completely blocked by a high-sodium diet. The maximal vascular contraction force of mesenteric arterial rings to noradrenaline was decreased with ageing while endothelium-dependent and -independent relaxation responses were unaltered with ageing. The sensitivity to sodium nitroprusside was impaired by the high-sodium diet in young rats. In both age groups the urinary excretion of calcium was increased during the high-sodium diet.

In conclusion, the increased intake of sodium produced different changes in cardiovascular function in normotensive rats depending on age. With advancing age, the sensitivity to sodium-induced increase in blood pressure was increased. In aged rats a high intake of dietary sodium elevated blood pressure, while in young rats it increased renal mass without increase in blood pressure. In both age groups sodium did not affect left ventricular hypertrophy. Both high-sodium intake and ageing attenuated or even abolished the cardiovascular effects of ACE inhibition.
Possible Involvement of Protein Kinase C in the Modulation of Inotropic and Chronotropic Effects Induced by Ouabain in Rat Right Atrial Muscles
Authors: Satoh Hiroyasu , Narushima Itaru , Nakashima Toshikatsu
Published: April 2011

Modulations of the inotropic and chronotropic effects of ouabain and protein kinase C (PKC) stimulation with phorbol esters in rat right atria were examined. Cumulative administration of ouabain (3–30 μm) caused a positive inotropic effect in a concentration-dependent manner, but did not produce a chronotropic effect. A single administration of ouabain (30 μm) also had similar effects: +744 ± 84% (n = 23, P < 0.01) in the contractile force and −0.7 ± 1.3% (n = 23, P > 0.05) in the sinus rate. Addition of phorbol esters reinforced the ouabain-evoked positive inotropic effect: 26.5 ± 8.9% (n = 6, P < 0.05) with 100 μm 4-β-phorbol-12,13-dibutyrate (PDB), and 6.4 ± 3.3% (n = 6, P > 0.05) with 100 μm 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Simultaneously, the mixture of ouabain and phorbol ester raised the resting tension. Phorbol esters alone caused a positive inotropic effect (by about 21–27%). Non-PKC activating phorbol ester, 4-α-phorbol-12,13-didecanoate (PDD, 100 μm), did not have any effect. Pretreatment with the PKC inhibitor (staurosporine 100 μm) significantly decreased the ouabain-induced positive inotropic effect and caused a negative chronotropic effect, but H-7 (1-(5-isoquinolinylsulphonyl)-2-methylpiperazine dihydrochloride) (5 μm) had no effect.

These results suggest that PKC stimulation may be involved in the ouabain-evoked responses in the right atria of rat as seen by increased cellular Ca2+ concentration (and Ca2+-sensitivity); thus the positive inotropic effect may not be due only to modulation of Na+/K+ pump activity.
Effects of Nonanal, trans-2-Nonenal and 4-Hydroxy-2,3-trans-nonenal on Cyclooxygenase and 12-Lipoxygenase Metabolism of Arachidonic Acid in Rabbit Platelets
Authors: Sakuma Satoru , Fujimoto Yohko , Tagano Shinya , Tsunomori Masahide , Nishida Hiroko , Fujita Tadashi
Published: April 2011

The effects of nonanal, trans-2-nonenal and 4-hydroxy-2,3-trans-nonenal on the formation of thromboxane B2 (TXB2), 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) from exogenous arachidonic acid in washed rabbit platelets were examined.

Nonanal and trans-2-nonenal at concentrations ranging from 0.25 to 2 μm inhibited TXB2, HHT and 12-HETE formation, reducing the amounts of these three arachidonic acid metabolites by 50% at nonanal and trans-2-nonenal concentrations of approximately 0.25 μm. The inhibition of TXB2, HHT and 12-HETE formation induced by 4-hydroxy-2,3-trans-nonenal (50% inhibition by 4-hydroxy-2,3-trans-nonenal at a concentration of approximately 100 μm) was 400 times weaker than that induced by nonanal and trans-2-nonenal.

These results suggest that nonanal and trans-2-nonenal can be modulators of platelet arachidonic acid metabolism by affecting the activity of cyclooxygenase and 12-lipoxygenase.
Epidural Metabolism of Articaine to its Metabolite Articainic Acid in Five Patients after Epidural Administration of 600 mg Articaine
Authors: Vree Tom B , van Oss Gertjan E C J M , Gielen Mathieu J M , Booij Leo H D J
Published: April 2011

The clinical pharmacokinetics, metabolism and renal excretion of articaine and its metabolite articainic acid have been investigated in man after epidural administration. (±)-Articaine and its metabolite (±)-articainic acid have different pharmacokinetic constants (P = 00079) except for lag-time (tlag; 0.06 min), first phase distribution of elimination (t½α; 0.49 ± 0.21 h), and elimination half life (t½α; 2.19 ± 0.98 h), which are all the same for both compounds. The total body clearance of articaine (103 ± 57 L h−1) is 10 times higher than that of the metabolite articainic acid (10.7 ± 1.80 L h−1, P = 0.0079). With similar half-life (t½β) values (2 h), the volumes of distribution (Vβ) are 10 times higher for the parent drug than for the metabolite ((329 ± 212 L compared with 38.4 ± 7.5 L, respectively; P = 0.0079). The difference between the areas under the curves for total plasma articainic acid and that formed in the plasma gives an indication of the percentage metabolism during epidural transfer (5.38 ± 1.51%). This percentage of metabolism corresponds to a mean epidural transfer time of 5 min. The main compound in the urine is articainic acid (64.2 ± 14.4%), followed by articainic acid glucuronide (13.4 ± 4.97%) and the parent drug (1.45 ± 0.77%). In total, 79.0 ± 18.5% of the dose is recovered in the urine. The renal clearance of articaine is 22.5 ± 13.9 mL min−1, whereas that of articainic acid is 119.6 ± 30.1 mL min−1 (P < 0.0001). The apparent renal clearance of articainic acid glucuronide was 25.4 ± 12.0 mL min−1. This value does not differ from that of the parent drug (P > 0.8). Articainic acid glucuronide is not present in plasma, but has an apparent renal clearance of 25 mL min−1.

These results suggest that articainic acid is glucuronidated by the tubular cells and then excreted.
Pharmacodynamic and Pharmacokinetic Studies in Rats of S-8-(2-Furyl)- and R-8-Phenyl-2-(di-n-Propylamino)Tetralin, Two Novel 5-HT1A Receptor Agonists In-vitro with Different Properties In-vivo
Authors: Yu Hong , Liu Ye , Li Hong B , Martin Arnold R , Hacksell Uli , Lewander Tommy
Published: April 2011

R- and S-8-(2-Furyl)- and R- and S-8-phenyl-2-(di-n-propylamino)tetralins (R- and S-LY-55 and R- and S-LY-49, respectively), novel enantiopure dipropylaminotetralins, have been screened as 5-HT1A receptor ligands.

All had nanomolar affinities for 5-HT1A receptors and fully inhibited forskolin-stimulated adenylyl cyclase in-vitro (i.e. the four compounds appeared to be 5-HT1A agonists). It was also found that the enantiomers of LY-55 behaved as typical 5-HT1A receptor agonists in rats in-vivo by inducing a typical behavioural 5-HT syndrome, hypothermia and a decrease in 5-HT synthesis and turnover, indicating effects both on postsynaptic 5-HT1A receptors and somatodendritic 5-HT1A autoreceptors. In contrast, R- and S-LY-49 did not cause any 5-HT1A receptor-related effects in-vivo except for a partial inhibition of 5-HT synthesis after high doses. The 5-HT1A receptor antagonist WAY-100635 was shown to attenuate the R-LY-49-induced inhibition of 5-HT synthesis, indicating the compound to be a weak agonist at somatodendritic 5-HT1A autoreceptors. R-LY-49 at a high dose and with a long pre-treatment time interval inhibited the hypothermic and behavioural effects, but not the inhibition of 5-HT synthesis induced by the 5-HT1A receptor agonist R-8-hydroxy-(dipropylamino)tetralin (R-8-OH-DPAT). Taken together, these findings seem to indicate, that R-LY-49 is a weak partial agonist at 5-HT1A receptors. A comparative pharmacokinetic study showed that the enantiomers of LY-55 entered the brain rapidly after subcutaneous administration and reached peak brain tissue/plasma concentration ratios within 15–30 min of injection, whereas the brain concentrations of R-LY-49 increased slowly, reaching a relatively low peak brain tissue/plasma concentration ratio 90 min after injection despite their similar lipophilicity.

The differences between the pharmacological activity of the two compounds in-vivo seem to be explained by their different abilities to cross the blood-brain barrier, and a weak agonistic activity of R-LY-49 on 5-HT1A receptors, both pre- and postsynaptically, compared with S-LY-55. Further studies are, however, needed for a deeper understanding of these differences.
Comparative Pharmacokinetics and Interspecies Scaling of Amphotericin B in Several Mammalian Species
Authors: Hutchaleelaha Athiwat , Chow Hsiao-Hui , Mayersohn Michael
Published: April 2011

This study employed several interspecies scaling methods, to evaluate the applicability of extrapolating to man, pharmacokinetic information obtained from animals for amphotericin B, an anti-fungal drug.

Pharmacokinetic parameters from four animal species (mouse, rat, monkey and dog) and man were obtained from the literature or from analysis of data reported in the literature. The allometric relationships (obtained from four animal species) as a function of species body weight (W; kg) for systemic clearance per maximum life span potential (CLS/MLP), steady-state volume of distribution (VSS), apparent volume of distribution (Vβ) and volume of the central compartment (VC) were: 5691W1.096; 2.46W0.839; 3.08W0.948 and 1.07W0.965, respectively. The allometric relationships for half-life (h) and mean residence time (h) did not scale well with body weight. The prediction of pharmacokinetic parameters in man from the allometric equations do not always agree with those reported in the literature which are based upon a limited number of studies with few human subjects. The plasma concentration-time profiles from these animals were adjusted by normalizing the concentration with dose/W0.948, and re-plotted on different pharmacokinetic time scales.

The syndesichrons plot produced an almost superimposable profile of adjusted concentrations as a function of adjusted time among the four species.
Ambroxol Improves the Broncho-spasmolytic Activity of Clenbuterol in the Guinea-Pig
Authors: Pairet Michel , Engelmann Peter , von Nicolai Hubertus , Champeroux Pascal , Richard Serge , Rauber Gerhard , Engelhardt Günther
Published: April 2011

The effects of ambroxol on the spasmolytic action of clenbuterol were investigated on acetylcholine-induced bronchospasm in guinea-pigs.

Ambroxol (50 mg kg−1 day−1) or vehicle was administered orally for 14 days. Approximately 45 min after the final dose on day 14, the animals were anaesthetized and the spasmolytic effects of clenbuterol (3, 6 or 12 μg kg−1 injected intravenously) were determined by use of acetylcholine (40 μg kg−1, i.v.)-induced bronchoconstriction. For both vehicle- and ambroxol-treated animals, a positive linear relationship was observed between the log-dose of clenbuterol and the percent inhibition of bronchospasm. The calculated ED25 of clenbuterol (i.e. the dose producing 25% inhibition of the acetylcholine-induced bronchospasm) was 3.98 μg kg−1 (3.29 to 4.82 μg kg−1, 95% confidence interval) in the presence of ambroxol and 5.81 μg kg−1 (4.98 to 6.79 μg kg−1) in the absence of ambroxol. The linear regressions with or without ambroxol differed from each other (P < 0001) but ran parallel (covariance analysis), enabling us to calculate a relative potency, the value of which was 1.46 (1.16 to 1.84).

These results demonstrate that the spasmolytic activity of clenbuterol is significantly improved in animals pretreated with ambroxol.
Anti-ulcer Activity of Cromakalim (BRL 34915), a Potassium-channel Opener, Against Experimentally Induced Gastric and Duodenal Ulcers in Rats and Guinea-pigs
Authors: Goswami Sailendra , Jain Sunita , Santani Devdas
Published: April 2011

The effect of cromakalim, a potassium-channel opener, was studied on pylorus ligation-induced, aspirin-induced and water-immersion plus restraint stress-induced gastric ulcers in rats and on histamine-induced duodenal ulcer in guinea-pigs.

Pretreatment with cromakalim (50–500 μg kg−1, p.o.) resulted in a significant reduction in the incidence of gastric and duodenal ulceration in each model. The anti-ulcer activity of cromakalim was comparable with that of cimetidine. Cromakalim at 100, 250 and 500 μg kg−1 caused a reduction in the volume of the gastric content in pylorus-ligated rats, and a dose of 250 μg kg−1 resulted in a significant reduction in total acidity (28.81 ± 11.73 mEq L−1, P < 0.02) in the pylorus ligation model. A significant reduction in total acid output was observed at doses of 250 μg kg−1 (84.27 ± 22.33 mEqH+, P < 0.02) and 500 μg kg−1 (120.17 ± 24.49 mEq H+, P < 001) in pylorus-ligated rats. A significant reduction in the ulcer index in pylorus-ligated rats was observed at all cromakalim doses: 50 μg kg−1 (0.23 ± 009, P < 0.05), 100 μg kg−1 (0.15 ± 0009, P < 0.02), 250 μg kg−1 (0.12 ± 0.05, P < 0.01) and 500 μg kg−1 (0.14 ± 0.03, P < 0.02). A significant reduction in the ulcer index of aspirin-treated rats was also observed at all cromakalim dose levels: 50 μg kg−1 (0.39 ± 0.03. P < 0.01), 100 μg kg−1 (0.28 ± 0.06, P < 0.01), 250 μg kg−1 (0.22 ± 0.04, P < 0.001) and 500 μg kg−1 (0.28 ± 0.03, P < 0.01). In the water-immersion plus restraint stress-induced gastric ulcer model, cromakalim significantly reduced gastric ulceration at all the dose levels: 50 μg kg−1 (28.2 ± 2.12, P < 0.001), 100 μg kg−1 (20.24 ± 1.71, P < 0.01), 250 μg kg−1 (19.95 ± 1.46, P < 0.001) and 500 μg kg−1 (21.61 ± 3.00, P < 0.001) but there was no consistent reduction of gastric bleeding. In addition to gastric ulcers, duodenal lesions were also reduced by pretreatment with cromakalim at all dose levels: 50 μg kg−1 (97.87 ± 20.03 mm2, P < 0.02). 100 μg kg−1 (70.72 ± 12.82 mm2, P < 0.02), 250 μg kg−1 (48.32 ± 8.42 mm2, P < 0.01) and 500 μg kg−1 (55.50 ± 12.50 mm2, P < 0.01). Cromakalim at a dose of 100 μg kg−1 also reduced total acidity (99.36 ± 9.12 mEq L−1, P < 0.02) and total acid output (172.22 ± 45.33 mEq of H+, P < 0.05) in this model.

These findings demonstrate the anti-ulcer activity of cromakalim in different experimental models and suggest its potential use in ulcer therapy.
Effects of Selective β-Adrenoceptor Antagonists on Gastric Ulceration in the Rat
Authors: Kaan Sheung Kei , Cho Chi Hin
Published: April 2011

Metoprolol and butoxamine, β-adrenoceptor antagonists which act selectively at the β1 and β2-adrenoceptors, respectively, have been investigated for their actions on the ethanol, indomethacin and cold-restraint stress ulcer models.

Oral administration of butoxamine but not metoprolol significantly attenuated gastric mucosal damage in the three types of ulcer model. Intraperitoneal injection of butoxamine reduced indomethacin ulceration but not that of the other two models. The stimulatory effect of butoxamine on the gastric mucosal potential difference and intramucosal mucus level correlated positively with its anti-ulcer action. Only oral administration of butoxamine significantly increased the mucosal prostaglandin E2 (PGE2) level but not after intraperitoneal injection. Oral administration of butoxamine also significantly increased the mucosal PGE2 level in the three types of ulcer model but this drug was only effective in the indomethacin ulcer model after intraperitoneal injection. Gastric acid and pepsin output were not affected by either drug. Metoprolol significantly reduced systemic blood pressure; this could be attributed to a reduction in gastric mucosal blood flow.

These results imply that β2-adrenoceptors play a significant role in the pathogenesis of gastric ulceration. We suggest that the anti-ulcer effect of butoxamine was in part a result of strengthening of the mucosal barrier but that this was not effected by modification of acid or pepsin secretions in the stomach. Stimulation of PGE2 in the gastric mucosa could contribute in part to the anti-ulcer action of the drug, especially when given by the oral route.
Antagonistic Effects of OPC-14597, a Novel Antipsychotic Drug, on Quinpirole- and (–)-Sulpiride-induced Changes in Evoked Dopamine Release in Rat Striatal Slices
Authors: Yamada Shigeto , Harano Mutsuo , Yokoo Hideyasu , Tanaka Masatoshi
Published: April 2011

The effects of a newly synthesized quinolinone derivative, 7-{4-(4-(2,3-dichlorophenyl)-1-piperazinyl) butoxy}-3,4-dihydro-2-(1H)-quinolinone (OPC-14597), a novel antipsychotic drug, on electrically evoked dopamine release in rat striatal slices were investigated.

OPC-14597 (0.1–10 μm) had no effect on the dopamine release evoked in the striatal slices. The decrease induced by quinpirole, a dopamine receptor agonist, in evoked dopamine release was attenuated by supervision with OPC-14597 (1 and 10 μm) which by itself had no effect on evoked dopamine release. The increase induced by (–)-sulpiride, a dopamine receptor antagonist, in evoked dopamine release was, moreover, also attenuated by 1 and 10 μm OPC-14597.

These findings indicate that OPC-14597 antagonizes both dopamine agonist- and antagonist-induced changes in evoked dopamine release in striatal slices in rats.
Antiperoxidative Activity of Neolignans from Magnolia obovata
Authors: Haraguchi Hiroyuki , Ishikawa Harumi , Shirataki Noritoshi , Fukuda Ayumi
Published: April 2011

Honokiol and magnolol, neolignans in Magnolia obovata, have been evaluated as antioxidants.

Microsomal lipid peroxidation induced by Fe(III)-ADP/NADPH and mitochondrial lipid peroxidation induced by Fe(III)-ADP/NADH were inhibited by these compounds. These neolignans protected mitochondrial respiratory chain enzyme activity against NADPH-induced peroxidative stress and protected red cells against oxidative haemolysis. The anti-oxidative activity of honokiol was more potent than that of magnolol.

Neolignans in M. obovata were shown to be effective in protecting biological systems and functions against oxidative stress.
Enhanced Anti-tumour Effects of Acriflavine in Combination with Guanosine in Mice
Authors: Kim Sang Geon , Kim Choon Won , Ahn E-Tay , Lee Kyung-Yung , Hong Eun-Kyung , Yoo Bo-Im , Han Yung-Bok
Published: April 2011

The anti-tumour activity of acriflavine in combination with guanosine has been evaluated in solid or ascitic tumour-implanted animal models. Guanosine is known to potentiate the anti-tumour effects of some chemotherapeutic agents.

Administration of acriflavine (15 mg kg−1 day−1, i.m., 14 days) to ICR mice subcutaneously implanted with Ehrlich carcinoma resulted in ∼30% inhibition in tumour growth. In contrast, minor tumour growth inhibition was observed in animals treated with guanosine at the same daily dose. Treatment of animals with both acriflavine and guanosine (AG60, 1:1, w/w) at 30 mg kg−1 resulted in ∼65% inhibition in tumour growth rate. Whereas treatment with acriflavine or guanosine resulted in 70% or 30% decrease in tumour weight, respectively, treatment of tumour-implanted mice with AG60 (30 mg kg−1) resulted in a 96% decrease in tumour weight, relative to control, 14 days after tumour-cell implantation. Dose-related inhibition in tumour growth rate was also observed in animals treated with AG60, with maximum (65%) inhibition noted at a dose of 30 mg kg−1 (ED50 23 mg kg−1). Suppression of body weight increase and elevated plasma glucose levels by acriflavine or AG60 indicated that glucose utilization might be impaired. The anti-tumour effect of AG60 was also determined in CDF1 mice intraperitoneally implanted with Ehrlich ascitic tumour. Ehrlich ascitic tumour proliferation was completely suppressed by AG60 (30 mg kg−1, i.p.). Microscopic analyses of intraperitoneal touch-prints revealed that AG60 was more effective in suppressing tumour proliferation than acriflavine alone. Fluorescent microscopic examinations demonstrated that acriflavine avidly bound with Yac-1 cell plasma membrane, leading to morphological changes in the cells, such as bleb formations, swelling and ballooning. The time-related changes in tumour cell morphology by acriflavine or AG60 might represent energy depletion, followed by osmotic lysis as a result of cationic influx. Enhanced anti-tumour activity of acriflavine in combination with guanosine might be explained by the blocking of nutrient transport through selective acriflavine binding with plasma membrane and by concomitant guanosine perturbation of cellular ATP production.

This study demonstrates that guanosine enhances the anti-tumour effects of acriflavine against a variety of cancer cells without serious adverse effects, providing a preclinical basis for potential application of this combination against cancer proliferation.
In-vitro Interaction of Artemisinin with Intact Human Erythrocytes, Erythrocyte Ghosts, Haemoglobin and Carbonic Anhydrase
Authors: Bakhshi Hamid B , Gordi Toufigh , Ashton Michael
Published: April 2011

The kinetics of the interaction of the antimalarial compound artemisinin with human erythrocytes, erythrocyte ghosts, haemoglobin and carbonic anhydrase were evaluated in-vitro. Artemisinin plasma concentrations, measured by HPLC (high pressure liquid chromatography), decreased with time during incubations with whole blood and erythrocyte suspensions of varying haematocrit. Artemisinin concentrations declined more rapidly during incubations under oxygen-poor as compared to oxygen-rich conditions. Artemisinin concentrations did not decrease during incubation with erythrocyte ghosts suspended in plasma suggesting that the drug does not bind avidly to red blood cell membranes. There was no decline in concentrations of artemisinin in the presence of carbonic anhydrase. The disappearance of the drug in solutions containing haemoglobin was very rapid and was even more so when the incubation was performed under an argon- instead of oxygen-rich atmosphere. The results suggest that drug blood clearance may be considered for inclusion in a pharmacokinetic model, but does not invalidate in-vivo plasma concentration-time data and their relevance for clinical effects. Furthermore, caution is advised when relating measurements of in-vitro potency to drug levels in patients. Finally, the enhanced artemisinin disappearance when oxygen tension is low may contribute towards the explanation of the selective toxicity of the endoperoxide drugs to Plasmodium falciparum parasite.
Release Characteristics of Implantable Cylindrical Polyethylene Matrices
Authors: Ertan G , Karasulu E , Demirtaş D , Arici M , Güneri T
Published: April 2011

The geometrical relationship between a hemisphere and a cylinder has been investigated for controlled-release systems.

The relationship was tested by comparing dissolution results with results from mathematical calculation based on the principles of diffusion for matrix systems. A procedure has been developed for producing implantable, cylindrical, low-density polyethylene matrices, uncoated or coated with a thin impermeable film and a thick paraffin layer except for a hole on the flat faces of the cylinder. Drug matrices were prepared from a blend of sodium salicylate and polymer compressed in an appropriately designed stainless-steel mould at 150°C. Differential scanning calorimetry revealed that no decomposition product was formed in the matrix. When the surface area and the number of holes is increased, drug release also increases. When density is increased, however, drug release decreases significantly. Zero-order drug release was obtained from high-density covered one-hole and two-hole matrices. The diffusion coefficient was calculated as 0.067 day−1.

The study suggested that true zero-order drug release could be obtained by drug diffusion from a hole, rather than from geometric shapes in the matrix systems. In addition, for constant release the diffusion area has to increase by approximately 25 mm2 every day, compared to the area of the previous day, because the diffusion distance increases logarithmically.
Influence of Moderate Haemodilution with Fluosol or Normal Saline on Carbaryl Disposition in Sprague-Dawley Rats
Authors: Shrewsbury R P , Johnson L W , Oliver S R
Published: April 2011

In rats carbaryl undergoes extensive biotransformation involving both albumin-mediated hydrolysis and cytochrome P-450-mediated metabolism; studies have suggested that approximately one-half of a carbaryl dose is hydrolysed and one-half is metabolized. Fluosol is known to be an inducer of cytochrome P-450, and Fluosol haemodilution reduces plasma albumin concentrations.

The disposition of carbaryl was, therefore, determined in rats for 72 h after 40 mL kg−1 haemodilution with Fluosol or normal saline (0.9% NaCl). Volumes of distribution were significantly reduced after saline haemodilution for 72 h but only at 48 h after Fluosol haemodilution. Fluosol and saline haemodilution had little influence on carbaryl total body clearance (CL).

These results indicate that both hepatic and non-hepatic clearance pathways were not influenced by the haemodiluents or the haemodilution procedure.
Synthesis of 3-Amino-2-(3-indolyl)propanol and Propanoate Derivatives and Preliminary Cardiovascular Evaluation in Rats
Authors: Pérez-Alvarez Victor , Morales-Ríos Martha S , Hong Enrique , Joseph-Nathan Pedro
Published: April 2011

A series of tryptamine analogues has been prepared and tested for their 5-HT1 receptor agonist properties.

The incorporation of an alkoxy group at the C-5 position of the indole nucleus resulted in a short-lived and dose-dependent immediate antihypertensive and bradycardic response in anaesthetized spontaneously hypertensive rats (SHR). In addition, a carbomethoxy function at the β-position of the side-chain of the tryptamines significantly increased the mean resting arterial blood pressure (MAP) in pithed rats and also produced contraction of the canine basilar artery in a dose-dependent fashion.

Structure-activity relationships (SAR) suggest that the 5-alkoxy group is an important pharmacophore in the production of the antihypertensive effect and that the introduction of a hydroxymethylene group on the side-chain, instead of the carbomethoxy group, changed the receptor affinity profile.
Fluorimetric Determination of Tissue Distribution and Differences Between the Activity of Aspirin Esterases I and II in Mice and Rats
Authors: Benedito Marco A C
Published: April 2011

A modification of available fluorimetric methods, based on the native fluorescence of salicylic acid, has been used to assay the activity of aspirin esterases I and II in small amounts of several tissues from rats and mice.

The results obtained showed that aspirin esterase I from mouse liver and kidney had the lowest activity and that the activity of aspirin esterase II from these organs was greater than that from the same organs from rats. Liver enzyme kinetics and tissue distribution in rats was shown to be similar to previous data obtained using a spectrophotometric method.

This fluorimetric method, which is more sensitive and rapid than the spectrophotometric method, may be useful in studies on aspirin metabolism.
Pharmacokinetics and Kinetic-Dynamic Modelling of Aminophenones as Methaemoglobin Formers
Authors: Marino Mark T , Urquhart Michael R , Sperry Michelle L , von Bredow Jurgen , Brown Larry D , Lin Emil , Brewer Thomas G
Published: April 2011

Methaemoglobin, the oxidized form of haemoglobin, can be formed by a variety of agents, most of which act to oxidize haemoglobin directly or indirectly. Cyanide has a higher affinity for methaemoglobin than for mitochondrial cytochromes, making methaemoglobin formation a basis for the treatment of cyanide poisoning. We used the beagle dog model to investigate the relationship between drug concentration and methaemoglobin levels for two candidate anti-cyanide compounds. The compounds studied were the aminophenones p-aminopropiophenone (PAPP) and p-aminoheptylphenone (PAHP). Both PAPP and PAHP were given as intravenous boluses and as two different oral formulations.

The kinetics of both compounds appeared to follow a three-compartment open model for intravenous bolus administration and a two-compartment open model for oral administration. The first distribution phase seen with the intravenous administration was obscured by the absorption phase during oral administration. Bioavailability for all formulations varied between 20 and 47%. For both compounds there was a delay between the appearance of drug in the plasma and the appearance of methaemoglobin (counter-clockwise hysteresis) which is suggestive of an active metabolite causing methaemoglobin formation. The pharmacodynamics were fit with an effect-compartment kinetic-dynamic model linked to a sigmoid Emax pharmacodynamic model. Maximum amounts of methaemoglobin occurred between 2 and 4 h for PAHP and between 1 and 3 h for PAPP. When administered intravenously estimates of EC50 were lower than the estimates of EC50 from oral administration for both compounds. This might be because of oral first-pass inactivation or a ‘first-pass’ activation through the lungs contributing to the formation of an active metabolite. The phenones as a class appear to have the drug cleared and methaemoglobin return to near baseline within 12 h.

Both compounds seem to produce sufficient methaemoglobin to treat acute cyanide poisoning and to serve as prophylactic agents against acute cyanide poisoning in a military setting.
Saturable Urinary Excretion Kinetics of Famotidine in the Dog
Authors: Boom Sandra P A , Hoet Sandra , Russel Frans G M
Published: April 2011

An important elimination route of the histamine H2 antagonist famotidine is active tubular secretion via the renal organic cation transport system. To characterize the excretion kinetics of famotidine in-vivo, the relationship between plasma concentration and urinary excretion rate was investigated in the beagle dog over a wide concentration range. The maximum transport capacity and the apparent Michaelis–Menten constant of tubular secretion were estimated.

Concentration-dependent renal clearance was determined either after intravenous infusion of high doses of famotidine for a short time or during continuous infusion. From individual experiments only indications of saturation were observed; these could not be quantified. A tubular titration curve, in which the active tubular famotidine secretion was plotted against the plasma concentration, was constructed from the data from all the experiments. Active tubular secretion was calculated for each experiment separately by subtracting the famotidine filtration rate from the total excretion rate. A tubular transport maximum of 2400 ± 220 μg min−1 and an apparent Michaelis–Menten constant for tubular secretion of 26 ± 4 μg mL−1 (76 ± 12 μm) were estimated from the curve.

To the best of our knowledge, this is the first time that saturation of famotidine renal clearance has been fully quantified in-vivo. Considering the low therapeutic plasma concentrations of famotidine (< 0.1 μg mL−1), these results suggest that clinically the drug has a low interactive potential.
Kinetics of Bupivacaine After Levcromakalim Treatment in Mice
Authors: Gantenbein M , Attolini L , Bruguerolle B
Published: April 2011

Previous workers have reported that 0.01 mg kg−1 of levcromakalim injected intraperitoneally did not modify bupivacaine-induced neurotoxicity but increased the duration of action of bupivacaine. This study was designed to document possible changes in the pharmacokinetic behaviour of bupivacaine and its main metabolite, N-desbutylbupivacaine in mice after a single 0.01 mg kg−1 intraperitoneal injection of levcromakalim.

The kinetic parameters of bupivacaine were determined after a single 20 mg kg−1 intraperitoneal injection of bupivacaine in controls and in levcromakalim-treated mice. It was found that levcromakalim did not change any kinetic parameters of bupivacaine or of its main metabolite, N-desbutylbupivacaine. The previously reported findings of the influence of the low dose (0.01 mg kg−1) of levcromakalim on bupivacaine-induced toxicity agree well with the lack of influence of 0.01 mg kg−1 of levcromakalim on bupivacaine and N-desbutylbupivacaine pharmacokinetics, although the reported increase in the duration of action of bupivacaine after levcromakalim treatment can hardly be explained by the pharmacokinetics of bupivacaine when associated with levcromakalim.

We suggest that levcromakalim might interfere directly with ion-channel block caused by bupivacaine by altering conduction properties or indirectly by enhancing bupivacaine-induced voltage and time-dependent sodium-channel block.
Estimation of the Chemosensitizing Activity of Modulators of Multi-drug Resistance via Combined Simultaneous Analysis of Sigmoidal Dose-Response Curves
Authors: Ecker Gerhard , Schaper Klaus-Jürgen , Chiba Peter
Published: April 2011

The potency of modulators which re-establish sensitivity of resistant tumour cells to cytotoxic drugs is not usually described by ED50 values, even though such values are needed for comparison of modulator activity.

Various methods are reported for the determination of ED50 values of propafenone-type modulators of multi-drug resistance in cytotoxicity assays. Best results were obtained by using a combined simultaneous analysis of dose-response curve families. This approach enables calculation of statistically highly significant ED50 values without any data reduction directly from the original data points obtained in daunomycin cytotoxicity assays.

The method also enables extrapolation of the ED50 values of compounds with low activity or poor solubility, or both.
Antidiabetic Efficacy of BRL 49653, a Potent Orally Active Insulin Sensitizing Agent, Assessed in the C57BL/KsJ db/db Diabetic Mouse by Non-invasive 1H NMR Studies of Urine
Authors: Connor S C , Hughes M G , Moore G , Lister C A , Smith S A
Published: April 2011

High resolution 1H nuclear magnetic resonance (NMR) spectroscopic analysis of biofluids is a recently established tool for evaluating inherited and acquired errors in metabolic control. In the present study 1H NMR analysis of urine was used to monitor efficacy of BRL 49653, a potent and selective antihyperglycaemic agent, following oral administration for up to 36 weeks to the genetically diabetic C57BL/KsJ db/db mouse. The effects of BRL 49653 on carbohydrate and fatty acid metabolism were monitored by determination of changes in concentrations of low molecular weight urinary metabolites.

A qualitative comparison of the NMR spectra of urine from untreated diabetic mice with those of lean littermates and literature examples revealed several abnormalities, the majority of which could be explained in terms of the non-insulin dependent diabetes syndrome exhibited by these animals. Quantitatively the most prominent was the extreme glycosuria of both young (8–12 weeks; 0.9 g glucose kg−1 h−1) and older (42 weeks; 2 g glucose kg−1 h−1) diabetic mice. This was accompanied by the excretion of a number of unassigned sugar derivatives and by ketone bodies. Administration of BRL 49653 (3 μmol kg−1) to db/db mice for 24 days reduced blood glucose concentrations to values comparable with non-diabetic lean littermates and reduced glycosuria by > 90%. BRL 49653 significantly reduced excretion of unassigned sugars, acetate, lactate, and the ketone bodies, acetoacetate, 3-d-hydroxybutyrate and acetone.

The anti-diabetic efficacy of BRL 49653, assessed from the pattern of urinary metabolites, was maintained over a 36-week treatment period. These results demonstrate the value of 1H NMR to evaluate non-invasively the efficacy of novel therapeutic agents.
Physical Stability of Solid Dispersions Containing Triamterene or Temazepam in Polyethylene Glycols
Authors: Dordunoo Stephen K , Ford James L , Rubinstein Michael H
Published: April 2011

The effect of storage on the physical stability of solid dispersions of triamterene or temazepam in polyethylene glycols was studied using differential scanning calorimetry (DSC), particle-size analysis and dissolution methods.

The enthalpies of fusion of the carriers, without included drug and previously fused and crystallized, increased on storage. Analysis of similarly treated solid dispersions, containing either 10% temazepam or 10% triamterene, showed that each drug influenced the morphology of the polyethylene glycol (PEG). The enthalpies and melting points of the solidus components of the dispersions' carriers were initially reduced after preparation, but on storage these increased. The particle sizes of the drugs dispersed in the PEGs increased on storage. The changes in dissolution after storage of triamterene or temazepam dispersions were smaller for dispersions in PEG 1500 than for dispersions in PEGs of higher molecular weight (PEG 2000, PEG 4000 or PEG 6000) in which the reduction in dissolution was particularly marked during the first month of storage. The rank order of changes in dissolution were PEG 1500 ≪ PEG 2000 < PEG 4000 ∼ PEG 6000.
The Mechanism of Excretion of Trientine from the Rat Kidney: Trientine is not Recognized by the H+/Organic Cation Transporter
Authors: Kobayashi Michiya , Tanabe Ryou , Sugawara Mitsuru , Iseki Ken , Miyazaki Katsumi
Published: April 2011

Trientine dihydrochloride is used to treat Wilson's disease by chelating copper and increasing its urinary excretion. The mechanism of renal excretion of trientine has been investigated in-vivo and in-vitro.

Trientine clearance in the rat was significantly faster than creatinine clearance. When trientine and the same number of moles of copper ions were administered simultaneously to the rat, however, trientine clearance decreased to almost the same level as the creatinine clearance. To clarify this active excretion system for trientine, the uptake of trientine and a physiological polyamine compound, spermine, was investigated using rat renal brush-border membrane vesicles. Although, because trientine and spermine are organic cations, the H+/organic cation transporter is expected to recognize these compounds, neither an outwardly directed H+ gradient nor an inward Na+ gradient stimulated trientine uptake. [14C]Spermine uptake was, nevertheless, trans-stimulated by both unlabelled spermine and trientine and the trans-stimulating effect of spermine on trientine uptake was, furthermore, completely abolished by addition of copper ions to the incubation medium.

These results suggest that there is a specific transport system for spermine and trientine on the renal brush-border membrane. This transport system contributes to the secretion of trientine in the kidney proximal tubule but does not recognize the trientine-copper complex.
Polyhydroxylated C60, Fullerenol, a Novel Free-radical Trapper, Prevented Hydrogen Peroxide- and Cumene Hydroperoxide-elicited Changes in Rat Hippocampus In-vitro
Authors: Tsai M-C , Chen Y H , Chiang L Y
Published: April 2011

The role of polyhydroxylated C60 (fullerenol), a novel free-radical trapper, in prevention of hydrogen peroxide- and cumene hydroperoxide-elicited damage was studied in hippocampal slices from the rat in-vitro. The interactions of polyhydroxylated C60, adenosine and 6,7-dinitroquinoxaline-2,3-dione (DNQX) were also compared.

Hydrogen peroxide (0.006–0.02%) and cumene hydroperoxide (0.5–1.0 mm) both reversibly reduced the amplitudes of CA1-evoked population spikes in the hippocampal slices. Deferoxamine (1 mm) had little effect on the population spikes. Deferoxamine (1 mm) significantly prevented the hydrogen peroxide (0006%)-elicited inhibition of the population spikes. Polyhydroxylated C60 (01 mm) significantly prevented hydrogen peroxide- or cumene hydroperoxide-elicited reduction of the population spikes and also prevented the effects of hydrogen peroxide and cumene hydroperoxide on paired-pulse facilitation in the hippocampal slice. Adenosine reduced the amplitude of population spikes and promoted paired-pulse facilitation in the CA1 region of the hippocampus. Polyhydroxylated C60 did not alter either of the effects of adenosine on the population spikes. DNQX reduced the amplitude of the population spikes in the CA1 region but did not affect the ratio of paired-pulse facilitation. Fullerenol did not alter either effect of DNQX on the population spikes.

These results suggested that polyhydroxylated C60 prevented hydrogen peroxide- and cumene hydroperoxide-elicited damage in the hippocampus slices. These effects might be associated with the free-radical scavenging activity of polyhydroxylated C60.