bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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 (&gt; 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

Abstract
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

Abstract
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

Abstract
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 &lt; 0.001) and 63% (P &lt; 0.01) 1 month and 1 year after nephrectomy was observed, respectively. The Λz (elimination rate constant) was reduced by 39 % (P &lt; 0.001) after 1 month and by 38% (P &lt; 0.001) 1 year after the operation and t1/2 was prolonged by 70% (P &lt; 0.001) and by 43% (P &lt; 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 &lt; 0.001) and 42% (P &lt; 0.01) 1 month after nephrectomy, and by 45% (P &lt; 0.001) and 42% (P &lt; 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &lt; 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

Abstract
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

Abstract
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

Abstract
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 &lt; 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

Abstract
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.