bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stereochemical Studies of the Isomerization of Novel 2-Alkyl-9-phenyl-2,3,4,4a- and 2,3,4,9-tetrahy dro-1H-indeno [2,1 -c]pyridines
Authors: Upton Christopher , Jaffar Mohammed 
Published: April 2011

Abstract
The published synthetic route to the antihistaminic tetrahydroindeno[2,1-c]pyridines (phenindamines) relies on catalytic reduction of the precursor dihydroindenopyridines. This reduction gives mixtures of 9,9a- and 4a,9a-enes and the clinically active 4a,9a isomer has to be isolated by recrystallization of an appropriate salt. The structure of the product recovered depends on the anion used to isolate the proton salt and appears to be arbitrary.
To rationalize this outcome a series of novel N-2 alkylated tetrahydroindeno[2,1-c]pyridines and their diene precursors has been synthesized from accessible piperidines. The structures and geometry of the piperidines and the dihydro- and tetrahydroindenopyridines have been determined by 1H and 13C NMR. An unusual feature of the proton spectra of the piperidines is the resonance of the axial protons at lower field than their equatorial counterparts. By controlling the reaction conditions for the reduction of the dihydroindenopyridines to their tetrahydro derivatives the kinetic or thermodynamic product can be selected as required.
A predictable outcome for the reductions investigated was achieved and is generally applicable.
Enterohepatic Cycling and Pharmacokinetics of Oestradiol in Postmenopausal Women
Authors: Vree Tom B , Timmer Cees J 
Published: April 2011

Abstract
The pharmacokinetics and enterohepatic cycling of oestradiol have been studied after three oral, single-dose administrations of equimolar doses of oestradiol alone, oestradiol plus desogestrel and oestradiol valerate, in a 3-way cross-over mode in 18 healthy postmenopausal women.
Oestradiol was readily absorbed and metabolized to oestrone, which reached much higher serum concentrations (140pgmL−1) than its parent compound (35pgmL−1). All three formulations had the same kinetic profile and were bioequivalent on testing. Noticeable first and second absorption phases were apparent from the oestradiol and oestrone serum concentration-time curves for all oestradiol formulations. The mean serum concentration-time curves of the metabolite oestrone (corrected for endogenous oestrone) showed a second maximum at approximately 25 h. By means of line feathering, serum concentration-time curves were constructed which belonged to the first, second and third phases of absorption. The maximum serum concentration, Cmax, of the second absorption or recirculation of oestrone was 20% that of the first, and the Cmax of the third circulation was 50% that of the second. The areas under the serum-concentration-time curves (AUC) for the second and third recirculations were similar—each comprised 12–13% of the total AUC. The oral clearance values of the recirculations were constant (590Lh−1).
Enterohepatic recirculation of endogenous compounds is aimed at maintaining a steady-state serum concentration for immediate use and hydrolysis in the target organs. It is concluded that exogenously added oestradiol and its metabolites follow the recirculation pathways of the endogenous oestrogen pool.
Relative Dispersions of Intra-albumin Transit Times across Rat and Elasmobranch Perfused Livers, and Implications for Intra- and Inter-species Scaling of Hepatic Clearance using Microsomal Data
Authors: Roberts Michael S , Ballinger Linsay N , Weiss Michael 
Published: April 2011

Abstract
It is recognized that vascular dispersion in the liver is a determinant of high first-pass extraction of solutes by that organ. Such dispersion is also required for translation of in-vitro microsomal activity into in-vivo predictions of hepatic extraction for any solute. We therefore investigated the relative dispersion of albumin transit times (CV2) in the livers of adult and weanling rats and in elasmobranch livers.
The mean and normalized variance of the hepatic transit time distribution of albumin was estimated using parametric non-linear regression (with a correction for catheter influence) after an impulse (bolus) input of labelled albumin into a single-pass liver perfusion. The mean±s.e. of CV2 for albumin determined in each of the liver groups were 0·85 ± 0·20 (n = 12), 1·48 ± 0·33 (n = 7) and 0·90 ± 0·18 (n = 4) for the livers of adult and weanling rats and elasmobranch livers, respectively.
These CV2 are comparable with that reported previously for the dog and suggest that the CV2 of the liver is of a similar order of magnitude irrespective of the age and morphological development of the species. It might, therefore, be justified, in the absence of other information, to predict the hepatic clearances and availabilities of highly extracted solutes by scaling within and between species livers using hepatic elimination models such as the dispersion model with a CV2 of approximately unity.
Time-dependent Effects of Klebsiella pneumoniae Endotoxin on Hepatic Drug-metabolizing Enzyme Activity in Rats
Authors: Nadai Masayuki , Sekido Tohru , Matsuda Izumi , Li Wang , Kitaichi Kiyoyuki , Itoh Akio , Nabeshima Toshitaka , Hasegawa Takaaki 
Published: April 2011

Abstract
The time-dependent effects of Klebsiella pneumoniae endotoxin on hepatic cytochrome P450-dependent drug-metabolizing capacity (cytochrome P450 and b5 content, activity of aminopyrine N-demethylase, p-nitroanisole O-demethylase, aniline hydroxylase and benzphetamine N-demethylase) and on the pharmacokinetics of antipyrine have been determined in rats. Measurement of enzyme activity and antipyrine (after intravenous injection of 20 mgkg−1) were performed 2, 24 and 96 h after a single intraperitoneal injection of endotoxin (1 mgkg−1) and after repeated doses (once daily for 4 days). The contribution of tumour necrosis factor α (TNFα) to the endotoxin-induced changes was also examined in rats pretreated with granulocyte colony-stimulating factor (G-CSF).
The systemic clearance of antipyrine and the activity of hepatic cytochrome P450-dependent drug-metabolizing enzymes were dramatically reduced 24 h after a single injection of endotoxin, but had returned to control levels by 96 h. The magnitudes of these decreases in these measurements after repeated doses of endotoxin were similar to those seen 24 h after the single dose. The systemic clearance of antipyrine correlated significantly with cytochrome P450 content and aminopyrine N-demethylase activity. In histopathological experiments, moderate hypertrophy of Kupffer cells was observed, with no evidence of severe liver-tissue damage. G-CSF pretreatment suppressed the increased plasma concentrations of TNFα produced 2 h after single endotoxin injection, but did not eliminate the endotoxin-induced decrease in the systemic clearance of antipyrine, suggesting that TNFα is not the sole component responsible for the reduction of cytochrome P450-mediated drug-metabolizing enzyme activity.
These results provide evidence that a single intraperitoneal injection of 1·0 mgkg−1 K. pneumoniae endotoxin in rats reduces hepatic P450 and b5 levels, and reduces the activity of various cytochrome P450-mediated drug-metabolizing enzymes without causing severe liver-tissue damage. This suggests that the effect of endotoxin on hepatic cytochrome P450-mediated drug-metabolizing isozymes is non-selective.
Endothelium-dependent Relaxation in Response to Ethanol Porcine Isolated Pulmonary Artery
Authors: Lawrence Rebecca N , Dunn William R , Wilson Vince G 
Published: April 2011

Abstract
Many drugs cannot be dissolved in distilled water and so other solvents such as ethanol, dimethylsulphoxide and methanol are used. Because very little is known about the direct effects of these three solvents on the cardiovascular system, we have examined their effects on isolated pulmonary and coronary arteries from the pig.
Increasing concentrations of ethanol, dimethylsulphoxide and methanol induced relaxation in porcine pulmonary (at 1·2% v/v, 59·9±9·0% (n = 9), 55·9±9·0% (n = 6) and 12·3±6·4% (n = 8), respectively, of U46619-induced tone) and coronary arteries (at 1·2% v/v, 69·9±7·1% (n = 10), 78·9±6·1% (n = 7) and 12·9±8·2% (n = 6) respectively, of U46619-induced tone). In the pulmonary arteries the relaxation in response to ethanol was found to be endothelium-dependent whereas the responses to dimethylsulphoxide and methanol were unaffected by removal of the endothelium. In the coronary arteries the relaxation to all three solvents was independent of the presence of the endothelium. Comparison of the sensitivity of the tissues to the solvents showed that ethanol and dimethylsulphoxide produced comparative responses in both the pulmonary and coronary arteries, whereas methanol was much less potent. The endothelium-dependent response to ethanol in the porcine pulmonary artery (maximum response, Emax, 67·1±9·3% of U46619-induced tone, n = 7) was attenuated by the cyclooxygenase inhibitor, flurbiprofen (Emax 31·9±12·0%, n = 7), the nitric oxide synthase inhibitor, L-NAME (NG-nitro-L-arginine methyl ester; Emax 23·5±10·2%, n = 7)) and the combination of both inhibitors (Emax 18·3±7·8%, n = 7). The residual relaxatory response to ethanol was abolished, and converted into a contractile response, both by removal of the endothelium (at 1·7% v/v ethanol 27·3±11·5% of U46619-induced tone, n = 7) and by the addition of a low concentration of KCl (49·9±10·3%, n = 6), suggesting the release of a non-prostanoid, non-nitric oxide factor from the endothelium. This response, however, was not attenuated by the cannabinoid receptor-antagonist SR141716A (N-(piperidin-1-yl)-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl; 52·5±4·3% relaxation, n = 8), suggesting that the factor released in this preparation by ethanol is not a cannabinoid.
The results of this study indicate that many solvents commonly used in pharmacological experiments have pronounced vasoactive properties. Methanol might be the vehicle of choice, because it was the least active solvent, whereas high concentrations of ethanol might influence vascular function at both the level of the smooth muscle and the endothelium, with the action on the endothelium involving the release of endothelium-derived relaxing factors.
Influence of Trimebutine on Inflammation- and Stress-induced Hyperalgesia to Rectal Distension in Rats
Authors: Lacheze C , Coelho A-M , Fioramonti J , Buéno L 
Published: April 2011

Abstract
The effects of trimebutine and its major metabolite, N-desmethyltrimebutine on inflammation- and stress-induced rectal hyperalgesia have been evaluated in rats fitted with electrodes implanted in the longitudinal striated muscle of the abdomen.
Intermittent rectal distension was performed before and 3 days after induction of rectal inflammation by local infusion of trinitrobenzenesulphonic acid (in ethanol). Stress consisted of 2 h partial restraint and rectal distension was performed before and 30min after the end of the partial restraint session. The animals were treated intraperitoneally with trimebutine or desmethyltrimebutine (5, 10 or 20mgkg−1) or vehicle 15min before rectal distension. Naloxone (1mgkg−1) or saline was injected subcutaneously before trimebutine and desmethyltrimebutine. Before treatment trimebutine at the highest dose (20 mgkg−1) reduced the abdominal response to rectal distension for the highest volume of distension (1·6mL) whereas desmethyltrimebutine was inactive. After rectocolitis the abdominal response to rectal distension was enhanced and trimebutine at 5mgkg−1 reduced and at 10mgkg−1 suppressed inflammation-induced hyperalgesia, an effect reversed by naloxone. Desmethyltrimebutine was inactive. Stress-induced hypersensitivity was attenuated or suppressed, or both, by trimebutine and desmethyltrimebutine at doses of 5, 10 or 20mgkg−1; greater efficacy was observed for desmethyltrimebutine and the effects were not reversed by naloxone.
It was concluded that trimebutine and desmethyltrimebutine are active against inflammation- and stress-induced rectal hyperalgesia but act differently. The effect of trimebutine on inflammation-induced hyperalgesia is mediated through opioid receptors.
Influence of Twinline, an Elemental Diet, on the Generation of Nitric Oxide and Reactive-oxygen Intermediates from Mouse Peritoneal Macrophages and Polymorphonuclear Leukocytes
Authors: Ueta Eisaku , Yoneda Kazunori , Yamamoto Tetsuya , Osaki Tokio 
Published: April 2011

Abstract
The influence of Twinline (SNN-6010), an elemental diet containing medium-chain triglycerides, on the generation of nitric oxide (NO) and superoxide (O2−) has been examined in mouse peritoneal macrophages and polymorphonuclear leukocytes (PMN).
When PMN and peritoneal macrophages obtained from untreated mice were cultured in medium containing 0·1% and 1% (v/v) Twinline for 48h and stimulated with phorbol myristate acetate or N-formyl-methionyl-leucyl-phenylalanine, their chemiluminescence and O2− generation were strongly suppressed, as was NO generation from peritoneal macrophages. PMN and peritoneal macrophages obtained from mice fed Twinline for 30 days generated much smaller amounts of O2− and NO compared with PMN and peritoneal macrophages from control mice. In conjunction with this suppressed NO generation, inducible NO synthase and its mRNA expression in peritoneal macrophages were suppressed by Twinline both in-vivo and ex-vivo. Although phagocytosis of PMN and peritoneal macrophages was not suppressed by Twinline; their candida-killing activity was markedly suppressed.
These results indicate that Twinline suppresses the host-defence function of PMN and peritoneal macrophages by down-regulating their generation of reactive-oxygen intermediates and NO.
Aqueous Stability of SB 210661: Kinetics and Primary Degradation Mechanisms of an N-Hydroxyurea-containing 5-Lipoxygenase Inhibitor
Authors: McLoughlin Martin , Kearney Albert S , Palepu Nagesh R 
Published: April 2011

Abstract
SB 210661, (S)-N-hydroxy-N-[2,3-dihydro-6-(2,6-difluorophenylmethoxy)-3-benzofuranyl]urea, is a potent and selective inhibitor of 5-lipoxygenase. Its aqueous stability was primarily evaluated to support development of analytical methods and formulations. The results also add to the growing database on the stability of N-hydroxyurea compounds.
Comparison of the stability of SB 210661 with that of two other N-hydroxyurea-containing compounds, zileuton and Abbott-79175, supported a common primary degradative pathway at pH &gt; 5 and different degradative pathways at pH &lt; 5. The pathway at pH &gt; 5 is consistent with the hydrolysis of the N-hydroxyurea group, whereas for SB 210661, the pathway at pH &lt; 5 is consistent with specific acid-catalysed nucleophilic displacement of the N-hydroxyurea group by water.
Intestinal Absorption of Stable Cyclic Dipeptides by the Oligopeptide Transporter in Rat
Authors: Mizuma Takashi , Masubuchi Satoshi , Awazu Shoji 
Published: April 2011

Abstract
Intestinal absorption of four cyclic dipeptides was studied in the everted small intestine of the rat.
Cyclic seryltyrosine (cyclo(Ser-Tyr)) was stable enough to be transported whereas linear seryltyrosine was not. The absorption clearance of cyclo(Ser-Tyr) was concentration-dependent, and for cyclo(Ser-Tyr) at 125 μM decreased in the presence of glycylsarcosine (10 mM) or cephalexin (10 mM), which were reported to be absorbed by oligopeptide transporter. The absorption clearance was also reduced at 4°C and in the presence of 1 mM dinitrophenol. Kinetic analysis of cyclo(Ser-Tyr) absorption showed that Km and Vmax were 19.8 μM and 0.295 nmol min−1 cm−1, respectively. It was also suggested that cyclic aspartylphenylalanine and cyclic histidylphenylalanine were absorbed by oligopeptide transporters, but cyclic histidylproline was not. The absorption clearance of cyclo(Ser-Tyr) in the control was much higher than the value of the correlation line representing a plot of passive transport (which was obtained from the absorption clearance of cyclic peptides in the presence of glycylsarcosine (10 mM)) against hydrophobicity (oil-water partition coefficient).
These results indicate that cyclo(Ser-Tyr) is absorbed by the oligopeptide transporter.
Effect of Sequence of Administration on the Pharmacokinetic In,t. eraction between the Anticholinergic n Drug Biperiden and ['H]Quinuclidinyl Benzylate or [5H]N-Methylscopolamine in Rats
Authors: Ishizaki Junko , Yokogawa Koichi , Nakashima Emi , Takayasu Tatsunori , Ohshima Tohru , Ichimura Fujio 
Published: April 2011

Abstract
In rats the pharmacokinetic interactions between the anticholinergic drug biperiden and [3H]quinuclidinyl benzylate ([3H]QNB) or [3H]N-methylscopolamine ([3H]NMS) is affected by the sequence in which the drugs are administered.
Drug concentrations in various tissues were determined after intravenous administration of [3H]QNB or [3H]NMS (325 ng kg−1). Biperiden (6.4 mg kg−1) was administered either 5 min before, concomitantly with or 20 min after injection of [3H]QNB or [3H]NMS. When biperiden was administered concomitantly with or before [3H]QNB, distribution of [3H]QNB among the regions of the brain and other tissues was reduced; at 4 h the ratio of the distribution of [3H]QNB for experimental animals to that for control animals ranged from 0.15 to 0.9. When biperiden was administered after [3H]QNB, the distribution of [3H]QNB in the brain and other tissues was significantly higher than for the other two treatments (P &lt; 0.01). However, for [3H]NMS the sequence of administration had no effect on the distribution of the drug in the brain and other tissues except for the kidney. In-vitro, in crude synaptosomal membranes, the amount of [3H]QNB at 2 h relative to the control concentration at equilibrium was 87% when biperiden was added before [3H]QNB and 56% when biperiden was added after [3H]QNB. In both instances the concentration of [3H]NMS reached equilibrium within 30 min.
These findings suggest that the difference between the rate constant of association and dissociation at the possible site of action gives rise to the effect of the sequence of administration on the pharmacokinetic interaction.
Sodium Nitroprusside Enhances Contractions of the Guinea-pig Isolated Vas Deferens
Authors: Ventura Sabatino , Hoyle Charles H V , Burnstock Geoffrey 
Published: April 2011

Abstract
The effects of sodium nitroprusside on the electrical and mechanical properties of the smooth muscle of the guinea-pig vas deferens, and its responses to transmitter substances, have been investigated by use of the sucrose-gap technique.
Isolated longitudinal segments of guinea-pig vas deferens contracted in response to electrical field stimulation (100 V, 0.04–0.1 ms, 1–5 Hz, 10 s train every 60 s) and application of ATP (1 mM) or noradrenaline (10 μM). Sodium nitroprusside (0.1 mM) did not affect resting tension but did enhance contractions evoked by electric-field stimulation but not by ATP or noradrenaline. The sodium nitroprusside-induced enhancement was unaffected by the nitric oxide synthase inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME) (0.1 mM). Conversely, electrically evoked contractions were unaffected by the nitric oxide precursor L-arginine (1 mM) or the nitric oxide donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) (0.1 mM). The amplitudes of electrically evoked excitatory junction potentials (EJPs) were not affected by application of sodium nitroprusside, although it caused a small depolarization of 0.7 ± 0.3 mV. Similarly, the depolarization caused by exogenous application of ATP or noradrenaline was unaffected by the presence of sodium nitroprusside. L-NAME, L-arginine and SNAP did not affect EJP amplitude or baseline membrane potential.
It is concluded that sodium nitroprusside enhances electrically evoked contractions of the guinea-pig vas deferens by reducing the threshold voltage for action potential firing in smooth-muscle cells.
Affinity Constants and β-Adrenoceptor Reserves for Isoprenaline on Cardiac Tissue from Normotensive and Hypzrtensive Rats
Authors: Doggrell Sheila A , Petcu Eugen B , Barnett Carolyn W 
Published: April 2011

Abstract
To determine whether there are differences in cardiac β-adrenoceptor responsiveness, isoprenaline affinity constants and fractional β-adrenoceptor occupancy—response relationships for isoprenaline in the early stages of established hypertension, we studied the effects of bromoacetylalprenololmenthane (BAAM) and ([3,5-diamino-6-chloro-N-(1[N-β-(2-hydroxyl-3-α-naphthoxypropylamino)ethylcarbamoyl]-1-methylethyl)-pyrazine-2-carboxamide (ICI 147 798), slowly reversible β-adrenoceptor antagonists, on the isoprenaline responses of the left ventricular papillary muscle and the left and right atria of 6-month-old Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR).
The papillary muscles, but not the right and left atria, of the SHR were less responsive to isoprenaline than those of the WKY. The isoprenaline pD2 values (the negative logarithms of the molar concentrations of agonist producing 50% of the maximum response) were 7.72 and 8.00 on the SHR and WKY papillary muscles, respectively. On the WKY papillary muscle the isoprenaline KA values were 2–3 times 10−6M, which is as expected for isoprenaline at β1 or β2-adrenoceptors. Isoprenaline had 100-fold greater affinity on the WKY and SHR left atria than on the papillary muscles; the isoprenaline KA values were 2–4 times 10−8M. On the WKY papillary muscle and left atrium, isoprenaline had to occupy 3–4% of the β-adrenoceptors to produce a 50% maximum response; on the WKY papillary muscle and left atrium isoprenaline had to occupy 25–35% and 55%, respectively, of the β-adrenoceptors to produce a 90% maximum response.
The SHR papillary muscles and left atrium had smaller β-adrenoceptor reserves for isoprenaline than did the WKY tissues. We were unable to obtain isoprenaline KA values on the WKY right atrium. The isoprenaline KA value on the SHR right atrium was 1–4 times 10−8M.
Because the isoprenaline KA values for the left and right atria are markedly different from those previously reported for isoprenaline at β1 or β2-adrenoceptors, we suggest that atypical β-adrenoceptors might be present on the atria of WKY and SHR. We have also demonstrated a lower β-adrenoceptor reserve on SHR papillary muscle and atria in the early stages of established hypertension.
A Study of the Anti-pyretic Effect of Quinine, an Alkaloid Effective Against Cerebral Malaria, on Fever Induced by Bacterial Endotoxin and Yeast in Rats
Authors: Santos F A , Rao V S N 
Published: April 2011

Abstract
The effect of quinine on fever induced by lipopolysaccharide and brewer’s yeast has been investigated in rats.
Oral administration of 50 or 100 mg kg−1 quinine, doses which had no effect on normothermic rats, significantly reduced lipopolysaccharide- (50 μg kg−1, i.m.) and yeast- (2 g kg−1) induced fever in rats. Pentoxifylline (100 mg kg−1), a tumour necrosis factor antagonist also attenuated the febrile response induced by lipopolysaccharide, but not that by yeast, in a manner similar to quinine. Piroxicam (5 mg kg−1), a cyclooxygenase inhibitor suppressed both types of fever with a longer duration of action. In addition to its anti-pyretic effect, quinine had a significant anti-inflammatory effect in the carrageenan model of acute inflammation in the hind-paw of rats.
The results indicate the anti-inflammatory and anti-pyretic potential of quinine which might be important in addition to its anti-plasmodial action in the therapy of cerebral malaria.