bluuebunny/crossref_metadata_2025 huggingface dataset:
Scutellaria baicalensis inhibits liver fibrosis induced by bile duct ligation or carbon tetrachloride in rats
Authors: Nan Ji-Xing , Park Eun-Jeon , Kim Yoon-Chul , Ko Geonil , Sohn Dong Hwan
Published: October 2002

This study was carried out to investigate the antifibrotic effects of methanol extracts from the traditional Chinese medicinal herb, the root of Scutellaria baicalensis Georgi, on liver fibrosis induced by bile duct ligation and scission (BDL) or carbon tetrachloride (CCl4) in rats. Liver fibrosis was assessed by histological observations and by measuring levels of liver hydroxy-proline, lipid peroxidation based on malondialdehyde (MDA) production, and serum enzyme activities. The morphological characteristics of liver tissue were examined by Masson's trichrome staining and immunostaining against smooth muscle cell α-actin. In both models, the levels of hydroxyproline and MDA in liver were significantly increased. Treatment with a methanol extract of S. baicalensis significantly reduced the levels of liver hydroxyproline and MDA, with improved histological findings. In both models, the liver areas positive for smooth muscle cell α-actin were considerably decreased by treatment with oral methanol extract of S. baicalensis (150 mg kg−1 daily for 28 days). A methanol extract of S. baicalensis root inhibits fibrosis and lipid peroxidation in rat liver induced by BDL or CCl4.
The output of flunisolide from different nebulisers
Authors: O'Callaghan Chris , White Judy , Jackson Judith , Barry Peter , Kantar Ahmad
Published: October 2002

The objective of this study was to determine the output, in-vitro, solution of a concentrated solution of flunisolide from two different nebulisers under simulated breathing conditions. The BimboNeb and Nebula nebulisers were used to nebulise 2.6 mL of flunisolide solution (600 μg). Particle size was determined by inertial impaction and the total output of drug from the nebulisers under simulated breathing conditions was measured using a sinus flow pump. Two different breathing patterns were used, simulating nebuliser use by a child and an adult. The mass median aerodynamic diameter of flunisolide particles from the BimboNeb and Nebula were both 3.9 μm. With the simulated paediatric breathing pattern, both nebulisers delivered similar amounts of flunisolide (56.4 μg (s.d. 1.4μg) and 56.1 μg (5 μg) over 5 min from the BimboNeb and Nebula, respectively). With the adult breathing pattern, flunisolide delivery from the BimboNeb was increased to 88.9 μg (3.3 μg), but delivery from the Nebula was only slightly increased to 64.6 μg (1.4 μg). With both nebulisers, little drug was released after 5 min of nebulisation. Both nebulisers delivered 9–15 % of the nominal dose of flunisolide to the breathing simulator, a similar percentage to previous studies with budesonide and more than previous studies with beclometasone. Drug delivery from the BimboNeb, but not the Nebula, was affected by the simulated breathing pattern. This study suggests that drug delivery from nebulisers is dependent upon the interaction between the nebuliser, the drug and the patient.
In-vitro release and oral bioactivity of insulin in diabetic rats using nanocapsules dispersed in biocompatible microemulsion
Authors: Watnasirichaikul Suchat , Rades Thomas , Tucker Ian G , Davies Nigel M
Published: October 2002

This study evaluated the potential of poly(iso-butyl cyanoacrylate) (PBCA) nanocapsules dispersed in a biocompatible microemulsion to facilitate the absorption of insulin following intragastric administration to diabetic rats. Insulin-loaded PBCA nanocapsules were prepared in-situ in a biocompatible water-in-oil microemulsion by interfacial polymerisation. The microemulsion consisted of a mixture of medium-chain mono-, di- and tri-glycerides as the oil component, polysorbate 80 and sorbitan mono-oleate as surfactants and an aqueous solution of insulin. Resulting nanocapsules were approximately 200 nm in diameter and demonstrated a high efficiency of insulin entrapment (> 80%). In-vitro release studies showed that PBCA nanocapsules could suppress insulin release in acidic media and that release at near neutral conditions could be manipulated by varying the amount of monomer used for polymerisation. Subcutaneous administration of insulin-loaded nanocapsules to diabetic rats demonstrated that the bioactivity of insulin was largely retained following this method of preparing peptide-loaded nanocapsules and that the pharmacodynamic response was dependent on the amount of monomer used for polymerisation. The intragastric administration of insulin-loaded nanocapsules dispersed in the biocompatible microemulsion resulted in a significantly greater reduction in blood glucose levels of diabetic rats than an aqueous insulin solution or insulin formulated in the same microemulsion. This study demonstrates that the formulation of peptides within PBCA nanocapsules that are administered dispersed in a microemulsion can facilitate the oral absorption of encapsulated peptide. Such a system can be prepared in-situ by the interfacial polymerisation of a water-in-oil biocompatible microemulsion.
Calorimetric studies of diclofenac sodium in aqueous solution of cyclodextrin and water-ethanol mixtures
Authors: Chadha R , Kashid N , Kumar A , Jain D V S
Published: October 2002

The technique of solution calorimetry has been employed to study the interaction between diclofenac sodium and β-cyclodextrin by determining the enthalpies of solution of the drug in water and in aqueous β-cyclodextrin solution. Thermodynamic parameters characterizing the binding process such as enthalpy ΔH0, equilibrium constant k, free energy ΔG0 and entropy ΔS0 have been calculated to be −12.00 kJ mol−1, 1670 dm3 mol−1, −19.03 kJ mol−1 and 22.98 J k−1 mol−1, respectively. Enthalpies of solution of diclofenac sodium have also been determined in water-ethanol mixtures.
The influence of caprate on rectal absorption of phenoxymethylpenicillin: experience from an in-vivo perfusion in humans
Authors: Lennernäs H , Gjellan K , Hällgren R , Graffner C
Published: October 2002

The aim of this in-vivo perfusion study in humans was to investigate the influence of a penetration enhancer, sodium caprate, on the rectal absorption of phenoxymethylpenicillin and antipyrine. Six subjects, 3 male and 3 female, were included in two separate studies using perfusion solution of different pH (T1 and T2, respectively). Each in-vivo rectal perfusion investigation lasted for 200 min and consisted of two periods of 100 min, the first serving as a control, and sodium caprate being added in the second period in both T1 and T2. The concentrations of phenoxymethylpenicillin, antipyrine and sodium caprate in the outlet perfusate were assayed by HPLC, as was the plasma concentrations of phenoxymethylpenicillin. At pH 6.0 (0–100 min) the fraction absorbed (fabs) and effective permeability (Peff) of phenoxymethylpenicillin were 0.3% and 0.06 × 10−4cms−1, respectively, and remained unaffected by the addition of sodium caprate. When the same subjects were perfused at pH 7.4, the fabs and Peff of phenoxymethylpenicillin were 2.4% and 0.11 times 10−4cms−1 (0–100 min), respectively, also remaining unchanged by addition of sodium caprate (100–200 min). It was possible to determine the plasma AUC of phenoxymethylpenicillin after addition of sodium caprate in three subjects at both pHs; this was in the range of 14.0–62.8 and 56.4–231 (min μ mol L−1) at pH 6.0 and 7.4, respectively. Interestingly, there was a correlation between Peff for sodium caprate and the individual plasma AUC and Cmax of phenoxymethylpenicillin, which indicates that the permeability of the enhancer in the tissue upon which it should act is crucial for achieving an effect. The fabs and the Peff of antipyrine were not affected at either pH when sodium caprate was added to the perfusion solution. In conclusion, the plasma pharmacokinetics of phenoxymethylpenicillin suggested a slightly increased rectal absorption at pH 7.4 in subjects where sodium caprate was transported into the rectal tissue. However, the increased Peff for phenoxymethylpenicillin was too small to detect from the outlet perfusate, which suggests that sodium caprate alone has a limited effect on the permeability in-vivo across the rectal epithelium when it is presented in a solution.
Effect of unilateral nephrectomy on the pharmacokinetics of amikacin in humans
Authors: Drozdzik M , Domanski L , Wojcicki J , Gawronska-Szklarz B , Machoy P , Pudlo A
Published: October 2002

As unilateral nephrectomy is not a rare surgical procedure, it gives rise to the question whether drugs predominantly eliminated through the urinary tract can be handled effectively by the remaining kidney. Amikacin is predominantly excreted via glomerular filtration with only a small fraction undergoing tubular reabsorption, and can be used as a model drug of glomerular elimination. The study was carried out in 28 subjects, 10 one month and 10 one year after unilateral nephrectomy, as well as in 8 healthy subjects. The pharmacokinetics of amikacin was investigated after a 1-h infusion of 5 mg kg−1 amikacin. Blood samples were collected for 24 h after the end of infusion. Pharmacokinetic parameters of amikacin were calculated using a one-compartment open model for intravenous administration. Amikacin concentrations were significantly elevated in nephrectomized patients as compared with control subjects, both 1 month and 1 year after the surgery, and were similar at these two time-points following unilateral nephrectomy. Pharmacokinetic parameters of amikacin in patients subjected to unilateral nephrectomy were significantly different from those observed in the control subjects. As compared with the controls, an increase in AUC (area under the serum concentration-time curve) by 81 % (P < 0.001) and 63% (P < 0.01) 1 month and 1 year after nephrectomy was observed, respectively. The Λz (elimination rate constant) was reduced by 39 % (P < 0.001) after 1 month and by 38% (P < 0.001) 1 year after the operation and t1/2 was prolonged by 70% (P < 0.001) and by 43% (P < 0.01) at the respective time-points following unilateral nephrectomy. CLT (total body clearance of the drug from plasma) and CLBW (clearance per kg body weight) were both significantly decreased in unilaterally nephrectomized subjects in comparison with the controls. CLT and CLBW were reduced by 53% (P < 0.001) and 42% (P < 0.01) 1 month after nephrectomy, and by 45% (P < 0.001) and 42% (P < 0.01) 1 year after the surgery, respectively. No significant differences among studied groups were found in C0 (initial serum drug concentration) and Vd (apparent volume of distribution). The results suggest that unilateral nephrectomy impairs elimination of amikacin, and possibly other drugs predominantly eliminated via glomerular filtration.
Responsiveness, affinity constants and β-adrenoceptor reserves for isoprenaline on aortae from normo-, pre-and hypertensive rats
Authors: Chen Ying-Yu , Doggrell Sheila A
Published: October 2002

The objective of this study was to determine the responsiveness, affinity constants and β-adrenoceptor reserves for isoprenaline on the isolated aorta in the maturation of normotensive and hypertensive rats. The effects of a very slowly reversible antagonist, bromoacetylalprenololmenthane (BAAM), on the relaxant responses of the aortae of 5- and 14-week-old Wistar kyoto normotensive rats (WkY) and spontaneously hypertensive rats (SHRs) to isoprenaline were determined. Five-week-old SHRs are pre-hypertensive and the aortic rings are less responsive to isoprenaline than age-matched WkY (pD2 values: WkY, 8.40; SHRs, 8.03). Similar relaxant responses to forskolin were obtained on the aortae of 5- and 14-week-old WkY and SHRs. The kA value for isoprenaline at the aortic β2-adrenoceptors of the 5-week-old WkY was 2.1 times 10−7 M, and similar values were obtained on the aortae of 5-week-old SHR and 14-week-old WkY and SHRs. In the maturation of the WkY aortae from 5 to 14 weeks, there was a reduction in the maximum response, a major loss of sensitivity and a loss of β2-adrenoceptor reserve for isoprenaline. On 5-week-old SHR aorta, the sensitivity to isoprenaline was 2.5-fold lower, and the β2-adrenoceptor reserve was less than on age-matched WkY. In the development of hypertension on the SHR aorta from 5 to 14 weeks, there was a reduction in the maximum response to isoprenaline. At 14 weeks, the sensitivity and the β2-adrenoceptor reserve to isoprenaline were similar, but the maximum responses were lower on the SHR than WkY. As there are differences in pre-hypertensive SHR and age-matched WkY aortic responses to isoprenaline, it is no longer valid to consider that the loss of responsiveness to isoprenaline in hypertension is solely owing to the hypertension. There are no changes in affinity, but major changes in the sensitivity, maximum responses and aortic β2-adrenoceptor reserves to isoprenaline in the maturation of normotensive and pre-hypertensive aortae.
Cytotoxicity issues pertinent to lipoplex-mediated gene therapy in-vivo
Authors: Dass Crispin R
Published: October 2002

Cationic liposomes bind with nucleic acids such as plasmids and oligodeoxynucleotides to form complexes known as lipoplexes. Although these lipoplexes have several advantages over other forms of nucleic acid transfer methods in cell culture and in-vivo, toxicity remains a problem, especially in-vivo. Nevertheless, these carriers have been used in clinical trials against cystic fibrosis and cancer and their usage is attributed mainly to their versatility, especially when it comes to the range of routes available for administration of nucleic-acid-based drugs in-vivo.
Stimulatory effect of paeoniflorin on the release of noradrenaline from ileal synaptosomes of guinea-pig in-vitro
Authors: Liu T P , Liu I M , Tsai C C , Lai T Y , Hsu F L , Cheng J T
Published: October 2002

The effect of paeoniflorin (an active principle of Paeoniae Radix, commonly used in traditional Chinese medicine) on the release of noradrenaline (norepineprhine) from nerve terminals was investigated using guinea-pig isolated ileal synaptosomes. Release was determined as the amount of noradrenaline, quantified by high-performance liquid chromatography-electrochemical detection, from samples incubated with paeoniflorin or vehicle. Paeoniflorin stimulated the release of noradrenaline in a concentration-dependent manner without an effect on the level of lactate dehydrogenase in the bathing medium. Tetrodotoxin abolished the action of paeoniflorin at concentrations sufficient to block sodium channels. The depolarizing effect of paeoniflorin on the membrane potential was also illustrated by a concentration-dependent increase in the fluorescence of bisoxonol. Moreover, the effect of paeoniflorin on bisoxonol fluorescence in ileal synaptosomes seems more potent than that of 4-aminopyridine. That paeoniflorin causes influx of calcium ions via the depolarization of nerve terminals could be considered. The noradrenaline-releasing action of paeoniflorin was abolished by removal of calcium chloride from the bathing medium. This action of paeoniflorin was also attenuated by Rp-cAMP at concentrations sufficient to inhibit the action of cyclic AMP. Therefore, paeoniflorin could induce a calcium-dependent and cyclic-AMP-related release of noradrenaline from sympathetic nerve terminals of guinea-pig ileum. Guanethidine inhibited the noradrenaline-releasing action of paeoniflorin in a concentration-dependent manner. The effect of paeoniflorin on the increase of bisoxonol fluorescence was not modified by atropine. Release of noradrenaline by paeoniflorin from noradrenergic nerve terminals was characterized. These findings suggest that paeoniflorin can stimulate tetrodotoxin-sensitive depolarization of membranes to result in a calcium-dependent and cyclic-AMP-related release of noradrenaline from noradrenergic nerve terminals.
Distribution of domperidone into the rat brain is increased by brain ischaemia or treatment with the P-glycoprotein inhibitor verapamil
Authors: Dan Yukihiko , Murakami Hideyasu , Koyabu Noriko , Ohtani Hisakazu , Sawada Yasufumi
Published: October 2002

Domperidone (DOM), a peripheral dopamine D2 receptor antagonist, is a substrate of P-glycoprotein (P-gp). Therefore, the transport of DOM into the brain may be restricted by P-gp function at the blood-brain barrier, and when the function of P-gp is impaired by ATP depletion under conditions of brain ischaemia (e.g. cerebral thrombosis), side-effects may be induced as a result of increased distribution of DOM into the brain. In this study, we investigated the effects of brain ischaemia and verapamil, a P-gp inhibitor, on the permeability coefficient-surface area product (PS values) of DOM across the blood-brain barrier by using an in-situ rat brain perfusion technique. The PS values of DOM were increased 3.4- and 3.6-fold after brain ischaemia for 10 and 20 min, respectively. Furthermore, co-administration of verapamil significantly increased the PS values of DOM by 42.6- and 43.3-fold in the normal and ischaemia groups, respectively. Brain vascular volume was not affected by ischaemia or verapamil. These results show that the transport of DOM into the brain is restricted by P-gp and that the brain distribution of DOM can be increased by cerebral ischaemia or co-administration of a P-gp inhibitor.
Isobolographic analysis of the analgesic interactions between ketamine and tramadol
Authors: Chen Yong , Chan Sui Y , Ho Paul C
Published: October 2002

Owing to different mechanisms of analgesia, we hypothesized that the combination of ketamine and tramadol could produce synergistic or additive antinociceptive effects. Swiss albino mice were administered intraperitoneally with ketamine, tramadol, a combination of ketamine and tramadol, or saline, and the resulting antinociceptive effects were tested in the mouse tail-flick and formalin tests. The potencies of the two drugs alone or in combination were obtained by fitting data to the Sigmoid Emax equation. Isobolographic analysis was performed to evaluate the interaction. CNS depression was also monitored. Results showed that tramadol exhibited apparent dose-dependent effects in the tail-flick test, and in phase 1 and phase 2 of the formalin test. Ketamine dose-dependently inhibited the phase 2 responses, but failed to modify the phase 1 and tail-flick responses. Combination of tramadol and ketamine produced significant synergistic interactions only in phase 2 of the formalin test (P < 0.05). The synergistic combinations also displayed less CNS depression than when an equianalgesic dose of ketamine was administered alone. We conclude that in the acute thermal or chemical pain model, ketamine is not effective and the net effect of ketamine and tramadol in combination was simply additive after systemic administration. However, the coadministration produced synergistic antinociception in the chemical-induced persistent pain model.
Spirotetrahydronaphthalene analogues of sympathomimetic catecholamines. Synthesis and adrenergic activity of 5,6- and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1(2H)-3′ -piperidines]
Authors: Macchia Bruno , Manera Clementina , Martinelli Adriano , Nencetti Susanna , Orlandini Elisabetta , Breschi Maria Cristina , Martini Claudia , Martinotti Enrica
Published: October 2002

The 5,6- (5a) and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1 (2H)-3′-piperidine] (6a) and their N-isopropyl derivatives (5b and 6b), DDSNPs, were synthesized. These compounds can be viewed as the result of the combination of the structure of the 3-(3,4-dihydroxyphenyl)-piperidine 2a or 2b, with the structure of the corresponding 1-(aminomethyl)-5,6-dihydroxy-(3a or 3b) or 1-(aminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (4a or 4b), 1-AMDTNs. The new compounds (5a, b and 6a, b) were assayed for their α and β adrenergic properties by means of binding experiments and functional tests and the results were compared with those obtained for catecholamines 1a, b and the previously described 3-(3,4-dihydroxyphenyl)piperidine (3-DPP; 2) and 1-AMDTNs (3, 4). Comparison of the affinity and activity data of novel derivatives with those of reference compounds 2, 3 and 4 shows a general low ability of DDSNPs 5 and 6 to interact with both α and β- adrenoceptors.
Effects of adenosine receptor agonists on guinea-pig isolated working hearts and the role of endothelium and NO
Authors: Maddock Helen L , Broadley Kenneth J , Bril Antoine , Khandoudi Nassirah
Published: October 2002

The hypothesis that the coronary vasodilator effects of adenosine receptor agonists are independent of the vascular endothelium or mediators derived therefrom was examined in guinea-pig isolated working hearts. Adenosine receptor agonists, 5′-(N-ethylcarboxamido)-adenosine (NECA; two-fold selective for A2 over A1 receptors), 2-[p-(2-carboxyethyl)phenylethylamino]-5′-N-ethylcarboxamidoadenosine (CGS21680; A2A selective), N6-cyclopentyl-adenosine (CPA; A1 selective) and N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA; A3 selective), were infused (3 times 10−7 M) after endothelium removal by passing oxygen through the coronary circulation. In spontaneously beating hearts, CGS21680 and NECA increased, while CPA decreased, coronary flow. NECA and CPA reduced heart rate, left ventricular pressure and aortic output. The nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine (L-NOARG; 3 times 10−5 M) abolished the vasodilatation by NECA but not CGS21680, indicating that nitric oxide (NO) of a non-endothelial source mediated the NECA response. Coronary vasodilatation by CGS21680 was inhibited by the A2A receptor antagonist, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo [2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385). Indometacin (10−6 M) attenuated the coronary vasodilatation to CGS21680, suggesting a partial role for cyclooxygenase products. IBMECA had no effect, indicating no A3 receptor involvement. In paced working hearts, the responses were similar except CPA had no effect on coronary flow or aortic output and CGS21680 increased left ventricular pressure and the maximum rate of ventricular pressure rise. This study has demonstrated functionally effective removal of the endothelium by a novel method of passing oxygen through the coronary vasculature. A coronary vasodilator action of adenosine receptor agonists mediated via A2A receptors is endothelium-and NO-independent, but partially involves cyclooxygenase products.
Effect of nizatidine on paracetamol and its metabolites in human plasma
Authors: Itoh Hiroki , Nagano Toshiaki , Takeyama Masaharu
Published: October 2002

The effect of the histamine H2-receptor antagonist, nizatidine, on plasma concentrations of paracetamol has been investigated with respect to hepatic metabolism. Paracetamol (1000 mg) together with 300 or 150 mg nizatidine or placebo was orally administered to five healthy male volunteers. Venous blood samples were taken before and after administration. Plasma paracetamol and paracetamol conjugates (glucuronide and sulfate) were measured by high-performance liquid chromatography. The pharmacokinetic parameters were calculated from the plasma paracetamol concentration-time curves of each volunteer. The plasma nizatidine concentration was highest (2420.0 ± 192.4 and 996.0 ± 54.6 ng mL−1) in the sample taken 1 h after administration of 300 mg nizatidine (high dose) and 150 mg nizatidine (low dose), respectively. Plasma paracetamol concentrations with nizatidine (high and low doses) were increased significantly at 45–120 min and 45–60 min, respectively, compared with placebo. The total area under the plasma paracetamol concentration-time curve from 0 to 180 min (2361.5 ± 146.4 and 2085.75 ± 73.5 μg min mL−1) significantly increased after coadministration of nizatidine (high and low doses), respectively (P < 0.01 vs placebo). Paracetamol glucuronide concentrations with nizatidine (high and low doses) were decreased significantly at 30–45 min and 30 min, respectively, compared with placebo. However, plasma paracetamol sulfate concentrations with nizatidine (high and low doses) were not significantly altered. The coadministration of nizatidine (150 and 300 mg) dose-dependently reduces plasma paracetamol glucuronide concentrations and increases plasma paracetamol concentrations. The effects of nizatidine could result from the inhibition of glucuronyltransferase. Thus, care is necessary when paracetamol and nizatidine are coadministered.
Use of a cholesterol-rich emulsion that binds to low-density lipoprotein receptors as a vehicle for paclitaxel
Authors: Rodrigues Debora G , Covolan Cristiane C , Coradi Silvana T , Barboza Renato , Maranhão Raul C
Published: October 2002

A cholesterol-rich emulsion (LDE) is taken up by malignant cells which over-express low-density lipoprotein (LDL) receptors and thus may be used as a carrier for drugs directed against neoplastic cells. In this study, we associated the antineoplastic agent paclitaxel to LDE and analysed the new formulation's incorporation efficiency, chemical and physical stability, cellular uptake and cytostatic activity against a neoplastic cell line and the acute toxicity to rats. A paclitaxel incorporation efficiency of approximately 75% was achieved when paclitaxel was mixed with LDE at a 6:1 lipid-to-drug molar ratio. The association of paclitaxel with LDE increased by 54% the mean diameter of the emulsion particles but did not damage the paclitaxel chemical structure as analysed by HPLC. Results from gradient ultracentrifugation and Sephadex G25 gel filtration indicated that the binding of the drug to the emulsion was stable. It was shown that the cellular uptake and the cytotoxic activity of LDE-paclitaxel by a neoplastic cell line (NCI-H292 cells) was indeed mediated by the LDL receptors. The antiproliferative activity of LDE-paclitaxel against NCI-H292 cells was less than that of a commercial paclitaxel preparation (50% inhibitory concentration, IC50 = 2.60 and 0.45 μM, respectively). This difference, however, can be ascribed to the in-vitro anti-proliferative activity of the commercial paclitaxel vehicle Cremophor EL; when Cremophor EL was added to the cultures with LDE-paclitaxel, the IC50 value was reduced to 0.45 μM, attaining that of the commercial paclitaxel preparation. The tolerability of LDE-paclitaxel in rats was remarkable, such that its lethal dose (LD50) was ten-fold greater than that of the commercial formulation (LD50 = 324 and 31.8 mg kg−1, respectively). Therefore, LDE-paclitaxel association is stable and the cytostatic activity of the drug is preserved while its toxicity to rats is small. By diminishing the side effects and directing paclitaxel to neoplastic tissues, LDE may be useful as adjuvant in chemotherapy with this drug.
Pharmacokinetic characterization of 14C-vascular endothelial growth factor controlled release microspheres using a rat model
Authors: Kim Tae-Kyoung , Burgess Diane J
Published: October 2002

The objectives of this study were to characterize the pharmacokinetics of vascular endothelial growth factor (VEGF) in poly(lactic-co-glycolic) acid (PLGA) microspheres using a rat model, and to develop a pharmacokinetic model for this controlled release formulation. 14C-VEGF was encapsulated using a solid-in-oil-in-water emulsification method. The microspheres were administered subcutaneously to rats and the pharmacokinetic parameters were compared with those of protein solutions. Intravenous administration of protein solutions resulted in short half-lives and subcutaneous administration resulted in rapid clearance from the subcutaneous tissue, with high plasma concentrations as expressed by rapid absorption and elimination. The subcutaneous administration of the VEGF microspheres produced low plasma concentrations and high subcutaneous concentrations over a period of 7 weeks. The area under the curve (AUC), the time required to achieve the maximum concentration (tmax), the maximum concentration (Cmax) in blood samples and the elimination rate constant (kel) values at the subcutaneous tissue site were selected to compare the pharmacokinetic characterization of VEGF microspheres with that of protein solutions. The in-vivo release profiles of the proteins were slower than the in-vitro release profiles and they followed the same trend as the in-vitro and in-vivo PLGA degradation rates. The PLGA microsphere degradation was the determinant step for VEGF release from the microspheres and its absorption at the subcutaneous site. Microspheres appear to be an attractive system for the localized rate-controlled delivery of VEGF. 14C-Methylation via reductive alkylation of VEGF did not affect its mitogenic activity, however approximately 25% activity was lost following release from PLGA microspheres. This loss of activity may be due to degradation in an acidic environment as a result of PLGA degradation.
Characterization of Ciclosporin A loaded poly (D,L lactide-co-glycolide) microspheres using modulated temperature differential scanning calorimetry
Authors: Passerini N , Craig D Q M
Published: October 2002

The aim of this study was to investigate the physical structure of poly (D,L lactide-co-glycolide) (PLGA) microspheres loaded with ciclosporin A in terms of the amorphous properties of the individual components and the phase separation characteristics of the binary systems. Microspheres were prepared using a standard oil-in-water emulsion technique. The thermal properties of the PLGA, ciclosporin A and loaded spheres were investigated using modulated temperature differential scanning calorimetry (MTDSC) using a TA Instruments MTDSC 2920, with scanning electron microscopy (SEM), X-ray powder diffraction (XRD) and high-performance liquid chromatography used as supportive techniques. MTDSC indicated a glass transition for ciclosporin A in the reversing heat flow signal at 107°C, supported by temperature cycling studies, while XRD showed clear evidence for diffraction peaks, thereby indicating that the material as received is semi-crystalline. The unloaded PLGA spheres showed a glass transition (Tg) at 43°C, with no reduction in Tg being observed on loading the peptide up to 50%, w/w. Similarly, no evidence for diffraction peaks were seen for the drug-loaded systems, although the glass transition corresponding to the peptide was observed for the loaded microspheres, suggesting that the drug is present as a separate amorphous phase. Similarly, SEM studies showed the appearance of distinct “islands” on the surface of the spheres that are suggested to correspond to the drug phase, with the size of the islands increasing with drug loading. Evidence is therefore presented that ciclosporin A may exist in a range of solid states, with the degree of crystallinity being altered by processing. In addition, there appears to be little or no miscibility between the drug and PLGA using the manufacturing protocol employed here. These findings may have implications for the choice of manufacturing protocol, the release of peptide drugs from PLGA microspheres and the chemical and physical stability of such drugs.
A pharmacokinetic model for analysis of drug disposition profiles undergoing enterohepatic circulation
Authors: Wajima Toshihiro , Yano Yoshitaka , Oguma Takayoshi
Published: October 2002

A new and simple pharmacokinetic model that can explain enterohepatic circulation profiles for both single and repeated dosing was developed, and its applicability and usefulness were assessed by an actual published data set and simulation study. The model is basically a conventional compartment model, and the transfer rate from the bile compartment to the central compartment is assumed to change periodically, with the sine function being used to describe this periodical change. Using this model, the effect of the parameter values on plasma time-course profiles was examined by simulation, and the applicability of the model was tested by curve fitting to obtain the parameter estimates using an actual published data set. These studies confirmed that our model can simulate the periodical increase of the concentration due to re-absorption. By averaging the sine function in the transfer rate from the bile compartment to the central compartment, a smoothed time-course profile in the elimination phase that is independent of the enterohepatic cycle can be obtained. Also, the apparent half-life in the elimination phase can be estimated, which is useful especially for evaluating drug accumulation during repeated dosing. It was suggested that the present model can be used to evaluate the drug disposition profile with enterohepatic circulation. The effects of sampling points and sampling time on parameter estimation are also discussed.
Structural requirements for the neuroprotective effects of aspirin analogues against N-methyl-D-aspartate and zinc ion neurotoxicity
Authors: Moon Ho-Sang , Nam Sung-Il , Kim Su-Dong , Kim Dong Yeon , Gwag Byoung Joo , Lee YoungAe , Yoon Sung-Hwa
Published: October 2002

In order to elucidate the structural requirements for the dual neuroprotective activity of aspirin against N-methyl-D-aspartate (NMDA) and zinc ion neurotoxicity, various aspirin analogues and derivatives, modified at the carboxylic group, the acetyl group, and the chain length between the carboxylic acid moiety and phenyl ring, were synthesized. Replacement of the carboxylic acid group with alkyl groups (compounds 2c and 2d) resulted in a dramatic increase in neuroprotective activity against NMDA neurotoxicity, while reduction of the carboxylic acid group to the alcohol (compound 2g) completely abolished this activity. In contrast to NMDA neurotoxicity, compounds that are devoid of the carboxylic acid group did not show any activity against zinc ion neurotoxicity. Replacement of the acetyl group with a propionyl (compound 5a) or butyryl group (compound 5b) did not significantly change the activity against NMDA neurotoxicity, but replacement of the acetyl group with a propionyl group (compound 5a) resulted in a slight decrease in activity against zinc ion neurotoxicity. Compound 12, which has ethylene units between the carboxylic acid moiety and phenyl ring in the structure of aspirin, exhibited greater neuroprotective activity against NMDA neurotoxicity than the compared compounds (aspirin, compound 9 and compound 17), which have different chain lengths. A similar trend was also observed in the neuroprotective activity against zinc ion neurotoxicity. These results indicate that the carboxylic acid group in aspirin is not indispensable for the inhibitory effect against NMDA neurotoxicity, but is essential for the inhibitory effect against zinc ion neurotoxicity. The acetyl group and ethylene unit's distance are favourable for the inhibitory effect against NM DA neurotoxicity as well as zinc ion neurotoxicity.
Synthesis and biological evaluations of brain-targeted chemical delivery systems of [Nva2]-TRH
Authors: Wu Jiaxiang , Yoon Sung-Hwa , Wu Whei-Mei , Bodor Nicholas
Published: October 2002

Various chemical delivery systems for [Nva2]-TRH were synthesized and their CNS activity was investigated and compared with that of a similar chemical delivery system of [Leu2]-TRH, previously studied. Sequential metabolism of the chemical delivery system delivered to the brain, starting with the conversion of the dihydrotrigonellyl (DHT) to the trigonellyl (T+) moiety, will provide the lock-in to the brain of the T+-chemical delivery system, which will undergo hydrolysis of the cholesteryl ester, formation of the Pr-amide and cleavage of the spacer-T+ part, allowing ultimately the sustained release of the active [Nva2]-TRH. The CNS activity was assessed by measuring the extent of antagonizing barbiturate-induced sleeping time in mice. The fully packaged DHT-Pro-Pro-Gln-Nva-Pro-Gly-OCh produced robust antagonism, reducing sleeping time from 89 min to 48 min, similar to the Leu2-analogue (49 min). However, the partially substituted [Nva2]-TRH analogues showed little or no CNS activity. The results indicate that the fully packaged delivery system is necessary to produce the successful brain targeting of the precursor construct and effective release of the Gln-Nva-ProNH2.
Ruscogenin glycoside (Lm-3) isolated from Liriope muscari inhibits lymphocyte adhesion to extracellular matrix
Authors: Liu Jianli , Chen Ting , Yu Boyang , Xu Qiang
Published: October 2002

We examined the effects of ruscogenin glycoside (Lm-3), isolated from Liriope muscari, on lymphocyte adhesion to extracellular matrix. Adhesion of Jurkat cells activated by anti-CD3 to type I collagen was inhibited by Lm-3 in a concentration- and time-dependent manner. Lm-3 also inhibited the cell attachment to fibronectin and laminin. However, the saponin did not influence anti-CD3-induced cell proliferation and Mn2+-induced adhesion. Protein kinase C activator, phorbol 12, 13-dibutyrate, significantly enhanced, while its inhibitor, chlorpromazine, almost completely blocked, the adhesion of anti-CD3-activated Jurkat cells to collagen. Against phorbol 12,13-dibutyrate-activated Jurkat cells, Lm-3 treatment, either before or after activation, significantly inhibited the cell adhesion to collagen. Lm-3 also inhibited the adhesion activated by both anti-CD3 and phorbol 12,13-dibutyrate. Similar inhibition by Lm-3 of the phorbol 12,13-dibutyrate-induced adhesion to collagen was also observed in lymphocytes freshly isolated from mice with contact dermatitis. Furthermore, Lm-3 significantly decreased the leucocyte accumulation in an animal model of experimental pleurisy. These results suggest that the blockade of lymphocyte adhesion to extracellular matrix through interference with the protein kinase C pathway may be one of the mechanisms by which Lm-3 exerts anti-inflammatory activity.
Effect of a potent cyclooxygenase inhibitor, 5-ethyl-4-methoxy-2-phenylquinoline (KTC-5), on human platelets
Authors: Liao Chang-Hui , Liao Cho-Hwa , Chang Ya-Ling , Guh Jih-Hwa , Kuo Shen-Chu , Huang Li-Jiau , Teng Che-Ming
Published: October 2002

Because the metabolites of arachidonic acid participate in many physiopathological responses, including inflammation and platelet aggregation, cyclooxygenase inhibitors are important in the treatment of associated diseases. A biologically active compound, 5-ethyl-4-methoxy-2-phenyl-quinoline (KTC-5), selectively and concentration dependently inhibited aggregation of platelets from man and ATP release caused by arachidonic acid (200 μM) and collagen (10 μ g mL−1) without affecting the aggregation caused by thrombin (0.1 U mL−1) and U46619 (2 μM). The IC50 value (drug concentration inhibiting maximum response by 50%) of KTC-5 for aggregation induced by arachidonic acid and collagen was 0.11 ± 0.04 μM and 0.20 ± 0.03 μM, respectively. This inhibitory effect of KTC-5 was reversible and time dependent. KTC-5 specifically inhibited intracellular calcium mobilization initiated by arachidonic acid or collagen without affecting that caused by thrombin or U46619 in human platelets. Furthermore, KTC-5 inhibited thromboxane B2 and prostaglandin D2 formation provoked by arachidonic acid. The IC50 value of KTC-5 for arachidonic-acid-induced thromboxane B2 formation was 0.07 ± 0.02 μM. Based on these observations, the data indicated that KTC-5 potently inhibited human platelet aggregation and ATP release mainly via the inhibition of the cyclooxygenase-1 activity. Moreover, KTC-5 inhibited lipopolysaccharide-induced prostaglandin E2 formation in RAW264.7 cells in the presence of external arachidonic acid with an IC50 value of 0.17 ± 0.06 μM. Immunoblot analysis showed that KTC-5 did not affect the cyclooxygenase-2 expression in the presence of lipopolysaccharide on RAW264.7 cells. This result indicated that KTC-5 affects the activity of cyclooxygenase-2. According to these data, we concluded that KTC-5 is a cyclooxygenase inhibitor for both subtypes.
Absorption characteristics of model compounds with different molecular weights from the serosal caecal surface in rats
Authors: Nishida Koyo , Nose Seiichi , Kuma Akiko , Mukai Takahiro , Kawakami Shigeru , Nakashima Mikiro , Sasaki Hitoshi , Sakaeda Toshiyuki , Nakamura Junzo
Published: October 2002

The purpose of this study was to clarify the absorption characteristics of drugs across the serosal caecal surface membrane, occupying a large absorption area in the peritoneal cavity in rats. Absorption of phenolsulfonphthalein (PSP) and fluorescein isothiocyanate dextrans (FDs) as model drugs after application to the rat serosal caecal surface was investigated using a cylindrical diffusion cell. PSP was absorbed from the rat serosal caecal surface, followed by appearance in the plasma and bile. The time course of the remaining PSP amount in the diffusion cell obeyed first-order kinetics, and the rate constant, Ka, was calculated to be 8.01 × 10−3min−1. No significant difference was seen in the absorption ratio of PSP, which was approximately 90% in 6 h for three doses (0.3, 0.5 and 1 mg), suggesting linear absorption. Moreover, the absorption ratios of FDs from the rat serosal caecal surface at 3 h decreased with an increase in the molecular weight (24.7 % for FD-4, 12.8% for FD-10 and 3.4% for FD-40).
The size order of the state vector of a continuous-time homogeneous Markov system with fixed size
Authors: Kipouridis I. , Tsaklidis G.
Published: October 2002

The variation of the state vectors p(t) = (pi(t)) of a continuous-time homogeneous Markov system with fixed size is examined. A specific time t0 after which the size order of the elements pi(t) becomes stable provides a criterion of the system's convergence rate. A method is developed to find t0 and a quickly evaluated lower bound for t0. This method is based on the geometric characteristics and the volumes of the attainable structures. Moreover, a condition concerning the selection of starting vectors p(0) is given so that the vector functions p(t) retain the same size order for every time greater than a given time t.
A stochastic covariate failure model for assessing system reliability
Authors: Ebrahimi Nader
Published: October 2002

Many failure mechanisms can be traced to an underlying deterioration process, and stochastically changing covariates may influence this process. In this paper we propose an alternative model for assessing a system's reliability. The proposed model expresses the failure time of a system in terms of a deterioration process and covariates. When it is possible to measure deterioration as well as covariates, our model provides more information than failure time for the purpose of assessing and improving system reliability. We give several properties of our proposed model and also provide an example.
Sensitivity analysis for Markov reward structures until entrance times
Authors: van Dijk N. M. , Korezlioglu H.
Published: October 2002

This work presents an estimate of the error on a cumulative reward function until the entrance time of a continuous-time Markov chain into a set, when the infinitesimal generator of this chain is perturbed. The derivation of an error bound constitutes the first part of the paper while the second part deals with an application where the time until saturation is considered for a circuit switched network which starts from an empty state and which is also subject to possible failures.
A join the shorter queue model in heavy traffic
Authors: Turner Stephen R. E.
Published: October 2002

We prove a new heavy traffic limit result for a simple queueing network under a ‘join the shorter queue’ policy, with the amount of traffic which has a routeing choice tending to zero as heavy traffic is approached. In this limit, the system considered does not exhibit state space collapse as in previous work by Foschini and Salz, and Reiman, but there is nevertheless some resource pooling gain over a policy of random routeing.
Weakly approaching sequences of random distributions
Authors: Belyaev Yuri , Sjöstedt-de Luna Sara
Published: October 2002

We introduce the notion of weakly approaching sequences of distributions, which is a generalization of the well-known concept of weak convergence of distributions. The main difference is that the suggested notion does not demand the existence of a limit distribution. A similar definition for conditional (random) distributions is presented. Several properties of weakly approaching sequences are given. The tightness of some of them is essential. The Cramér-Lévy continuity theorem for weak convergence is generalized to weakly approaching sequences of (random) distributions. It has several applications in statistics and probability. A few examples of applications to resampling are given.
Families of birth-death processes with similar time-dependent behaviour
Authors: Lenin R. B. , Parthasarathy P. R. , Scheinhardt W. R. W. , van Doorn E. A.
Published: October 2002

We consider birth-death processes taking values in but allow the death rate in state 0 to be positive, so that escape from is possible. Two such processes with transition functions are said to be similar if, for all there are constants cij such that for all t ≥ 0. We determine conditions on the birth and death rates of a birth-death process for the process to be a member of a family of similar processes, and we identify the members of such a family. These issues are also resolved in the more general setting in which the two processes are called similar if there are constants cij and ν such that for all t ≥ 0.
Preservation results for life distributions based on comparisons with asymptotic remaining life under replacements
Authors: Bhattacharjee M. C. , Abouammoh A. M. , Ahmed A. N. , Barry A. M.
Published: October 2002

We investigate some preservation properties of two nonparametric classes of survival distributions and their duals, under appropriate reliability operations. The aging properties defining these nonparametric classes are based on comparing the mean life of a new unit to the mean residual life function of the asymptotic remaining survival time of the unit under repeated perfect repairs. They are motivated from a point of view that realistic notions of degradation, applicable to repairable systems, should be based on contrasting some aspect of the remaining life of a repairable unit (under a given repair strategy, such as renewals) to the life of a new unit.
The delay distribution of a type k customer in a first-come-first-served MMAP[K]/PH[K]/1 queue
Authors: Van Houdt B. , Blondia C.
Published: October 2002

This paper presents an algorithmic procedure to calculate the delay distribution of a type k customer in a first-come-first-served (FCFS) discrete-time queueing system with multiple types of customers, where each type has different service requirements (the MMAP[K]/PH[K]/1 queue). First, we develop a procedure, using matrix analytical methods, to handle arrival processes that do not allow batch arrivals to occur. Next, we show that this technique can be generalized to arrival processes that do allow batch arrivals to occur. We end the paper by presenting some numerical examples.
On the equivalence of floating- and fixed-strike Asian options
Authors: Henderson Vicky , Wojakowski Rafał
Published: October 2002

There are two types of Asian options in the financial markets which differ according to the role of the average price. We give a symmetry result between the floating- and fixed-strike Asian options. The proof involves a change of numéraire and time reversal of Brownian motion. Symmetries are very useful in option valuation, and in this case the result allows the use of more established fixed-strike pricing methods to price floating-strike Asian options.
Ageing and stochastic comparisons for a covariate failure model
Authors: Pellerey Franco , Semeraro Patrizia
Published: October 2002

Ebrahimi (2001) proposes an interesting model for assessing a system's reliability, expressing the failure time of the system in terms of a deterioration process and covariates. He also provides illustrative examples and gives some properties of the model. In this note, we give conditions for negative ageing of the system's lifetime, and we correct one of his statements. Moreover, for the lifetimes of two systems of the same kind, some stochastic comparisons are presented.