bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Kinetic Profile of Gentamicin in Premature Neonates
Authors: Rocha M J , Almeida A M , Afonso E , Martins V , Santos J , Leitão F , Falcão A C 
Published: July 2003

Abstract
The kinetic profile of gentamicin in premature infants has been studied to enable the development of optimized dosage schedules for neonatal intensive-care units and to stress the relationship between the pharmacokinetic parameters and several demographic, developmental and clinical factors which might be associated with changes in gentamicin disposition.
Sixty-eight newborn patients of 24- to 34-weeks gestational age and 600–3100 g current weight in their first week of life, undergoing routine therapeutic drug monitoring of their gentamicin serum levels, were included in this retrospective analysis.
Gentamicin pharmacokinetic parameters were determined through non-linear regression by using a single-compartment open model. By regression analysis the current weight (g) was shown to be the strongest co-variate, and both gentamicin clearance (Lh−1) and volume of distribution (L) had to be normalized. Additionally, gentamicin clearance depended on gestational age with a cut-off at 30 weeks, which allowed the division of the overall population into two subsets (&lt; 30 weeks and between 30–34 weeks of gestational age).
The younger neonates (&lt; 30 weeks of gestational age) showed a lower gentamicin clearance (0.0288 vs 0.0340 Lh−1 kg−1), a slightly higher volume of distribution (0.464 vs 0.435 L kg−1), and a longer half-life (11.17 vs 8.88 h) compared with the older subgroup (30.34 weeks of gestational age).
On the basis of the pharmacokinetic parameters obtained, we suggest loading doses of 3.7 and 3.5 mg kg−1 for the two subgroups of neonates (&lt;30 weeks and 30–34 weeks of gestational age), respectively. The appropriate maintenance doses in accordance with the characteristics of the patients should be 2.8 mg kg−1/24h and 2.6 mg kg−1/18h for neonates &lt; 30 weeks and between 30–34 weeks of gestational age, respectively. Finally, when compared with previous studies, the information obtained on the pharmacokinetics and determinants of the pharmacokinetic variability of gentamicin in neonates was shown to be consistent.
Pharmacokinetics and Hepatoprotective Effects of 2-Methylaminoethyl-4,4‘-diiiethoxy-5,6,5’,6‘-dimethylenedioxybiphenyl-2-carboxylic acid-2’-carboxylate monohydrochloride in Rats with CCl4-induced Acute Hepatic Failure
Authors: Oh S Y , Lee C H , Ku Y S 
Published: July 2003

Abstract
The pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2-carboxylic acid-2′-carboxylate monohydrochloride (DDB-S) have been investigated in rats with CCl4-induced acute hepatic failure.
To study the pharmacokinetics of DDB-S, rats were divided into a control group and a CCl4-intoxicated group. DDB-S 50 mg kg−1 was administered by intravenous bolus injection to both groups of rats. In the CCl4-intoxicated rats the plasma concentrations of DDB-S were significantly higher, the area under the plasma concentration-time curve from time zero to time infinity was significantly greater (6.46 vs 3.34 mg min mL−1), and the total body (7.74 vs 15.0 mL min−1 kg−1), renal (2.55 vs 5.10 mL min−1 kg−1), nonrenal (5.07 vs 9.65 mL min−1 kg−1), and biliary (1.48 vs 2.69 mL min−1 kg−1) clearances were significantly slower compared with the control rats. This could be due to decreased hepatic cytochrome P450 activity and impaired kidney function induced by CCl4.
To study the hepatoprotective effects of DDB-S, rats were divided into three groups, control rats and CCl4-intoxicated rats with or without DDB-S pretreatment (50 mg kg−1, i.p.). The effects of DDB-S pretreatment on CCl4-induced liver injury were considerable; the serum levels of alanine transaminase, aspartate transaminase, and alkaline phosphatase were significantly lower by 54.3, 44.6 and 67.2%, respectively, compared with the CCl4-intoxicated-only group.
In an in-vitro study, rat hepatocytes were exposed to fresh medium containing 10 mM CCl4 and various concentrations of DDB-S (10 or 100 μg mL−1). The levels of alanine transaminase and aspartate transaminase in the medium were measured as an indicator of hepatocyte injury. DDB-S dose-dependently decreased the levels of alanine transaminase and aspartate transaminase compared with CCl4-intoxication only.
These results indicate that DDB-S has hepatoprotective activity.
Analogues of Arginine Vasopressin Modified in Position 2 or 3 with Naphthylalanine: Selective Antagonists of Oxytocin In-vitro
Authors: Sobocińska M , Lempicka E , Konieczna E , Derdowska I , Lammek B , Melhem S , Kozik W , Janecka J , Janecki M , Trzeciak H I 
Published: July 2003

Abstract
In this study we describe the synthesis and some pharmacological properties of six new analogues of arginine vasopressin (AVP).
Five of the peptides were substituted in position 2 with L-1-naphthylalanine (L-1-Nal) or D-1-naphthylalanine (D-1-Nal); one had D-1-Nal in position 3. All analogues were tested in bioassays for pressor and antidiuretic activity. We also tested the uterotonic activity of the peptides in-vitro. Two of the new peptides were moderately potent V1a and oxytocin antagonists. The modifications proposed resulted in a drop or the removal of antidiuretic activity and in the removal of pressor activity, or conversion into moderate antagonists. Two peptides ([Mpa1, (L-1-Nal)2]AVP and [Mpa1, (D-1-Nal)2]AVP) which appear not to interact with V1a and V2 receptors were exceptionally selective oxytocin antagonists in-vitro.
These compounds with selective oxytocin antagonistic activity may be promising candidates for the development of potential tocolytic agents for the prevention of pre-term labour.
Development of Anti-influenza Drugs: II. Improvement of Oral and Intranasal Absorption and the Anti-influenza Activity of Stachyflin Derivatives
Authors: Yoshimoto J , Yagi S , Ono J , Sugita K , Hattori N , Fujioka T , Fujiwara T , Sugimoto H , Hashimoto N 
Published: July 2003

Abstract
The in-vivo anti-influenza-virus activity of Stachyflin derivatives (III and its phosphate ester, III-Phos), a new class of haemagglutinin fusion inhibitor, and the improvement of their absorption after oral or intranasal administration were studied in mice, rats, and ferrets.
The absorption of III in PEG 4000 and III-Phos aqueous solution increased about three and four fold in AUC after oral administration to uninfected mice compared with that of 0.5% HPMC (hydroxypropyl-methylcellulose) suspension. Using a mouse influenza virus infection model, significant anti-influenza-virus activity was observed in infected mice treated orally with these compounds dissolved in PEG 4000 or distilled water, respectively, but not in mice treated with 0.5% HPMC. The in-vivo anti-influenza-virus activity in ferrets, a good model for influenza virus infection in man, was also studied. Although the concentration of III in plasma was above the IC50 against the influenza virus strain used for 6h after the oral administration of III in PEG 400 to uninfected ferrets, no in-vivo anti-influenza-virus activity was observed at the same dosage given 4 times daily for 3 days. The intranasal administration of III-Phos, which was expected to have a more notable in-vivo anti-influenza-virus activity, was examined. III-Phos, whose intranasal absorption had been improved by the modification of III with phosphate ester in rats, inhibited viral replication in the nasal cavity and suppressed influenza-virus-induced fever when administered intranasally to infected ferrets.
This study demonstrates that intranasally administered compounds with anti-influenza-virus activity must permeate the nasal membranes to produce their anti-influenza-virus effect.
Tissue Distribution and Excretion of CDRI-81/470 in Rats
Authors: Nagaraja Nelamangala V , Singh Sheo K , Paliwal Jyoti K , Gupta Ram C 
Published: July 2003

Abstract
Methyl-N[5[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]-1H-benzimidazol-2-yl] carbamate (CDRI-81/470) is a broad spectrum anthelmintic agent, effective against both intestinal and systemic parasitism. Tissue distribution and excretion of CDRI-81/470 were studied in rats after a single oral dose of 100 mg kg−1 CDRI-81/470.
One of the metabolites was identified in pilot studies as its N-decarboxylate derivative and characterized by synthesis. HPLC assay methods for the simultaneous estimation of CDRI-81/470 and its N-decarboxylate derivative in tissues, bile, urine, and faeces were developed and validated. The parent compound was quantitated in all major tissues and organs up to 48 h post-dose. Among the tissues other than serum, the highest concentrations of CDRI-81/470 were found in liver, whereas only trace levels were found in brain. Approximately 3% of the administered dose was excreted unchanged in urine at 120 h post-dose, whereas approximately 7% was recovered in faeces. The contribution of the biliary route for the excretion of parent compound was less than 0.5%. The N-decarboxylate derivative was quantitated in faeces (1–4%) and bile (&lt; 0.1%) but was absent in serum, tissues, and urine. An additional metabolite was isolated from bile and characterized as the pyridinyl-5-hydroxy derivative of CDRI-81/470.
CDRI-81/470 showed rapid absorption and distribution into all major organs and tissues, and underwent extensive metabolism in rats. Two metabolites in bile were identified and characterized by synthesis.
Effect of Rifampin on Plasma Concentrations of Mefloquine in Healthy Volunteers
Authors: Ridtitid Wibool , Wongnawa Malinee , Mahatthanatrakul Werawath , Chaipol Pinyada , Sunbhanich Methi 
Published: July 2003

Abstract
Mefloquine is a 4-quinolinemethanol compound structurally related to quinine. Quinine is mainly metabolized by the cytochrome P450 3A4 isozyme (CYP3A4), whereas rifampin, a potent inducer of CYP3A4, is known to markedly decrease plasma quinine concentration. Our aim was to study the effect of rifampin on the pharmacokinetics of mefloquine, and explore a possible role of CYP3A4 on mefloquine metabolism.
In an open, two-phase crossover study, seven healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone, or 500 mg mefloquine plus a long-term administration of 600 mg rifampin. Blood samples were collected at specific time points over a 56-day period. Plasma mefloquine and its carboxylic acid metabolite were measured by HPLC for pharmacokinetic analysis. The results indicate that rifampin significantly decreased the area under the plasma concentration-time curve (AUC0-∞) of mefloquine by 68% (P&lt;0.01), maximum plasma concentration (Cmax) by 19% (P&lt;0.01), and elimination half-life (t 1/2) by 63% (P &lt; 0.01), whereas the time to reach Cmax (tmax) of mefloquine was unaffected. The apparent oral clearance (CL) of mefloquine was significantly increased by 281% (P &lt; 0.01). After administration of rifampin, the Cmax of the carboxylic acid metabolite of mefloquine was significantly increased by 47% (P &lt; 0.05), whereas the t 1/2 was significantly decreased by 39% (P &lt; 0.01), and tmax by 76% (P &lt; 0.01). The AUC0-∞ and CL of the mefloquine metabolite were increased by 30% and 25%, respectively, but were not significantly different from the control phase.
The results indicate that rifampin reduces the plasma concentration of a single oral dose of 500 mg mefloquine by increasing metabolism of mefloquine in the liver and gut wall. The CYP3A4 isozyme most likely plays an important role in the enhanced metabolism of mefloquine. Simultaneous use of rifampin and mefloquine should be avoided to optimize the therapeutic efficacy of mefloquine and prevent the risk of Plasmodium falciparum resistance in malarial treatment.
Rapid Identification of Digitalis purpurea Using Near-Infrared Reflectance Spectroscopy
Authors: Kudo Mariko , Watt Robert A , Moffat Anthony C 
Published: July 2003

AbstractGlycosides from Digitalis are widely used for the treatment of various cardiac conditions. The potential for near-infrared (NIR) spectroscopy as a technique for the rapid identification of Digitalis purpurea was studied. If successful, this method would be advantageous over traditional methods which are destructive and time-consuming.It was possible to identify D. purpurea from other plants using a Maximum Distance in Wavelength Space statistical comparison method on standard normal variate-corrected, second-derivative spectra. Match values ranged from 1.65 to 2.26 for correct identification and were greater than 112.1 for other plants. It was also possible to discriminate between different plant parts of D. purpurea, with match values ranging from 1.52 to 2.26 for leaves and greater than 29 for other parts of the same plant. The use of correlation coefficients and the Correlation in Wavelength Space methods proved less conclusive, with resulting values for leaves from different plants being very high, and in all but one case, above 0.9. A two-wavelength, nearest neighbours analysis was carried out for de-trended (baseline corrected), standard normal variate-corrected spectra at 1150 and 2160 nm. This resulted in the successful identification of unknown samples.NIR spectroscopy has the potential for the rapid identification of D. purpurea, and possibly for other natural products of pharmaceutical interest.
In-vitro Antioxidant and In-vivo Photoprotective Effect of Three Lyophilized Extracts of Sedum telephium L. Leaves
Authors: Bonina Francesco , Puglia Carmelo , Tomaino Antonio , Saija Antonella , Mulinacci Nadia , Romani Annalisa , Vincieri Franco F 
Published: July 2003

Abstract
Sedum telephium L. is a medicinal plant used in antiquity to cure many types of inflammatory skin diseases. The leaves (without the external cuticle), are used to promote healing and reduce skin inflammation and pain, and contain various components. We found two major components: flavonol glycosides and polysaccharides, with molecular weight between 13 000 and 13 500 Da. We evaluated the in-vitro antioxidant and in-vivo skin photoprotective effects of three lyophilized extracts obtained from the juice of S. telephium L. leaves: a total lyophilized juice, a lyophilized flavonolic fraction, and a lyophilized polysaccharidic fraction. Two in-vitro models were used: the bleaching of the stable 2,2-diphenyl-1-picrylhydrazyl (DPPH*) radical, and the protective effect against UV-induced peroxidation on phosphatidylcholine multilamellar vesicles, as model membranes. The antioxidant/radical scavenging activity of each lyophilized extract was also assessed in-vivo by determining their ability to reduce UVB-induced skin erythema (monitored by reflectance spectrophotometry) in healthy human volunteers.
The findings of the in-vitro experiments clearly demonstrated that, unlike the lyophilized polysaccharidic fraction, the lyophilized flavonolic fraction and total lyophilized juice possess strong antioxidant/free radical scavenging properties, which are likely due to phenolic compounds. Consistent with these findings, gel formulations of both the total lyophilized juice and, to a greater degree, the lyophilized flavonolic fraction appeared to possess a strong protective effect against UV-induced skin erythema in-vivo, whereas the lyophilized polysaccharidic fraction was completely ineffective.
The in-vitro and in-vivo results suggest that, both the total lyophilized juice and, in particular, the lyophilized flavonolic fraction, but not the lyophilized polysaccharidic fraction of S. telephium L. leaves, have photoprotective effects against UVB-induced skin damage.
Effects of Naturally Occurring Stilbene Glucosides from Medicinal Plants and Wine, on Tumour Growth and Lung Metastasis in Lewis Lung Carcinoma-Bearing Mice
Authors: Kimura Yoshiyuki , Okuda Hiromichi 
Published: July 2003

Abstract
Stilbene glucosides are naturally occurring phytoalexins, found in a variety of medicinal plants. Among the stilbene derivatives, resveratrol 3-O-D-glucoside (piceid) is found in grapes and wine. We studied the effects of stilbene glucosides isolated from medicinal plants and grapes on tumour growth and lung metastasis in mice bearing highly metastastic Lewis lung carcinoma (LLC) tumours. We also studied the inhibitory effects of stilbene glucosides on differentiation of human umbilical vein endothelial cells (HUVECs) to form a capillary network.
Tumour growth in the right hind paw and lung metastasis were inhibited by oral administration of the stilbene glucosides, piceid and 2,3,5,4′-tetrahydroxystilbene-2-O-D-glucoside for 33 consecutive days, in LLC-bearing mice. As the number of CD8+ and NK1.1+ T cells in the spleen was not affected, the inhibitory effects of these stilbene glucosides on tumour growth and lung metastasis could not be explained by natural killer or cytotoxic T lymphocyte activation. Piceid inhibited the DNA synthesis in LLC cells at a concentration of 1000 μm, but not at lower concentrations (10–100 μM). 2,3,5,4′-Tetra-hydroxystilbene-2-O-D-glucoside also inhibited DNA synthesis in LLC cells (IC50 81 μM). In addition, both stilbene glucosides inhibited the formation of capillary-like tube networks (angiogenesis) of HUVECs at concentrations of 100 to 1000 μM.
We suggest that the antitumour and antimetastatic activity of the stilbene glucosides, piceid and 2,3,5,4′-tetrahydroxystilbene-2-O-D-glucoside, might be due to the inhibition of DNA synthesis in LLC cells and angiogenesis of HUVECs.
Effect of Rhazya stricta Decne on Monoamine Oxidase and Cholinesterase Activity and Brain Biogenic Amine Levels in Rats
Authors: Ali B H , Tanira M O M , Bashir A K , Al-Qarawi A A 
Published: July 2003

Abstract
The effect of treatment with the medicinal plant Rhazya stricta Decne, on monoamine oxidase (MAO) and cholinesterase activity, and on the concentration of brain biogenic amines was studied in rats.
R. stricta extract, at doses of 0.2 and 0.5 g kg−1, significantly (P &lt; 0.05-0.01) increased the hepatic and cerebral activity of MAO by 36–127%. The higher doses used (2.0 and 8.0 g kg−1) produced smaller (10–26%) and statistically insignificant increases in MAO activity in liver and brain. Cholinesterase activity in blood, liver and brain was not significantly influenced by treatment with R. stricta. The concentrations of the measured biogenic amines (noradrenaline, adrenaline, 5-hydroxytryptamine and dopamine) were significantly lowered in rats treated with R. stricta.
The observed increase in MAO activity may be responsible for the lowered biogenic amines levels and may, in part, be responsible for the pharmacological effects of R. stricta extract in rats.
Thermal Dependence of Multidrug-resistant-modulator Efficiency: a Study in Anionic Liposomes
Authors: Castaing Madeleine , Loiseau Alain , Dani Michele 
Published: July 2003

Abstract
This study was designed to test the hypothesis that there exists a correlation between the ability of lipophilic drugs to mediate the reversal of multidrug-resistance (MDR) by interacting with the membrane phospholipids and the metabolic level in tissues. The permeation properties of five MDR-modulators were studied by quantifying their ability to induce the leakage of Sulphan blue through unilamellar liposomes, over the temperature range 27–42°C.
The dye leakage induced by a non-ionic detergent (Triton X-100), two calcium blockers (diltiazem and verapamil) and two antiparasitic agents (thioacridine derivative and mepacrine) was temperature-dependent. The permeation process was a co-operative one (1.1 &lt; Hill coefficient &lt; 7.5) and the permeation doses inducing 50% dye leakage (PD50) were 1.5–14.9 mM. The permeation ability of the MDR-modulators (log(1/PD50)) decreased significantly as the net electric charge (z) increased. The passive dye leakage (ΔG &lt; 0) was found to be an endothermic process (ΔH &gt; 0), favoured by an increase in the membrane disorder (ΔS &gt; 0). The apparent enthalpy factor (ΔH50) associated with 50% dye leakage increased with the net electric charge of the compound, and this energetically non-favoured event was entirely offset by the concomitant increase in the entropy factor (ΔS50). The apparent permeation enthalpy (ΔH50) and entropy (ΔS50) showed the lowest values for Triton X-100 (ΔH50 = 7.1 ± 0.53 kJ mol−1, ΔS50=76.9 ± 1.86 J mol−1 K−1), and the highest values for mepacrine (ΔH50 = 79.5±3.80 kJ mol−1, ΔS50 = 306.7 ± 5.97 J mol−1 K−1). When the temperature was increased from 27 to 42°C, the apparent Gibbs free energy (ΔG50) of the dye leakage induced by Triton X-100 decreased by less than 10% of the initial value, and that induced by mepacrine decreased by nearly 40%.
The results provide evidence that in tissues with high metabolic levels and therefore high temperatures, MDR-reversal is likely to be enhanced via favourable drug-membrane interactions controlled by the electric charge of the modulators.
Synergistic Effects of Iontophoresis and Jet Injector Pretreatment on the In-vitro Skin Permeation of Diclofenac and Angiotensin II
Authors: Sugibayashi Kenji , Kagino Midori , Numajiri Sachihiko , Inoue Naoko , Kobayashi Daisuke , Kimura Masayuki , Yamaguchi Masatoshi , Morimoto Yasunori 
Published: July 2003

Abstract
A non-needle syringe (jet injector) was utilized to increase skin permeation of drugs by iontophoresis. Briefly, physiological saline was initially flushed by the injector to make a pore in the stratum corneum of excised hairless rat skin, and the iontophoretic skin permeation of two model compounds, sodium diclofenac and angiotensin II, was followed using a 2-chamber diffusion cell. Constant voltage and constant current iontophoresis treatments were evaluated.
Pretreatment using the jet injector alone resulted in about 13- and 22-fold increases in the steady-state flux of diclofenac and angiotensin II, respectively, through the skin, compared with non-treated controls. Jet injector pretreatment with constant voltage iontophoresis further enhanced skin permeation of diclofenac and angiotensin II, and the enhancement was also greater than that by constant voltage iontophoresis alone. Thus, a synergistic effect was observed. The ratio of enhancement was greater compared with the control. Jet injector pretreatment with constant current iontophoresis, however, did not always yield higher skin permeation of the drugs than injector pretreatment alone, although the lag time was shortened. The difference in the enhancement between the constant voltage- and constant current iontophoresis can be explained by the electric current through the excised skin.
Constant current iontophoresis after a short period of constant voltage iontophoresis with multiple jet injector pretreatments may be the best way to increase drug permeability while preventing severe skin damage.