bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic Administration Does Not Alter the Pharmacokinetic Profile of L-Dopa in the Rat
Authors: Rose S , Jenner P , Marsden C D 
Published: April 2011

Abstract
Chronic administration of L-dopa (200 mg kg−1 day−1 for 12 months) plus carbidopa (25 mg kg−1 day−1) or carbidopa (25 mg kg−1 day−1) alone did not alter the t½, AUC0–∞ k10, k12, k21, CLp or Vdss of L-dopa following intra-aortic (i.a.) administration (50 mg kg−1) alone or after carbidopa (25 mg kg−1, i.p.) pretreatment, or the t½, AUC0–∞, tmax or the bioavailability (F) of L-dopa (50 mg kg−1) administered orally, alone or after acute pretreatment with carbidopa (25 mg kg−1 i.p.). The peripheral metabolism of l-dopa was unaltered by chronic administration of L-dopa plus carbidopa or carbidopa alone as measured by unaltered AUC0·360 min for 3-O-methyldopa, dopamine, DOPAC or homovanillic acid in the plasma of rats following acute administration of L-dopa (50 mg kg−1, p.o. or i.a.) alone or following pretreatment with carbidopa, and unaltered hepatic dopa decarboxylase activity.
The Effect of Fluorine Substitution on the Physicochemical Properties and the Analgesic Activity of Paracetamol
Authors: Barnard Sallyann , Storr R C , O’Neill P M , Park B K 
Published: April 2011

Abstract
The physicochemical properties and analgesic action of six fluorinated analogues of 4-hydroxyacetanilide (paracetamol) have been investigated. Fluorine substitution adjacent to the hydroxyl group increased lipophilicity and oxidation potential whilst substitution adjacent to the amide had little effect on lipophilicity but led to a greater increase in oxidation potential. Lack of coplanarity and conjugation of the amide group and aromatic ring was also apparent with the analogues that had fluorine in the 2 and 6 positions. Introduction of fluorine into the amide group of paracetamol increased the lipophilicity 4-fold and also increased the oxidation potential of paracetamol. ED50 values for analgesic activity in the phenylquinone-induced abdominal constriction test on male Swiss White mice showed that ring substitution by fluorine reduced activity, especially at the 2,6-positions. Introduction of fluorine into the amide group enhanced activity significantly. Correlation of the analgesic activity with the physicochemical properties indicated that conjugation (and planarity) of the amide group with the aromatic ring is essential for activity and that ease of oxidation may also be an important factor.
Potent Antinociceptive Activity of a Hydroalcoholic Extract of Phyllanthus corcovadensis
Authors: Gorski Franco , Corrêa Clovis R , Filho Valdir C , Yunes Rosendo A , Calixto João B 
Published: April 2011

Abstract
This study analyses the analgesic effect of a hydroalcoholic extract (HE) from Phyllanthus corcovadensis in several models of pain in mice. HE (3–60 mg kg−1, i.p.) or (100–500 mg kg−1, p.o.) caused a graded and potent analgesic effect against the abdominal constriction response caused by acetic acid and acetylcholine with an ID50 of about 3 and 100 mg kg−1, respectively. In the tail-flick model HE (up to 500 mg kg−1, p.o.) was without effect, while morphine (1–10 mg kg−1, s.c.) caused a graded increase in pain latency (ID50, 3 mg kg−1). HE (1–300 mg kg−1) given both intraperitoneally and orally caused a potent and graded inhibition of the second phase of formalin-induced persistent pain in mice with an ID50 of 1 and 80 mg kg−1, respectively. In contrast, morphine (1–5 mg kg−1, s.c.) inhibited both phases of formalin-induced pain with an ID50 of 2·5 mg kg−1. Indomethacin (1–10 mg kg−1, i.p.) only inhibited the second phase of formalin-induced pain with an ID50 of about 3 mg kg−1. The analgesic effect of indomethacin, but not that caused by morphine and HE was accompanied by a graded inhibition of formalin-induced mouse paw oedema. In addition, HE up to 1 g kg−1 failed to prevent carrageenan- and dextran-induced rat hindpaw oedema. It is concluded that HE exhibits a potent antinociceptive profile, either when given intraperitoneally or orally. The mechanisms that underly its analgesic effect are unclear at present, but appear to be unrelated to inhibition of synthesis of arachidonic acid via cyclo-oxygenase or to activation of opioid receptors.
Pharmacokinetic Study of Loprinone Hydrochloride, a New Cardiotonic Agent, in Beagle Dogs
Authors: Uemura Yuji , Tanaka Shigeru , Ida Satoshi , Yuzuriha Teruaki 
Published: April 2011

Abstract
Pharmacokinetic parameters and bioavailability of a new cardiotonic agent, loprinone hydrochloride, in beagle dogs were determined by measuring plasma levels of loprinone after intravenous bolus and oral administration. The plasma half-life after intravenous administration of loprinone varied among individuals over the range 2·65–15·40 h. The bioavailability after oral administration of loprinone as a solution was 37·1%. Effects of enterohepatic circulation on the time-course of plasma levels after intravenous administration of the drug were also studied in bile-duct-cannulated beagle dogs. The amounts of loprinone and its glucuronide excreted in bile during 8 h after administration were 25·4 and 8·6% of the dose, respectively, indicating the possibility of enterohepatic circulation. The plasma half-life in bile-ductcannulated beagle dogs was 1·98 h. These results indicate that the variation in the half-life in beagle dogs resulted from enterohepatic circulation and that the true half-life is about 2 h. The relative bioavailability after oral administration of the drug as a powder in a capsule compared with a solution was 95·7%. In addition, the amounts of loprinone and its glucuronide excreted in bile, and the AUC of plasma level after infusion for 30 min into the portal vein in bile-duct-cannulated beagle dogs were similar to those after bolus intravenous administration. These results show that the low bioavailability reflects incomplete absorption.
Rolipram inhibits airway microvascular leakage induced by platelet-activating factor, histamine and bradykinin in guinea-pigs
Authors: Ortiz José L , Cortijo Julio , Vallés José M , Bou Josep , Morcillo Esteban J 
Published: April 2011

Abstract
Rolipram (0·1–1000 μg kg−1, i.v.) reduced the increase in microvascular permeability induced by platelet-activating factor (PAF; 50 ng kg−1, i.v.) at different sites of the guinea-pig airways. Rolipram (1–100μg kg−1, i.v.) inhibited histamine (30μg kg−1, i.v.)-and bradykinin (0·3 μg kg, i.v.)-induced airway microvascular leakage. These effects of rolipram were obtained at doses which inhibit histamine (7–20 μg kg−1 min−1)-induced bronchoconstriction (IC50 = 3 ± 1 μg kg, i.v.) without depressing arterial blood pressure in the guinea-pig. Aminophylline (50 mg kg−1) did not change the effect of PAF. The anti-exudative effect of rolipram is of potential therapeutic value in asthma.
Protection from reperfusion-induced arrhythmias by polyethylene glycol 600
Authors: Hoffmann P , Klapperstü M , Scholz J , Weise M , Döpfer K-P 
Published: April 2011

Abstract
The effects of polyethylene glycol (PEG) 600 on cardiovascular parameters and reperfusion-induced arrhythmias were investigated using a 5-min period of ligation of the left anterior descending coronary artery followed by reperfusion in an anaesthetized open-chest rat model. PEG 600 was effective in reducing reperfusion arrhythmias, such as ventricular fibrillation and ventricular tachycardia. Mortality was decreased from 29.4%) (5/17) in the saline-control to 0% (0/14) in the PEG-treated group (P &lt; 0.05). Biochemical investigations during the ischaemia/reperfusion period revealed that PEG infusion resulted in a reduction of cardiac lactate as well as a striking maintenance of the glutathione content of the heart.
Wide-angle X-ray Diffraction of Human Stratum Corneum: Effects of Hydration and Terpene Enhancer Treatment
Authors: Cornwell P A , Barry B W , Stoddart C P , Bouwstra J A 
Published: April 2011

Abstract
Wide-angle X-ray-diffraction experiments were used to investigate the molecular organization of barrier components of human stratum corneum. Diffraction lines related to the side-by-side lipid packing arrangements in the intercellular bilayers were identified as were patterns arising from secondary protein structures in intracellular keratin. Reflections were also identified which may be produced by proteins in the corneocyte envelopes. The effects of hydration on stratum corneum structure were monitored using 0, 20–40, 40–60, 60–80 and approximately 300% hydrated samples. The packing arrangements in the intercellular lipid bilayers remained the same over the entire hydration range, as did keratin structures. A new diffraction ring, attributable to liquid water, was produced by 300% hydrated samples with a repeat spacing of 0.35 to 0.30-0.29 nm. The effects of three terpene enhancers, (+)-limonene, nerolidol and 1,8-cineole, on stratum corneum structure were monitored. Treatment with each of the terpenes produced additional reflections which were attributed to the presence of the respective liquid enhancers within the stratum corneum. (+)-Limonene produced an additional reflection at 0.503-0.489 nm, nerolidol, an additional reflection at 0.486-0.471 nm and 1,8-cineole, an intense reflection at 0.583–0.578 nm. Reflections characteristic of gel-phase lipids and crystalline lipids also remained after all terpene treatments. These results provide no clear evidence of lipid bilayer disruption by the terpenes and suggest that areas of liquid terpene exist within the stratum corneum. The mechanisms underlying propylene glycol synergy with terpene enhancers were investigated. Treatment of stratum corneum with each terpene mixed with propylene glycol gave rise to two additional reflections. One reflection, always positioned at 0.452–0.448 nm, had been observed in control studies following propylene glycol treatment and may have been associated with bilayer structures disrupted by propylene glycol or altered keratin structures. The second reflection was developed by the respective terpene enhancer. For example, treatment with a 1,8-cineole/propylene glycol mixture produced reflections at 0.457—0.451 nm (propylene glycol-disrupted lipids or altered keratin) and 0.591—0.578 nm (liquid 1,8-cineole). Since the reflection at 0.452—0.448 nm was unaffected by co-application of propylene glycol with terpene enhancers, this study offers no evidence to support the theory that propylene glycol synergy with the terpenes occurs through enhanced lipid disruption.
Absorption Enhancement of Intrapulmonary Administered Insulin by Various Absorption Enhancers and Protease Inhibitors in Rats
Authors: Yamamoto Akira , Umemori Shinji , Muranishi Shozo 
Published: April 2011

Abstract
The effects of absorption enhancers and protease inhibitors on the pulmonary absorption of insulin were examined by means of an in-situ pulmonary absorption experiment. Absorption enhancers used in this study were sodium glycocholate, linoleic acid-surfactant mixed micelles and N-lauryl-β-d-maltopyranoside whereas aprotinin, bacitracin and soybean trypsin inhibitor were used as protease inhibitors. The absorption of insulin from the lung was evaluated by its hypoglycaemic effect. In the absence of these additives, a slight hypoglycaemic effect was obtained following intrapulmonary administration of insulin. However, we found significant and continuous hypoglycaemic effects after the insulin administration with these additives. N-Lauryl-β-d-maltopyranoside and bacitracin appeared to be more effective for enhancing the pulmonary absorption of insulin than the other adjuvants. These findings suggest that the use of these two adjuvants would be a useful approach for improving the pulmonary absorption of insulin.
Effect of Terfenadine on Substance P and Vasoactive Intestinal Polypeptide Concentrations in Nasal Secretions from Patients with Nasal Allergy
Authors: Takeyama Masaharu , Mori Kazuo , Morikawa Norifumi , Asakura Shunji , Chaen Tokuo , Watanabe Noritake , Mogi Goro 
Published: April 2011

Abstract
Before terfenadine treatment, the mean substance P and vasoactive intestinal polypeptide (VIP) concentrations in nasal secretions from nasal allergy patients tended to be higher than the values of healthy subjects. During terfenadine treatment, the mean substance P concentrations in nasal secretions from patients allergic to house dust or pollen were significantly decreased to 62 and 39% of the initial values, respectively. The mean VIP concentrations in nasal secretions from the house dust allergy patients and the pollen allergy patients were significantly decreased to 52 and 18% of the initial values, respectively. Plasma substance P and VIP concentrations were not affected by nasal allergic symptom and terfenadine treatment.
Pharmacokinetics and Cardiovascular Effects of YM-21095, a Novel Renin Inhibitor, in Dogs and Monkeys
Authors: Shibasaki Masayuki , Usui Takashi , Inagaki Osamu , Asano Masaharu , Takenaka Toichi 
Published: April 2011

Abstract
The pharmacokinetics and cardiovascular effects of YM-21095 ((2 RS), (3S)-3-[Nα-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-butyl]-l-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg−1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t½α = 4·9±0·2 min, t½β = 2·76±0·79 h, Vdss = 3·86±1·04 L kg−1, plasma clearance = 2·22 ± 0·39 L kg−1, and AUC= 1445 ± 266 ng h mL−1. After 30 mg kg−1 oral dose, maximum plasma concentration, tmax and AUC of YM-21095 were 28·8 ± 9·6 ng mL−1, 0·25 h and 23·6 ± 7·7 ng h mL−1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0·16 ± 0·04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg−1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg−1 oral dose to monkeys was 71·8 ± 41·5 ng mL−1, which was reached 0·5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively. These results suggest that oral absorption of YM-21095 is low in dogs and monkeys, and YM-21095 shows a blood pressure lowering effect by inhibiting plasma renin activity in sodium-depleted monkeys.
Sympathomimetic Actions of Methylenedioxymethamphetamine in Rat and Rabbit Isolated Cardiovascular Tissues
Authors: Fitzgerald J L , Reid J J 
Published: April 2011

Abstract
The aim of this study was to investigate the actions of methylenedioxymethamphetamine (MDMA) in several isolated cardiovascular tissues. In spontaneously beating rat atria, concentration-dependent positive chronotropic responses to MDMA and amphetamine were blocked by the neuronaluptake inhibitor desipramine (1 μm) and the β-adrenoceptor antagonist propranolol (1 μm). In atria incubated with [3H]noradrenaline to label transmitter stores, 10 μm MDMA and 1 μm amphetamine increased the resting outflow of radioactivity, while 1 μm desipramine had no effect on resting outflow. The MDMA- and amphetamine-induced release of radioactivity were blocked by 1 μm desipramine. MDMA, amphetamine and desipramine each enhanced the electrical stimulation-induced (2 Hz, 30-s train) release of radioactivity; the enhancing effects of MDMA and amphetamine were blocked by 1 μm desipramine. In rat isolated perfused hearts, MDMA (1 and 10 μm) increased heart rate by a similar amount to the increase caused by noradrenaline (10 and 50 Nm). MDMA also induced dysrhythmias in 7 out of 11 rat isolated perfused heart preparations. In rabbit isolated perfused and superfused ear arteries preloaded with [3H]noradrenaline, MDMA increased the resting release of radioactivity by 230 ± 18% (n = 6) of control resting release; the increase was accompanied by a rise in perfusion pressure of 17 ± 7 mmHg (n = 6). MDMA also facilitated the vasoconstrictor responses to noradrenaline (3–9 ng) and perivascular nerve stimulation (1–5 Hz, 10-s train). MDMA-induced vasoconstriction and the facilitation of vasoconstrictor responses to noradrenaline and electrical stimulation were blocked by 1 μm desipramine. These results suggest that MDMA has similar sympathomimetic activity to amphetamine on cardiovascular tissues. The sympathomimetic actions of MDMA could account for the cardiovascular side-effects associated with its use.
Determination of Protein Binding of a Highly Lipophilic Drug, Isocarbacyclin Methyl Ester (TEI-9090), Using a Polydimethylsiloxane-coated Glass Beads Assay
Authors: Minagawa Toshiya , Kohno Yoshiro , Suwa Toshio , Tsuji Akira 
Published: April 2011

Abstract
An adsorption technique with polydimethylsiloxane-coated glass beads (PDMS-GB) was developed to determine the protein binding of a highly lipophilic and hydrophobic drug. The present assay method is based on the quantitative adsorption of unbound drug to the PDMS-GB. This method of batch separation in a glass assay tube has an advantage of simplicity and rapidity. To evaluate the reliability of PDMS-GB assay, we compared the protein binding of diazepam in serum in-vitro measured by ultrafiltration and PDMS-GB assay. There was no significant difference between the extent of binding measured by each method. Using PDMS-GB assay, we determined the protein binding of the prostaglandin I2 (PGI2) analogue isocarbacyclin methyl ester (TEI-9090), whose binding cannot be measured by commonly employed techniques (equilibrium dialysis, ultrafiltration, gel filtration or ultracentrifugation) because of a high degree of adsorption to membranes, resins or tubes. The percentage of TEI-9090 bound in human serum, 4% human serum albumin (HSA, fatty acid-free) and dog serum were ∼98, ∼87 and ∼95%, respectively, and these values were independent of TEI-9090 concentration up to 10 ng mL−1. The binding of isocarbacyclin (TEI-7165) to serum protein in man, dogs, rabbits and rats, determined by ultrafiltration, was also high (&gt;90%). While the displacement of TEI-9090 and TEI-7165 binding to HSA by aspirin, salicylic acid and indomethacin was not observed, clofibric acid and free fatty acids significantly inhibited the protein binding of both compounds. These results indicate that the binding site of TEI-9090 and TEI-7165 on HSA could be identical with the possible binding site of PGI2.
Factors Influencing Gel-strengthening at the Mucoadhesive-mucus Interface
Authors: Mortazavi S Alireza , Smart John D 
Published: April 2011

Abstract
Mechanical spectroscopy was used to examine some of the factors that may affect mucus gel strengthening: the effect of adding various concentrations of sodium chloride; mucoadhesive polymer molecular weight and its concentration; and the introduction of anionic, cationic and neutral polymers. A reduction in the storage modulus of the mucus/mucoadhesive mixture was observed with the introduction of sodium chloride. A poly(acrylic acid) with a molecular weight of 750 kDa gave the optimum mucus gel strengthening effect relative to other molecular weights. An anionic polymer was found to strengthen the mucus gel much more than a neutral or cationic polymer. It was proposed that the gel strengthening effect could be due to the formation of hydrogen bonded intermolecular complexes between the mucoadhesive and the mucus molecules. Furthermore, the complex formed is influenced by the ionic strength of the environment, and the molecular weight, nature and concentration of the mucoadhesive. In all cases the changes in the rheological properties of the mixes could be correlated directly to the strength of mucoadhesion reported in previous studies.
Depletion of Pulmonary Glutathione Using Diethylmaleic Acid Accelerates the Development of Oxygen-induced Lung Injury in Term and Preterm Guinea-pig Neonates
Authors: Langley Simon C , Kelly Frank J 
Published: April 2011

Abstract
Dietary or chemical depletion of pulmonary glutathione in adult rats and mice, has been demonstrated to exacerbate the toxic effects of high oxygen concentrations. The present paper has examined this phenomenon in a guinea-pig model of prematurity, using the electrophilic agent diethylmaleic acid (DEM) to provide a transient (up to 12 h) pulmonary glutathione depletion. Full-term and 3-days preterm guinea-pig pups were studied to assess the possible role for glutathione deficiency as a mechanism mediating the increased susceptibility of the immature lung to oxygen free-radical damage. The administration of DEM to guinea-pig neonates depleted lung glutathione by 90% (term) or 68% (preterm) over 2 h. On exposure of pups to 95% oxygen for 48 h, DEM increased the incidence of oxygen-related death to 31 % in term pups and 100% in preterm pups. Term pups exposed to hyperoxia and treated with DEM showed evidence of pulmonary injury, indicated by an influx of neutrophils into the lung airspaces, and elevated microvascular permeability. Control pups exposed to 95% oxygen were found to have uninjured lungs after 48 h. We conclude that glutathione is an essential component of the pulmonary antioxidant array in neonates. Glutathione may be of particular importance in the early phase of oxygen exposure. The deficiency of lung glutathione observed in preterm animals may account for their increased susceptibility to oxygen-induced pulmonary injury.
N
G-Nitro-l-arginine methyl ester inhibits the effect of an H3-histaminergic receptor agonist on NANC contraction in guinea-pig perfused bronchioles
Authors: Burgaud J L , Oudart N 
Published: April 2011

Abstract
A role for nitric oxide in the H3-histaminergic agonist-induced inhibition of the non-adrenergic, non-cholinergic (NANC) contraction has been studied in guinea-pig perfused bronchioles. (R)-α-Methylhistamine ((R)-α-MeHA), an agonist for H3 receptors, inhibited the NANC contraction induced by electrical field stimulation. NG-Nitro-l-arginine methyl ester (l-NAME) (50 μm), an inhibitor of nitric oxide synthesis, blocked the effect of (R)-α-MeHA. The effect of l-NAME was reversed by l-arginine (50 μm). l-NAME, l-arginine or (R)-α-MeHA were without effect on exogenous substance P- or neurokinin A-induced contractile responses of the perfused bronchioles. These results show that an H3-agonist inhibited the release of neurotransmitters in NANC nerve endings of guinea-pig perfused bronchioles presumably by production of nitric oxide.
Pharmaceutical Evaluation of Carbamazepine Modifications: Comparative Study for Photostability of Carbamazepine Polymorphs by using Fourier-transformed Reflection-absorption Infrared Spectroscopy and Colorimetric Measurement
Authors: Matsuda Yoshihisa , Akazawa Rieko , Teraoka Reiko , Otsuka Makoto 
Published: April 2011

Abstract
The tablet surface was evaluated without physical damage by means of Fourier-transform infrared reflection-absorption spectroscopy (FT-IR-RAS) and colorimetric measurement (colour difference, AE) of the carbamazepine polymorphs I, II and III, after photodegradation at two irradiation intensities (30 and 120 J cm−2 s−1) under a near-UV fluorescent lamp. The surface of sample pellets of all crystalline forms turned gradually from white to yellow-orange upon exposure to light, and the discoloration rate of form II was faster than that of forms I and III, indicating that form II was the most unstable of the three. The major photoproducts were identified by HPLC, NMR and MS analyses. The carbamazepine content on the surface of the tablet was determined based on the absorption at 1685 cm−1 atributable to C = O stretch vibration in the FT-IR-RAS spectra before and after irradiation by a near-UV fluorescent lamp. The semilogarithmic plots of the photodegradation profiles of the various polymorphs were straight lines, including the induction period, indicating that degradation of the drug on the surface followed first-order kinetics. The induction periods of all forms were not significantly different. However, the degradation rate constant of form II at 12.0 Jcm−2 s−1 was 5·1 and 1·5 times larger than those of forms I and III, respectively.