bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Doxazosin on Functional Alterations of Isolated Coronary Arteries from Cholesterol-fed Rabbits
Authors: Simonsen Ulf , Prieto Dolores , Nyborg Niels C B , Mulvany Michael J
Published: April 2011

Anti-hypertensive treatment is much less successful at reducing coronary artery disease than at reducing mortality from stroke and congestive heart failure. The effects of the α-adrenergic antagonist doxazosin on progression of atheromatous lesions and functional responses of isolated coronary arteries from cholesterol-fed rabbits have been investigated.

Normotensive rabbits were fed either a standard chow (control, n = 8) or a 1% cholesterol-rich diet (n = 16) for 20 weeks. After 3 weeks the cholesterol-fed animals were assigned randomly to two groups either given placebo capsules (n = 8) or treated with doxazosin (5 mg kg−1 day−1; n = 8). Doxazosin reduced the mean arterial blood pressure by 10% that of the control and placebo-treated cholesterol-fed rabbits, but did not affect the plasma cholesterol, triacylglycerol and phospholipid levels, which were, after 20 weeks, severalfold increased in the cholesterol-fed rabbits compared with controls. Histological examination showed atheromatous lesions in proximal (but not distal) coronary arteries from both groups of cholesterol-fed rabbits. Doxazosin either had no effect on reduced contractions to 125 mmol L−1 potassium saline solution or increased contractions to 5-hydroxytryptamine in proximal isolated coronary arteries from the cholesterol-fed rabbits. It did, however, abolish the hyper-responsiveness of the large atheromatous coronary arteries to noradrenaline. In both vehicle-and doxazosin-treated cholesterol-fed rabbits the maximum relaxation and sensitivity to acetylcholine were significantly reduced in proximal segments compared with the control group, whereas responses to acetylcholine in distal coronary segments were not significantly different. The relaxation to sodium nitroprusside, adenosine diphosphate and isoprenaline in proximal and distal coronary arteries were similar in the three experimental groups.

These results indicate that treatment of normotensive cholesterol-fed rabbits with doxazosin prevents the hyper-responsiveness to noradrenaline of proximal coronary arteries, although it does not prevent the progression of other functional alterations observed in the coronary circulation.
Effects of Antibiotics on Epithelial Ion Transport in the Rabbit Distal Colon In-vitro
Authors: Goldhill J M , Rose K , Percy W H
Published: April 2011

One side-effect of the therapeutic use of antimicrobial agents is respiratory paralysis as a result of inhibition of skeletal neuromuscular transmission; cholinergic neuro-effector motor transmission in the gastrointestinal tract is inhibited by the same classes of antimicrobial agent. Study of the effects of several classes of antibiotic compound on intestinal motility has suggested that antibiotic-induced alterations of intestinal motility may be related to the onset of diarrhoea or the development of antibiotic-associated colitis. These compounds may, however, also initiate or exacerbate diarrhoea by altering control of epithelial function, a possibility that has not previously been rigorously investigated. This series of experiments investigated the effect of six antibiotics on rabbit distal colonic epithelial ion transport.

Of all the antibiotics studied, only ampicillin was without effect. Clindamycin, erythromycin, gentamicin and lincomycin, each reduced the response of the epithelium to electrical field stimulation. In addition, the lincosamides clindamycin and lincomycin reduced basal short circuit current and the epithelial response to acetylcholine. Vancomycin had no effect on the response to electrical field stimulation or acetylcholine but enhanced the secretory action of prostaglandin E2.

These data suggest that, in addition to their ability to alter intestinal motility, a number of potential antibiotic interactions with the epithelium and its innervation may contribute to the pathogenesis of antibiotic-associated diarrhoea and colitis.
Measurement of Molecular Association in Drug: Cyclodextrin Inclusion Complexes with Improved 1H NMR Studies
Authors: Loukas Yannis L
Published: April 2011

The molecular association of haloperidol with hydroxypropyl-β-cyclodextrin, expressed by the binding constant of the inclusion complex formed, was calculated from the changes on the 1H NMR spectra of the drug in the presence of the cyclodextrin.

The stoichiometry of the complex was calculated by use of the continuous variation method (Job plot), and found to be 1:1. The binding constant for the 1:1 complex was calculated using improved non-linear models, which were solved by non-linear least-squares regression analysis, applying an iteration procedure.

Three improved mathematical models for more accurate calculation of binding constants are proposed. The models are free from any assumptions and from practical or theoretical shortcomings.
Nebulized Interleukin 2 Liposomes: Aerosol Characteristics and Biodistribution
Authors: Khanna Chand , Waldrep J Clifford , Anderson Peter M , Weischelbaum Ralph W , Hasz Diane E , Katsanis Emmanuel , Klausner Jeffrey S
Published: April 2011

Although interleukin 2 (IL-2) has been associated with modest anti-tumour responses in man, treatment-related toxicity has limited its widespread use. The local delivery of liposomal formulations of interleukin 2 to the lung as aerosols has been demonstrated to be non-toxic, biologically active, and associated with regression of spontaneous pulmonary metastases in dogs. This study was undertaken to evaluate the physical and biological characteristics of nebulized interleukin 2 liposomes.

The aerosol droplet size distribution and the physical stability of interleukin 2 liposomes were examined in-vitro using an Andersen cascade impactor and studies of liposome entrapment of interleukin 2 before and after nebulization. The biological stability of interleukin 2 liposomes after nebulization was demonstrated using the CTLL-2 bioassay for interleukin 2. In-vivo studies of pulmonary biodistribution and clearance of inhaled technetium (99mTc)-labelled interleukin 2 liposomes were undertaken in a normal dog. Aerosols of free interleukin 2 and of interleukin 2 liposomes were compared in both in-vitro and in-vivo experiments. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of interleukin 2 liposomes were 1–98 μm and 202, respectively. Independent analysis of aerosol particle-size distribution using the constitutive components of the interleukin 2 liposomes (interleukin 2: lipid: HSA) demonstrated a close correlation of size distributions (r = 0.9445; P < 0.001). The entrapment of interleukin 2 in liposomes was 93 ± 4.3% before nebulization and 90 ± 8.9% after. After delivery to an anaesthetized dog, interleukin 2 liposome aerosols were deposited evenly throughout the lung (mean ± s.d. central lung-to-peripheral lung deposition was 1–12 ± 0.03). After approximately 24 h inhalation, interleukin 2 liposomes were retained within the lung and were taken up in part by the spleen.

The results of this study are indicative of the stability of this interleukin 2 liposome formulation to nebulization. Such nebulization might be an attractive immunotherapeutic strategy for treatment of pulmonary metastases and primary lung cancers.
Effects of Meloxicam, Compared with other NSAIDs, on Cartilage Proteoglycan Metabolism, Synovial Prostaglandin E2, and Production of Interleukins 1, 6 and 8, in Human and Porcine Explants in Organ Culture
Authors: Rainsford K D , Ying C , Smith F C
Published: April 2011

Some non-steroidal anti-inflammatory drugs (NSAIDs) can accelerate joint damage in osteoarthritis by enhancing the production of pro-inflammatory cytokines or inhibiting cartilage proteoglycan synthesis. Meloxicam, a new NSAID, was compared with standard NSAIDs for its effect on proteoglycan synthesis and degradation in human and porcine cartilage explants, as well as the production of prostaglandin E2 (PGE2) and interleukins 1 and 6 by human synovial tissue explants in-vitro.

Meloxicam at submicromolar concentrations inhibited synovial PGE2 production but, up to therapeutic drug concentrations (≤ 4 μm), did not affect synovial production of the pro-inflammatory cytokine IL-1. In contrast, hydrocortisone, 10 μm, a positive control, inhibited release of this cytokine, and indomethacin, 100 μm, increased its production. The lack of effects of meloxicam were evident irrespective of intrinsic IL-1 bioactivity of the synovia, production of IL-1 inhibitors or time of incubation. Production of the part antiinflammatory cytokine IL-6, was significantly increased by therapeutic concentrations of meloxicam, as well as by indomethacin. Another major pro-inflammatory cytokine, IL-8, was unaffected by therapeutic concentrations of meloxicam. Meloxicam, 0.1–4.0 μm, did not affect cartilage proteoglycan production whereas indomethacin, 100 μm, significantly reduced synthesis of these macromolecules.

Thus meloxicam, at concentrations within the therapeutic range and at which pronounced inhibition of prostaglandin production is evident, affects neither cartilage proteoglycan production nor the production of those cytokines likely to be important in cartilage destruction.
Evidence of Hydroxyl Free Radical Generation by Calcium Overload in Rat Myocardium
Authors: Obata Toshio , Tamura Minoru , Yamanaka Yasumitsu
Published: April 2011

Although calcium (Ca2+) is important in cardiac dysfunction and has also been reported as a source of oxidative toxicity, the connection between Ca2+ overload and oxygen free radicals in the myocardium is not clear. We have investigated whether Ca2+ overload generates hydroxyl free radicals in rat ventricle.

HPLC with electrochemical detection was used to measure the levels of 2,3- and 2,5-dihydroxybenzoic acid (DHBA) formed when the hydroxyl free radical reacts with salicylate. Ringer's solution containing salicylic acid (0.5 nmol μL− min−) was infused through a microdialysis probe in the region of the left anterior descending coronary artery of the rat ventricle. A positive linear correlation was obtained between Ca2+ and hydroxyl free radical formation trapped as 2,3-DHBA (r2 = 0.976) and 2,5-DHBA (r2 = 0–982) in the myocardial dialysate. The administration of ouabain (1 mg kg−, i.v.), a Ca2+ elevator, into the femoral vein significantly increased the level of 2,3- and 2,5-DHBA.

These results indicate that Ca2+ overload generates hydroxyl free radicals in rat heart.
The Predominant Contribution of Oligopeptide Transporter PepT1 to Intestinal Absorption of β-Lactam Antibiotics in the Rat Small Intestine
Authors: Tamai Ikumi , Nakanishi Takeo , Hayashi Kiyomi , Terao Toshimitsu , Sai Yoshimichi , Shiraga Toshiyuki , Miyamoto Ken-Ichi , Takeda Eiji , Higashida Haruhiro , Tsuji Akira
Published: April 2011

Although recent evidence suggests that certain β-lactam antibiotics are absorbed via a specific transport mechanism, its nature is unclear. To confirm whether peptide transport in the rat can be largely ascribed to the intestinal oligopeptide transporter PepT1, the transporter has been functionally characterized and its significance in the intestinal absorption of β-lactam antibiotics was evaluated.

For evaluation of transport activity complementary RNA (cRNA) of rat PepT1 was synthesized in-vitro and expressed in Xenopus laevis oocytes. cRNA induced uptake of several β-lactam antibiotics and the dipeptide [14C]glycylsarcosine; this was specifically inhibited by various dipeptides and tripeptides but not by their constituent amino acids or by terra- or pentapeptides. The transport activity of PepT1 for β-lactam antibiotics correlated well with their in-vivo intestinal transport and absorption. Furthermore, mutual inhibitory effects on uptake were observed between glycylsarcosine and β-lactam antibiotics. Hybrid depletion of the functional expression of rat PepT1 in oocytes injected with rat intestinal epithelial total mRNA was studied using an antisense oligonucleotide corresponding to the 5′-coding region of PepT1. In oocytes injected with rat mRNA pre-hybridized with the antisense oligonucleotide against rat PepT1, the uptake of [14C]glycylsarcosine was almost completely abolished, whereas its uptake was not influenced by a sense oligonucleotide for the same region of PepT1. Similarly, the uptake of β-lactam antibiotics was also reduced by the antisense oligonucleotide against rat PepT1.

These results demonstrate that the intestinal proton-coupled oligopeptide transporter PepT1 plays a predominant role in the carrier-mediated intestinal absorption of β-lactam antibiotics and native oligopeptides in the rat.
Antinociceptive Effect of the Hydroalcoholic Extract of Bauhinia splendens Stems in Mice
Authors: Filho Arnaldo Willain , Breviglieri Eduardo , Filho Valdir Cechinel , Santos Adair R S
Published: April 2011

The analgesic effect of the hydroalcoholic extract of the stems of Bauhinia splendens (Leguminosae) has been investigated in chemical and thermal models of nociception in mice.

The hydroalcoholic extract of B. splendens, 3–60 mg kg− intraperitoneally or 50–400 mg kg− orally, caused dose-related, and long-lasting (up to 3 h) inhibition of acetic acid-induced abdominal constriction in mice, with ID50 values of 3.2 and 177.6 mg kg− and maximum inhibition of 95 ± 2 and 61 ± 6%, respectively. In the formalin test, the extract given intraperitoneally (1.60 mg kg−) or orally (50–400 mg kg−) caused graded inhibition of both phases of formalin-induced pain, being about 5- to 6-fold more potent in attenuating the second phase of pain. The calculated mean ID50 values for the first and the second phases were 11.5 and 2.5 mg kg−, respectively, for intraperitoneal administration and > 200 and 70 mg kg−, respectively, for oral administration; the percentages of maximum inhibition for the first and the second phases were 68 ± 6 and 99 ± 1, respectively, for intraperitoneal administration and 37 ± 6 and 69 ± 9, respectively, for oral administration. However, at the same doses the extract did not significantly affect the oedematogenic response induced by formalin. The treatment of animals with naloxone (5 mg kg−, i.p.) completely reversed the analgesic effect caused by morphine (5 mg kg−, s.c), but had no effect against the antinociceptive effect of the hydroalcoholic extract of B. splendens (60 mg kg−, i.p.) when assessed against acetic acid-induced abdominal constrictions. Furthermore, the extract, in contrast with morphine, had no analgesic effect in the hot-plate test.

These data show that the hydroalcoholic extract of B. splendens has significant analgesic action when assessed against several models of pain. The mechanism underlying its analgesic effect still remains unknown, but seems to be unrelated to interaction with opioid systems.
Garlic Compounds Protect Vascular Endothelial Cells from Oxidized Low Density Lipoprotein-induced Injury
Authors: Ide Nagatoshi , Lau Benjamin H S
Published: April 2011

Oxidation of low density lipoprotein (LDL) has been recognized as playing an important role in the initiation and progression of atherosclerosis. In this study, the effects of aged garlic extract and one of its major compounds, S-allylcysteine, on oxidized LDL-induced cell injury were studied.

Pulmonary artery endothelial cells were pre-incubated with the garlic extract (1, 2.5 and 5 mg mL−) or 5-allylcysteine (01, 1, 10 and 20 mm) at 37°C and 5% CO2 for 24 h, washed, and then exposed to 01 mg mL− oxidized LDL for 24 h. Lactate dehydrogenase release as an index of membrane damage, methylthiazol tetrazolium assay for cell viability and thiobarbituric acid reactive substances indicating lipid peroxidation were determined. Preincubation of endothelial cells with the extract or S-allylcysteine significantly prevented membrane damage, loss of cell viability and lipid peroxidation.

The data indicate that these compounds can protect vascular endothelial cells from injury caused by oxidized LDL, and suggest that they may be useful for prevention of atherosclerosis.
Effects of the Calcium Antagonist AE0047 on the Development of Neurological Deficit and Infarction after Middle Cerebral Artery Occlusion in Stroke-prone Spontaneously Hypertensive Rats
Authors: Shinyama Hiroshi , Kawamura Toru , Iwamoto Minori , Egi Yasuhiro , Tanaka Hideki , Kawabata Yoshiyasu , Nakamura Norifumi , Kagitani Yoshio
Published: April 2011

AE0047 [4-(4-benzhydrylpiperazino)phenethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate dihydrochloride] is a new dihydropyridine calcium antagonist with protective effects against cerebral ischaemia and the occurrence of stroke in several animal models. We investigated the effects of AE0047 on focal ischaemia induced by middle cerebral artery occlusion in stroke-prone spontaneously hypertensive rats.

AE0047 at a dose causing 20 or 40% systemic hypotension (1 or 3 mg kg−) was given orally twice, 15 min and 24 h after occlusion. The neurological status of animals was investigated 2, 24 and 48 h after occlusion. Infarct area of brain was measured 48 h after occlusion. Middle cerebral artery occlusion resulted in the progressive deterioration of neurological status and large infarction in middle cerebral artery territories with 40% mortality. AE0047 dose-dependently attenuated the deterioration of neurological status, and reduced mortality to 0 or 10%. AE0047 significantly reduced infarct size and left/right hemispheric area ratio, an index of brain swelling.

These results suggest that AE0047 has the ability to ameliorate ischaemic cerebral stroke in hypertensive patients.
Daunorubicin-induced Smooth Muscle Contraction: Involvement of Ca2+ Entry Mechanism
Authors: Masui Hidehisa , Wakabayashi Ichiro , Yoshimoto Sachiko , Sakamoto Kunihiro
Published: April 2011

The mechanisms of the smooth muscle contractile action of daunorubicin were investigated using guinea-pig aortae, and the involvement of the Ca2+ entry mechanism was compared among different smooth-muscle preparations.

In the aorta, daunorubicin showed a concentration-dependent contractile action at concentrations of 10–200 μm. The contractile response to daunorubicin was completely dependent on extracellular Ca2+, but only slightly sensitive to verapamil or nifedipine. Trifluoperazine abolished the contraction by daunorubicin, but no significant effect was noted with amiloride, phentolamine, indomethacin or staurosporine. The order of potency (sensitivity) for daunorubicin-induced smooth muscle contraction was oesophagus = gall bladder = iliac artery > bronchus = aorta, while that of maximum reactivity was iliac artery = aorta > bronchus = oesophagus = gall bladder. In the portal vein, daunorubicin showed no contractile action. Although the smooth muscle contraction induced by daunorubicin was strongly dependent on extracellular Ca2+ in the aorta, iliac artery, bronchus, oesophagus and gall bladder, its sensitivity to verapamil varied among the different smooth muscle preparations, with the sensitivity being iliac artery = gall bladder > bronchus = oesophagus > aorta.

These results suggest that daunorubicin has contractile action on various kinds of smooth muscle, mainly via the transplasmalemmal Ca2+ entry mechanism, but the degree of involvement of the voltage-dependent Ca2+ channel differs among the different smooth muscle preparations.
Absorption of Ciprofloxacin and Norfloxacin when Administered as Niosome-encapsulated Inclusion Complexes
Authors: D'Souza S A , Ray J , Pandey S , Udupa N
Published: April 2011

An attempt has been made to design suitable niosome-encapsulated drug delivery system for ciprofloxacin and norfloxacin. Encapsulation of ciprofloxacin and norfloxacin in niosomes was investigated and the nasal and intestinal absorption of the products studied.

More than 80% of the drugs were successfully encapsulated to give products with sustained release characteristics. Encapsulation in niosomes also improved the stability of the antibacterial compounds.

Although the systemic availability of these niosome-encapsulated antibacterial compounds was not increased after nasal administration, intestinal absorption was significantly higher in comparison with that of plain inclusion complexes.
Renal Excretion of Vancomycin in Rats with Acute Renal Failure
Authors: Nakamura Tsutomu , Kokuryo Toshiyuki , Takano Mikihisa , Inui Ken-Ichi
Published: April 2011

We have investigated the renal excretion of vancomycin in rats with acute renal failure (ARF) induced by uranyl nitrate or cisplatin.

The renal clearance of the antibiotic after uranyl nitrate or cisplatin injection was separately evaluated by calculating the glomerular filtration rate (GFR) and secretory clearance. The reduced renal clearance of vancomycin in these ARF rats was a result of a decrease in both GFR and secretory clearance. The extents of the decreases in GFR and in secretory clearance were not, however, proportional, the extent of the decrease in secretory clearance being more pronounced.

These results suggest that the renal tubular secretion of vancomycin was reduced more predominantly than glomerular filtration in these ARF models.
Comparison of HPLC and Enzymatic Recycling Assays for the Measurement of Oxidized Glutathione in Rat Brain
Authors: Sian J , Dexter D T , Cohen G , Jenner P G , Marsden C D
Published: April 2011

Glutathione (reduced, GSH and oxidized, GSSG) concentrations were analysed in rat cerebellar homogenate using high performance liquid chromatography with ultraviolet detection (HPLC-UV) or enzymatic recycling assays.

GSSG levels found using the HPLC-UV assay were 200-fold higher than those obtained with the enzymatic recycling procedure. Reduction of synthetic GSSG by glutathione reductase showed total conversion to GSH as assessed by HPLC-UV analysis. In contrast, only approximately 50% of the HPLC peak for GSSG could be reduced by glutathione reductase. Increasing the period of incubation with glutathione reductase for longer than 15 min did not alter GSSG levels.

These results suggest that another substance present in brain tissue is derivatized and eluted at the same time as GSSG using the HPLC-UV assay, thus contributing to the apparently high GSSG levels found employing this technique.
Modelling of the Void Space of Tablets Compacted Over a Range of Pressures
Authors: Ridgway Cathy J , Ridgway Kenneth , Matthews G Peter
Published: April 2011

A previously developed computer model, named Pore-Cor, has been used to simulate the changes in the void-space dimensions which occur during the compaction of tablets over a range of pressures.

The tablets were made by mixing pharmaceutical grade crystalline lactose and an anti-inflammatory compound in the proportion 4:1. Compacts were made by placing a weighed amount of the mixed powder into a stainless-steel die and applying pressure with a hand-operated calibrated hydraulic press. Compacts were prepared at eight pressures over the hydraulic pressure range 1 to 8 ton in−2 (15.4–123.2 MPa) in 1 ton in−2 increments. Mercury-intrusion curves were measured for the eight samples by use of a porosimeter and the Pore-Cor package was then used to simulate the mercury-intrusion curves and generate void-space models of the correct porosity.

The experimental and simulated characteristic throat diameter, the experimental and simulated porosity, and the simulated permeability of the tablets have all been shown to follow expected trends. The successful modelling of void-structure parameters, which are difficult or impossible to measure experimentally, opens the way to an improved understanding of the strength of compacts.
Effects of Grinding and Humidification on the Transformation of Conglomerate to Racemic Compound in Optically Active Drugs
Authors: Piyarom Sujimon , Yonemochi Etsuo , Oguchi Toshio , Yamamoto Keiji
Published: April 2011

The effects of grinding and humidification on the transformation of conglomerate to racemic compound have been investigated by X-ray powder diffraction (XPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy for leucine, norleucine, valine, serine, tartaric acid and malic acid.

Racemic physical mixtures were prepared by physical mixing of equimolar quantities of d and l crystals using a mortar and pestle. Ground mixtures were obtained by grinding the physical mixtures with a vibrational mill. Humidification was performed by storing the physical mixtures and the ground mixtures in a desiccator containing saturated aqueous salt solutions at 40°C.

When physical mixtures of malic acid, tartaric acid and serine were ground, the XPD peaks of the racemic compounds were observed. The XPD patterns of humidified physical mixtures of these compounds also showed the formation of the racemic compounds. This indicated that grinding or humidification of malic acid, tartaric acid and serine induced the transformation of conglomerate to racemic compound crystals. When, on the other hand, the physical mixtures of valine, leucine and norleucine were ground, peaks of racemic compounds were not detected in the XPD pattern. After humidification of the ground mixtures of valine, leucine and norleucine, however, the XPD peaks of racemic compounds were observed. DSC and IR studies revealed consistent results.

We concluded that grinding or humidification of malic acid, tartaric acid and serine could induce the transformation of a conglomerate to racemic compound. In contrast, humidifying after grinding was needed to bring about the transformation in leucine, norleucine and valine.
Biochemical Basis for Deficient Paracetamol Glucuronidation in Cats: an Interspecies Comparison of Enzyme Constraint in Liver Microsomes
Authors: Court Michael H , Greenblatt David J
Published: April 2011

Unlike most other mammalian species, domestic cats glucuronidate phenolic compounds poorly and are therefore highly susceptible to the toxic side effects of many drugs, including paracetamol. In this study, we evaluated the role of enzyme constraint, a characteristic that limits the activity of all uridine 5′-diphosphoglucuronosyltransferase (UGT) enzymes, in the aetiology of this species-dependent defect of drug metabolism.

Detergent activation experiments were performed using hepatic microsomes from cats (4), dogs (4), man (4), and 6 other mammalian species (1 liver each). In addition, we used microsomes from Gunn rats which are sensitive to paracetamol toxicity because of a genetic defect affecting all family 1 UGTs. Increase in paracetamol-UGT activity at optimum concentrations of detergent was used as an index of enzyme constraint. Native activity (measured in the absence of detergent) was less than one-sixth in cats compared with other species. Optimum detergent treatment tended to enhance rather than abolish this difference, however, indicating relatively lower levels of constraint of paracetamol-UGT in cats compared with other species. Similarly, detergent treatment failed to reduce the native activity difference between homozygous mutant and normal Gunn rats. Initially CHAPS (3-(3-cholamidopropyl)-dimethylamrnonio-1-propanesulphonic acid) was used as the detergent activator; in 3 of 4 microsomal preparations from man, however, inhibition rather than activation was observed at all detergent concentrations used. Studies were repeated using the non-ionic detergent, Brij 58 (polyoxyethylene 20-cetyl ether), which resulted in similar although more profound activation and no inhibition.

We conclude that deficient paracetamol glucuronidation in cats does not result from increased paracetamol-UGT constraint in this species compared with other mammalian species. Other causes, such as differences in enzyme protein concentration or substrate affinity might be responsible.
The Effects of Lag-time and Dwell-time on the Compaction Properties of 1 : 1 ParacetamoUmicrocrystalline Cellulose Tablets Prepared by Pre-compression and Main Compression
Authors: Akande Oloniyon F , Ford James L , Rowe Philip H , Rubinstein Michael H
Published: April 2011

The effects of lag-time and dwell-time on the compaction properties of tablets compressed from a 1:1 blend of paracetamol and microcrystalline cellulose have been examined using a compaction simulator.

Increases in lag-times (from 0.06 to 0.53s) resulted in small increases in the tensile strengths of the tablets when combinations of 80 and 160MPa were used as the compression pressures. Further increases in lag-time did not alter the tablet strengths. When combinations of 240 and 320 MPa were used for pre-compression and main compression, the effects on the tensile strengths were more complex, partly because the high elastic recoveries of the tablets resulted in greater variability in the data. Increases in lag-times from 0.06 to 0.97 s resulted in an increase of between 12 and 28% in tensile strength. Longer lag-times (1.24 or 1.52s) did not result in further increases in tensile strength. The application of a dwell-time of 0.26 s during pre-compression or main compression pressures of 80 and 160 MPa generally led to a decrease (14–22%) in tensile strength compared with tablets where no dwell-time was used. This was because of increases in both the elastic recoveries and elastic energies. Subsequent increases in dwell-time from 0.26 to 0.9 s resulted in increases in tablet strength compared with that obtained when no dwell-time was applied. The tensile strengths of tablets made with a pre-compression of 160 MPa then a main compression of 80 MPa were 11–33% higher than those of tablets made with a pre-compression of 80 MPa then a main compression of 160 MPa. This was because higher plastic energies and more plastic deformation occurred at the higher pre-compression.

Generally, the application of dwell-time resulted in greater increases in tensile strengths than lag-time, which had less effect on the compaction properties.
Polyamine-mediated Heart Hypertrophy Induced by Clenbuterol in the Mouse
Authors: Cubría J C , Reguera R , Balaña-Fouce R , Ordónez C , Ordóñez D
Published: April 2011

The use of β-agonists as growth-promoting agents in cattle could lead to toxic side-effects in man. One such effect is the accumulation of polyamines which seem to be implicated in muscle and heart hypertrophy. We have studied the induction of cardiac hypertrophy after treatment with clenbuterol and the role of polyamines in this effect.

Treatment of mice with repeated doses of clenbuterol, a specific β-adrenergic agonist, resulted in a marked increase in heart muscle weight whereas total body weight did not change significantly. Clenbuterol-linked cardiac hypertrophy could be prevented by coadministration of either the non-specific β-adrenergic antagonist, propranolol, or the irreversible inhibitor of ornithine decarboxylase, α-difluoromethylornithine. The clenbuterol-induced cardiac hypertrophy was associated with a corresponding increase in the level of the polyamines putrescine, spermidine and spermine.

These observations are indicative of the role of polyamines in cardiac hypertrophy induced by clenbuterol.
Different Absorption Profiles of Deramciclane in Man and in Dog
Authors: Kanerva Harri , Klebovich Imre , Drabant Sandor , Urtti Arto , Nevalainen Timo
Published: April 2011

We have studied the dog model for predicting the oral absorption of deramciclane, a novel anxiolytic compound, as a model acid-labile drug. The absorption profile of deramciclane was studied in man and beagle dogs after administration of conventional capsules and enteric coated tablets. Absorption in dogs pretreated with pentagastrin or saline was also studied after administration of conventional capsules. The in-vitro stability of deramciclane was determined over the pH range 1.2–6.0.

The rate of degradation of deramciclane increased ten-fold as the pH was reduced from 2.1 to 1.2 (t.β (elimination half-life) 9 h and 39 min, respectively). Deramciclane was stable at pH. 3. The two formulations were bioequivalent in dogs and there were no significant differences between pharmacokinetic parameters measured for dogs pretreated with pentagastrin or saline. In man the mean relative bioavailability and Cmax (peak plasma concentration) for the conventional capsules were approximately 75% and 83% of those for the enteric coated tablets (P = 0.0004 and P = 0.0031, respectively). This was probably because of degradation of deramciclane at lower pH of man’s stomach compared with that of the dog. Pentagastrin was probably unsuccessful in reducing gastric pH and thus no change in absorption was observed.

It is concluded that the absorption of deramciclane, and possibly other acid-labile drugs, cannot be predicted by use of the dog model.
Some 1-[(Benzofuran-2-yl)methy1]imidazoles as Inhibitors of 17α-Hydroxylase1:7, 20-lyase (P450 17) and Their Specificity Patterns
Authors: Bahshwan Saleh A , Owen Caroline P , Nicholls Paul J , Smith H John , Ahmadi Masoud
Published: April 2011

Four 1-[(benzofuran-2-yl)methyl]imidazoles (1–4) have been evaluated as in-vitro inhibitors of human testicular and bovine adrenal microsomal 17α-hydroxylase: 17,20-lyase (P450 17) as potential anti-prostatic agents. Their specificity towards other steroidogenic and liver enzymes has been compared with that of ketoconazole.

All four compounds were inhibitors of the testicular enzyme (2, IC50 (concentration resulting in 50% inhibition) 0.185 μm; 4, IC50 0.18 μM) but less potent than ketoconazole (IC50 0.03 μM). Towards bovine adrenal enzyme 2 and 4 were 35- and 31-fold more potent than ketoconazole (IC50 = 39.8 μM).

Compound 2 is a useful lead compound but although less potent than ketoconazole towards P450SCC and P45011β, but not P450C21, at the enhanced dose required for equivalent effects in-vivo on P450 17 it is likely that cortisol and aldosterone production will be affected to a greater extent than with ketoconazole.
Amitriptyline and Clomipramine Increase the Concentration of Administered L-Tryptophan in the Rat Brain
Authors: Eriksson Tomas , Wålinder Jan
Published: April 2011

The tricyclic antidepressant amitriptyline has been shown to reduce concentrations of large neutral amino acids (LNAA) in rat plasma. Compounds with that property might interact with such amino acids used as therapeutic agents with a central site of action by causing a change in the relationship between the administered LNAA and its endogenous LNAA competitors for carrier-mediated transport through the blood–brain barrier into the brain. This study was performed to investigate if the antidepressant agents amitriptyline and clomipramine could, by such a mechanism, increase brain concentrations of administered tryptophan.

Intraperitoneal administration of L-tryptophan alone (100 mg kg−1) resulted in an increase in the concentration of tryptophan in the rat brain from 14 ±0.7 to 100 ± 4.3 nmol g−1 compared with rats given saline only. When rats were given tryptophan with amitriptyline (25 mg kg−1, i.p.) or clomipramine (25 mg kg−1, i.p.) brain concentrations of tryptophan were increased even further, to 150 ±4.5 and 157 ± 10.2 nmol g−1, respectively. Administration of L-tryptophan alone resulted in an increase in the rat plasma tryptophan ratio [(concentration of tryptophan)/(total concentration of LNAAs)] from 0.14±0.003 to 0.42±0.011 compared with rats given saline only. When rats were given tryptophan with amitriptyline or clomipramine the plasma tryptophan ratios were increased even further to 0.52 ±0.017 and 0.54 ±0.025, respectively. All these effects were statistically significant (P < 0.001).

These findings support the hypothesis that tricyclic antidepressants could interact with administered tryptophan by changing the relationship in plasma between tryptophan and its endogenous LNAA competitors for transport into the brain, resulting in higher concentrations of tryptophan in the brain. It is possible that this could be the mechanism of the previously reported finding that clomipramine and tryptophan potentiate each other in the treatment of depression.
Activation of 11 β-Hydroxysteroid Dehydrogenase by Dehydroepiandrosterone Sulphate as an Anti-hypertensive Agent in Spontaneously Hypertensive Rats
Authors: Homma Masato , Onodera Toshiaki , Hirabatake Masaki , Oka Kitaro , Kanazawa Masao , Miwa Takashi , Hayashi Tohru
Published: April 2011

The anti-hypertensive properties of dehydroepiandrosterone sulphate (DHEAS) have been investigated by studying its effects on blood pressure, on serum concentrations of corticosterone and dehydrocorticosterone, and on 11 β-hydroxysteroid dehydrogenase (11 β-HSD) activity in spontaneously hypertensive rats (SHR).

SHR were given intraperitoneal injections of DHEAS (10 mg day−1 for 70 days) from six to 16 weeks of age. The blood pressure–time curve was significantly (P<0.05) suppressed immediately after administration of DHEAS. There was no difference between the heart rates of control and DHEAS groups. Serum concentrations of corticosterone and dehydrocorticosterone in the DHEAS group were significantly (P < 0.05) lower than those of the control group. The dehydrocorticosterone/corticosterone concentration ratio was, however, significantly (P < 0.05) higher in the DHEAS group, suggesting that treatment with DHEAS enhanced the overall interconversion of corticosterone to dehydrocorticosterone. The activity of 11 β-HSD in specific organs of the DHEAS group was affected, characteristic changes being increases in the kidney (14–58%), decreases in the liver (11–27%) and no change in the testis. Direct addition of DHEAS to 11 β-HSD preparations from the kidneys of control SHR had the same effect as that observed in the in-vivo experiments.

The fall in serum corticosterone in the DHEAS group is considered to be related, at least partly, to increased activity of kidney 11 β-HSD. The inverse correlation of kidney 11 β-HSD activity with serum corticosterone and blood pressure (—r = 0.628, P < 0.01, and —r = 0.478, P < 0.05, respectively) suggest that DHEAS delayed the development of hypertension in SHR by selective promotion of kidney 11 β-HSD activity which in turn resulted in lower serum concentrations of corticosterone and its minimal aldosterone-like activity.
Anti-inflammatory Activity in Rats and Mice of Phenolic Acids Isolated from Scrophularia frutescens
Authors: Fernández M A , Sáenz M T , García M D
Published: April 2011

Different species of the Scrophularia genus (Scrophulariaceae) have been reported to have bacteriostatic and anti-inflammatory properties. In previous studies the anti-inflammatory and antibacterial activity of different extracts from Scrophularia frutescens were investigated and p-coumaric, caffeic, ferulic gentisic, protocatechuic, syringic and isovanillic acids were isolated and identified. In this work the anti-inflammatory activity of these compounds, administered orally, has been studied against carrageenan-induced rat paw oedema and, administered topically, against tetradecanoylphorbol acetate (TPA)-induced mouse ear oedema. The compounds’ myeloperoxidase activity in inflamed ear was also investigated.

Some of the phenolic acids were remarkably active in the TPA test (protocatechuic 71.59% inhibition, P < 0.001; syringic 74.43%, P < 0.001; ferulic 71.02% P < 0.001) and all significantly inhibited mouse ear oedema. They were only moderately active, or were without activity, in the carrageenan test.

These results imply that the phenolic acids assayed are more effective topically than as oral anti-inflammatory agents and that their action is markedly influenced by the inhibition of neutrophil migration into inflamed tissue. This study has also enabled us to make some observations on the possible relationship between the chemical structure and antiinflammatory activity of the compounds assayed.
Development of an In-vitro Model to Study the Growth Characteristics of Staphylococcus epidermidis in Continuous Ambulatory Peritoneal Dialysis
Authors: Brant Janet A , Hanlon Geoffrey W , Denyer Stephen P
Published: April 2011

An in-vitro model of peritonitis in continuous ambulatory peritoneal dialysis (CAPD) has been developed which integrates the parameters of environmental gaseous tension, the changing biochemical profile of the dialysate, and the periodic challenge of fresh fluid.

Dwell times of 4 h during the day and 10 h at night were used to reflect the in-vivo situation. Biochemical analysis of dialysate within the model showed that the profiles for creatinine, glucose and protein approximated those found in patients. Staphylococcus epidermidis growing in synthetic dialysis effluent or pooled dialysis fluid were seen to adapt rapidly to the environment after an initial lag phase; a tendency to aggregate together increased over the 50-h period of operation.

In conclusion, the results presented here suggest that this in-vitro model creates an environment which is reflective of the in-vivo situation and therefore has potential for the study of peritonitis in CAPD.
Submicron Oil-in-water Emulsion Formulations for Mefloquine and Halofantrine: Effect of Electric-charge Inducers on Antimalarial Activity in Mice
Authors: Mbela T K M , Deharo E , Haemers A , Ludwig A
Published: April 2011

Stearylamine, oleic acid, phosphatidylserine and dicetylphosphate have been studied to determine their capacity to induce electric charge on non-ionic submicron emulsions containing halofantrine and mefloquine.

The in-vivo antimalarial activity of drug-loaded emulsions, evaluated in mice, was affected by the nature of the additives used. In particular, the electric-charge inducers markedly affected the pharmacological activity of mefloquine, but not of halofantrine. After subcutaneous administration ED50 values (the doses affording 50% protection) were 3 and 15 mg kg−1, respectively, for halofantrine and mefloquine emulsions without charge inducers. The mefloquine-loaded emulsions with charge inducers were active at 10 mg kg−1 for dicetylphosphate, 17 mg kg−1 for phosphatidylserine, 23 mg kg−1 for oleic acid and 27 mg kg−1 for stearylamine, again after subcutaneous administration.

This work has enabled the formulation of stable emulsions, incorporating drugs with high antimalarial activity, which are proposed for parenteral delivery of these fairly soluble drugs.
The Role of the Iminium Bond in the Inhibition of Reverse Transcriptase by Quaternary Benzophenanthridines
Authors: Kerry Mark A , Duval Olivier , Waigh Roger D , Mackay Simon P
Published: April 2011

The quaternary benzo[c]phenanthridines fagaronine, nitidine and O-methylfagaronine have been reviewed as potential antitumour and antiviral agents. Their mode of action has not been established, but their ability to bind with DNA by intercalation is believed to be involved.

Of the three synthetic analogues of O-methylfagaronine which we have synthesized, methoxidine and ethoxidine are active against HIV-1 reverse transcriptase (IC50 values 2.8 μM and 2.4 μM respectively) whereas hydroxidine is inactive. One of the prerequisites for the enzyme inhibitory activity of this class of molecule is the presence of an iminium group-it is well known that a positive charge on a polyaromatic nucleus facilitates intercalative binding with DNA. Through UV spectrophotometric and modelling studies, we have shown that the iminium bond plays a more fundamental role in enzyme inhibition through its susceptibility to nucleophilic attack—the inactive analogue hydroxidine has a non-electrophilic iminium bond.

Consequently, we have demonstrated that iminium bond electrophilicity is a parameter which needs to be considered in ternary complex formation with reverse transcriptase.
Effect of Butylidenephthalide on Calcium Mobilization in Isolated Rat Aorta
Authors: Ko Wun-Chang , Charng Chuan-Yin , Sheu Joen-Rong , Tzeng Shu-Huey , Chen Chi-Ming
Published: April 2011

Butylidenephthalide (Bdph), an antispasmodic compound originally isolated from the rhizome of Ligusticum chuaxiong, has a selective anti-anginal effect without changing blood pressure. Experiments have been performed to determine the mechanism of this action.

Synthetic Z-butylidenephthalide concentration-dependently relaxed phenylephrine (1 μM)- or KC1 (60 mM)-induced precontractions of intact and denuded rat aorta rings. The relaxation induced by Bdph was endothelium-independent. Bdph (30–300 μM) concentration-dependently reduced cumulative phenylephrine- and KCl-induced contractions of intact rat aortic rings and non-competitively inhibited their log concentration-response curves. The pD2′ values of Bdph for phenylephrine- and KCl-induced contraction were 3.66 ± 0.13 (n = 8) and 3.71 ± 0.07 (n = 8), respectively, which were not significantly different from each other. Bdph also concentration-dependently reduced cumulative Ca2+-induced contractions of intact rat aortic rings in high-KCl (60 mM) Ca2+-free physiological salt solution and non-competitively inhibited its log concentration—response curve. The pD2′ value of Bdph for the Ca2+-induced contractions was 3.21±0.01 (n = 7) which was significantly different from the pD2′ value obtained from the cumulative KCl-induced contractions.

These results suggest that Bdph inhibits calcium release from calcium stores more selectively than calcium influx from extracellular space via voltage-dependent calcium channels. The inhibition by Bdph of calcium release from KCl-sensitive calcium stores might be similar to its inhibition of calcium release from phenylephrine-sensitive calcium stores. However, because phenylephrine generates inositol-1,4,5-trisphosphate (IP3) whereas KCl does not, the inhibitory effect of Bdph might not be related to IP3 production.
Effects of Tamoxifen on Striatal Dopamine and 5-Hydroxytryptamine Release in Freely Moving Male Rats: An In-vivo Microdialysis Investigation
Authors: Chaurasia Chandra S , Chen Chu-En , Rubin Jason , Dewey Stephen L
Published: April 2011

Recent studies indicating interaction of oestrogens with central cholinergic, dopaminergic and 5-HTergic systems have led to the assumption of a protective role of oestrogens in certain neurodegenerative disorders. The non-steroidal drug tamoxifen, a mixed oestrogen agonist—antagonist, has been shown to modulate central nervous system functions in the corpus striatum. In this study we used a microdialysis technique to examine the effects of tamoxifen upon the striatal dopaminergic and 5-HTergic systems in intact freely moving male rats.

The extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid were measured after intraperitoneal administration of either the control or tamoxifen, and were compared with their corresponding baseline levels. Significant 25–35% increases in the baseline levels of dopamine and 3,4-dihydroxyphenylacetic acid were observed after the highest doses of tamoxifen (1.5mgkg−1 and 3.Omgkg−1, respectively), whereas the lowest dose of tamoxifen (0.3mgkg−1) elevated dopamine and 3,4-dihydroxyphenylacetic acid levels by a detectable 15% of the basal. In addition, the ratio of 3,4-dihydroxyphenylacetic acid-to-dopamine remained unchanged in comparison with that of the pretreatment levels. Whereas no change in the striatal 5-hydroxyindoleacetic acid concentrations was seen with the lowest and highest dose regimen, the intermediate dose elicited a moderate increase (20%) in basal 5-hydroxyindoleacetic acid levels.

The pharmacological relevance of the effects of tamoxifen on the dopaminergic and 5-HTergic systems, as a prelude to the development of non-steroidal oestrogenic compounds in reducing the risk of neurodegenerative disorders such as Alzheimer’s disease, is discussed.