bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apolipoprotein A-I, Cyclodextrins and Liposomes as Potential Drugs for the Reversal of Atherosclerosis. A Review
Authors: Dass Crispin R , Jessup Wendy 
Published: July 2003

Abstract
Several studies have revealed that high-density lipoprotein (HDL) is the most reliable predictor for susceptibility to cardiovascular disease. Since apolipoprotein A-I (apoA-I) is the major protein of HDL, it is worthwhile evaluating the potential of this protein to reduce the lipid burden of lesions observed in the clinic. Indeed, apoA-I is used extensively in cell culture to induce cholesterol efflux. However, while there is a large body of data emanating from in-vitro and cell-culture studies with apoA-I, little animal data and scant clinical trials examining the potential of this apolipoprotein to induce cholesterol (and other lipid) efflux exists. Importantly, the effects of oxysterols, such as 7-ketocholesterol (7KC), on cholesterol and other lipid efflux by apoA-I needs to be investigated in any attempt to utilise apoA-I as an agent to stimulate efflux of lipids.
Lessons may be learnt from studies with other lipid acceptors such as cyclodextrins and phospholipid vesicles (PLVs, liposomes), by combination with other effluxing agents, by remodelling the protein structure of the apolipoprotein, or by altering the composition of the lipoprotein intended for administration in-vivo. Akin to any other drug, the usage of this apolipoprotein in a therapeutic context has to follow the traditional sequence of events, namely an evaluation of the biodistribution, safety and dose-response of the protein in animal trials in advance of clinical trials. Mass production of the apolipoprotein is now a simple process due to the advent of recombinant DNA technology.
This review also considers the potential of cyclodextrins and PLVs for use in inducing reverse cholesterol transport in-vivo. Finally, the potential of cyclodextrins as delivery agents for nucleic acid-based constructs such as oligonucleotides and plasmids is discussed.
Body Distribution of Poly-DL-lactide-poly(ethylene glycol) Microspheres with Entrapped Leptospira interrogans Antigens Following Intravenous and Oral Administration to Guinea-pigs
Authors: Li Xiaohong , Zhang Yanhua , Yan Ronghua , Zhang Min , Yuan Minglong , Deng Xianmo , Huang Zhitang 
Published: July 2003

Abstract
Poly-DL-lactide-poly(ethylene glycol) (PELA) microspheres with entrapped antigens were administered intravenously and orally into guinea-pigs to quantitatively determine the in-vivo distribution and release profiles.
PELA microspheres containing 125I-labelled outer-membrane protein Leptospira interrogans antigens (125I-OMP) were prepared by double-emulsion solvent extraction procedure, and characterized with respect to size, morphology and in-vitro release profiles. The fractured sections of liver and spleen were inspected by scanning electron microscopy, which indicated that microspheres had successfully been entrapped within the above tissues after intravenous injection and oral administration. At predetermined intervals, the blood and such tissues as the liver, spleen, kidney, thyroid, small intestine and mesentery were collected, and the radioactivity was measured by gamma scintillation counting. Following intravenous administration, 56.7% of administered microspheres were accumulated in immunization-related tissues, and 40.1% of microspheres were located in the liver and spleen. However, there was limited uptake efficiency (8.33%) following oral administration, and 49.5% of the absorbed microspheres were located in the intestinal mucosa. Compared with in-vitro release, the in-vivo release profiles of 125I-OMP from PELA microspheres, determined from the decreasing radioactivity in the above tissues, were much faster and the burst effect was higher.
Antigen-loaded PELA microspheres were efficiently entrapped within immunization-related tissues after intravenous administration, but orally administered PELA microspheres showed limited uptake efficiency. Further investigation is needed to improve intestinal absorption.
A Human Oral-throat Cast Integrated with a Twin-stage Impinger for Evaluation of Dry Powder Inhalers
Authors: Srichana T , Martin G P , Marriott C 
Published: July 2003

Abstract
The aim of this study was to investigate the applicability of replacing the glass throat from a twin-stage impinger (TSI) with a human oral-throat cast. Monodisperse aerosols were used to calibrate the human oral cast-TSI at 60 L min−1 and cut-off in particle size was compared with that of the TSI described in the British Pharmacopoeia which employs a glass throat. The amount of salbutamol sulphate (and lactose) delivered by the Cyclohaler depositing on various elements of the in-vitro model were determined.
The calibration of the model containing a human oral-throat cast at 60 L min−1 gave a particle size cut-off of 5.2 μm which was less than that of the TSI (6.3 μm). The oral-throat cast trapped more drug than the glass throat model with a formulation that employed the larger carrier (63–90 μm; P&lt;0.05) while it trapped a lesser amount of drug with those filled with the lower size carrier (Lactochem, micronised lactose). The greater amount of lactose in the formulation that employed the larger-sized carrier (63–90 μm) was deposited closer to the inlet of the oral-throat cast than to the inlet of the glass throat model.
Replacement of the glass throat in the TSI by the human oral-throat cast, leads to a change in deposition efficiency, with the cast having a higher filter efficiency and hence more aerosol particles being captured before their entry into the TSI. This should be investigated further to determine whether such a model might provide a more realistic assessment of the in-vivo characteristics of an aerosol in comparison with the TSI currently being employed, which utilises the glass throat as the portal of entry.
Cytotoxicity and Teratogenicity of Chlorhexidine Diacetate Released from Hollow Nylon Fibres
Authors: Ostad S Nasser , Gard Paul R 
Published: July 2003

Abstract
Intra-uterine contraceptive devices are associated with an increased incidence of pelvic infections, possible due to the introduction of vaginal bacteria into the uterus at insertion. One potential means to overcome this problem is the use of a device which releases the antimicrobial agent chlorhexidine although such an approach carries with it the risk of adverse effects on the endometrium and, possibly, teratogenic effects.
Cultured monolayers of endometrial cells were used to assess the cytotoxicity of both chlorhexidine and chlorhexidine-releasing devices. The results indicated that the agent is toxic at concentrations of 1 μg mL−1 and that the devices potentiated the toxicity. When the devices were tested in a guinea-pig model, endometrial damage was seen only at the high dose of chlorhexidine, suggesting that there is greater distribution of chlorhexidine in-vivo. Assessment of the teratogenic effects of chlorhexidine in rat embryonic limb bud tissue cells in-vitro showed that the foetal cells were highly susceptible to the toxic effects of chlorhexidine, but that there was no evidence of teratogenicity.
Overall, the findings suggest that chlorhexidine-releasing devices may be a safe means of reducing infections related to intra-uterine devices, but that the chlorhexidine may have a toxic effect on foetal cells.
Investigations of the In-vitro Metabolism of Three Opioid Tetrapeptides by Pancreatic and Intestinal Enzymes
Authors: Krondahl Eva , Von Euler-Chelpin Hans , Orzechowski Achim , Ekström Gunilla , Lennernäs Hans 
Published: July 2003

Abstract
The metabolism of three opioid tetrapeptides, Tyr-D-Arg-Phe-Nva-NH2, Tyr-D-Arg-Phe-Phe-NH2 and Tyr-D-Ala-Phe-Phe-NH2, was investigated in the presence of pure pancreatic enzymes (trypsin, chymotrypsin, elastase, carboxypeptidase A and carboxypeptidase B), as well as in the presence of pure carboxylesterase and aminopeptidase N. The cleavage patterns of the pure pancreatic enzymes were then compared with those found in rat and human jejunal fluid. Metabolism was also studied in homogenates from different intestinal regions (duodenum, jejunum, ileum and colon) and in enterocyte cytosol from rats. The effect of various protease inhibitors was investigated in the jejunal homogenate. The parent peptides were assayed by high-performance liquid chromatography and metabolites were identified by means of liquid chromatography-mass spectrometry.
Of the pure enzymes, the quickest hydrolysis of the peptides was observed for the pancreatic enzymes chymotrypsin, trypsin and carboxypeptidase A. In most cases they formed the corresponding deamidated tetrapeptides (chymotrypsin and trypsin) or tripeptides with a missing C-terminal amino acid (carboxypeptidase A). Regional differences in intestinal metabolism rates were found for all three peptides (P &lt; 0.001), with the highest rates observed in jejunal and/or colonic homogenates. The deamidated tetrapeptides were formed both in rat intestinal homogenates and in enterocyte cytosol. Metabolism in the jejunal homogenate was markedly inhibited by some serine and combined serine and cysteine protease inhibitors.
In conclusion, the C-terminal amide of these tetrapeptides did not fully stabilise them against intestinal deamidase and carboxypeptidase activities. The significant hydrolysis of the peptides by pure chymotrypsin, trypsin and carboxypeptidase A showed that lumenal pancreatic proteases might be a clear metabolic obstacle in oral delivery even for small peptides such as these tetrapeptides.
Recombinant Factor VIII SQ—Stability of VIII: C in Homogenates from Porcine, Monkey and Human Subcutaneous Tissue
Authors: Fatouros Angelica , Lidén Ylva , Sjöström Brita 
Published: July 2003

Abstract
The aim of this paper was to investigate whether a formulation-based approach to understanding and addressing stability could generate a subcutaneous factor VIII preparation for patients as an alternative to the existing intravenous products. The low bioavailability of subcutaneously administered factor VIII could have several causes: proteolytic degradation of the protein in the interstitium; adsorption to tissue, in particular to acidic phospholipids such as L-α phosphatidyl-L-serine (phosphatidylserine); the absence of free von Willebrand factor in the interstitum; phagocytosis by macrophages in the interstitium or in the lymph nodes; and coagulation could be initiated upon injection. This study was undertaken to investigate the first three factors in-vitro (i.e., proteolytic degradation, adsorption to tissue and the protective effect of von Willebrand factor). The influence of some other macromolecular stabilisers and protease inhibitors was also investigated. The stability of factor VIII activity (VIII: C) was investigated in homogenates from porcine, monkey and human subcutaneous tissue. Possible coagulation was prevented in these studies by the presence of both citrate and antithrombin. An exploratory in-vivo study was performed in the pig; plasma samples were assayed with a factor VIII: Ag (90 kDa) ELISA.
The decrease in VIII:C appeared to be more pronounced in homogenates from monkey and human tissues than in porcine homogenate. The results from human tissue homogenate resembled the degradation profile seen in monkey homogenate. Both the von Willebrand factor and phosphatidylserine/phosphatidylcholine (PS/PC) liposomes showed a significant stabilising effect on VIII:C in the tissue homogenates. The qualitative pattern was similar in porcine, monkey and human tissue. A combination of several protease inhibitors seemed to have a protective effect on the stability of VIII:C albeit at high concentrations of inhibitors and the effect was less than that of PS/PC. An exploratory in-vivo study was performed in the pig with phosphatidylserine in two formulations; either in the form of PS/PC liposomes or together with Polysorbate 80 in the form of mixed micelles (phosphatidylserine/P80). Including phosphatidylserine in the formulations appeared to increase the availability of subcutaneously administered r-VIII SQ in the pig. However, further studies are necessary, preferably in the monkey where in-vitro studies indicate a closer resemblance to the human.
In conclusion, a proposed inactivation mechanism for r-VIII SQ in subcutaneous tissue could be adsorption to phospholipid surfaces followed by proteolytic degradation. However, additional studies are required due to the multitude of factors influencing the subcutaneous absorption route. A combination of protease inhibitor(s) together with phosphatidylserine-containing liposomes are suggested for further investigation, preferably in a monkey animal model.
Intravenous Formulations of the Enantiomers of Thalidomide: Pharmacokinetic and Initial Pharmacodynamic Characterization in Man
Authors: Eriksson Tommy , Björkman Sven , Roth Bodil , Höglund Peter 
Published: July 2003

Abstract
Thalidomide, a racemate, is coming into clinical use as an immunomodulating and antiinflammatory drug. These effects may chiefly be exerted by S-thalidomide, but the enantiomers are interconverted in-vivo. Thalidomide is given orally, although parenteral administration would be desirable in some clinical situations. The aim of this study was to prepare solutions of the enantiomers of thalidomide for intravenous administration and to investigate their pharmacokinetics and sedative effects following infusion in man.
Solubility and stability of the enantiomers in 5% glucose solution was investigated. After a dose-determination experiment in one subject, six healthy male volunteers received R- and S-thalidomide separately by 1-h infusions in a randomized double-blind crossover study. Blood was sampled over 22 h and sedative effects were recorded. Blood concentrations of the enantiomers were determined by stereospecific HPLC. A four-compartment model consisting of a two-compartment model for each enantiomer, with elimination from both compartments, connected by rate constants for chiral inversion was fitted to the concentration data, while the sedative effects were correlated with the blood concentrations of R- and S-thalidomide by means of logistic regression. The enantiomers of thalidomide were chemically stable in solution for at least a week at room temperature. The infusions were well tolerated. Sedation, which was the only observed effect, was related to the blood concentration of R-thalidomide. Inter-individual variation in the disposition of the enantiomers was modest (e.g. terminal half-lives ranged between 3.9 and 5.3 h). Pharmacokinetic modelling predicted that varying the infusion time of a fixed dose of S-thalidomide between 10 min and 6 h would have little influence on the maximal blood concentration of formed R-thalidomide.
To our knowledge this is the first time that thalidomide has been administered intravenously.
Isolation and Identification of Three Potential Impurities of Pholcodine Bulk Drug Substance
Authors: Denk Oliver M , Gray Alexander I , Skellern Graham G , Watson David G 
Published: July 2003

Abstract
Three previously unreported manufacturing impurities were isolated from a pholcodine mother liquor using preparative reversed-phase HPLC.
The liquor was the residue remaining after recrystallisation of a production batch of pholcodine. The impurities, which are structurally related to pholcodine, were initially detected by thin-layer chromatography (TLC). Their structures were determined after separation by preparative HPLC (Econo-Prep 5 μm C18 column, 30 cm × 21.2 mm i.d.). Structure elucidation was carried out using nuclear magnetic resonance (NMR) spectroscopy, mass spectroscopy (MS) and ultra violet (UV) spectroscopy.
The impurities were identified as alkylated derivatives of pholcodine possessing second 2-morpholinoethyl substituents at various positions.
In-vitro In-vivo Correlation Models for Glibenclamide after Administration of Metformin/Glibenclamide Tablets to Healthy Human Volunteers
Authors: Balan Guhan , Timmins Peter , Greene Douglas S , Marathe Punit H 
Published: July 2003

Abstract
In this study, level C and A in-vitro in-vivo correlation (IVIVC) models were developed for glibenclamide. In-vitro dissolution data were collected for the glibenclamide component of three metformin/glibenclamide tablets using a USP Type II apparatus. In-vivo plasma concentration data were obtained after administration of the prototype formulations to 24 healthy volunteers and subject to deconvolution analysis to obtain percentage in-vivo absorbed profiles. Multiple linear level C models were developed for CMAX and AUC(0–48) using percentage in-vitro dissolved data at 10, 45 and 120 min. Initially, the level A model was constructed for the first 2 h only, based on availability of in-vitro data. Another level A model was attempted using a time-scaled approach, with percentage in-vivo absorbed at time t and percentage in-vitro dissolved at time t/I as the correlating data. Internal predictability was evaluated for the level C and time-scaled level A models.
For all level C approaches, linear regression models with r2 &gt; 0.99 were determined. The prediction errors (% PE) for Cmax and AUC(0–48) were less than 1% for all formulations at all three chosen time points. The deconvolution analysis indicated biphasic absorption for glibenclamide, with one phase occurring at 2–3 h and another at 6–12 h after dose administration. The level A model using 2-h data was not unique for all formulations and was therefore not developed. The time-scaling factor I correlated highly (r2 = 0.99) with in-vitro mean dissolution time (MDT). A linear regression time scaled model (r2 = 0.97) was successfully developed using in-vitro and in-vivo data from all 3 formulations. However, the internal predictability of the time-scaled model was poor, with % PE values for Cmax and AUC(0–48) being as much as 30.5% and 18.7%, respectively.
The results indicate that level C models have good internal predictability. Though a time-scaled level A IVIVC model was successfully developed, the model was found to have poor internal predictability.
Tiospirone and the Reinforcing Effects of Cocaine in the Conditioned Place Preference Paradigm in Rats
Authors: Arolfo Maria Pia , McMillen Brian A 
Published: July 2003

Abstract
Tiospirone (TSP) is an atypical antipsychotic drug. It has 5HT-2 antagonistic properties as well as affinity for D2, 5HT-1a, 5HT-6 and sigma receptors.
Behavioural studies in our laboratory, which used a 24 h free access to food and fluids paradigm, showed a decreased alcohol and increased food intake after twice-daily administration of TSP; the maximal effect was obtained at a dose of 0.48 mg kg−1. This study used the conditioned place preference paradigm to determine the effect of TSP on the reinforcing properties of cocaine. Intraperitoneal administration of 5.0 mg kg−1 cocaine, but not saline, increased the time rats spent in the drug-paired compartment of a three-compartment shuttle box by 104.9%. Two doses of TSP, 0.143 and 0.48 mg kg−1, were tested subcutaneously 60 min before saline or cocaine administration during the conditioning phase only. A dose-response effect was observed with a significant reduction in the time rats spent in the cocaine-paired compartment on the drug-free test day produced by the dose of 0.48 mg kg−1 (an increase of only 38.1% when post-conditioned times were compared with preconditioned times).
These findings suggest that TSP reduces the reinforcing properties of cocaine exhibited in the conditioned place preference paradigm.
The Effects of Potassium Channel Blockers on Progesterone-Induced Suppression of Rat Portal Vein Contractility
Authors: Mukerji Mark S , Leathard Helen L , Huddart Henry 
Published: July 2003

Abstract
The suppression of contractility of rat portal vein caused by progesterone appears to be due to the potassium (K+) channel opening effect of this hormone. The identity of the specific K+ channels involved has been investigated using a variety of K+ channel blockers.
Incubation with 100 nM iberiotoxin antagonised the progesterone-induced inhibition of spontaneous and 20 mM K+-induced phasic activity of the portal vein such that the contractions resembled those of the non-progesterone, non-iberiotoxin control tissues treated with the corresponding solvent vehicles. Incubation with barium chloride (20 and 100 μm), 4-aminopyridine (1 mM), tetraethylammonium chloride (1 mM), glibenclamide (1 μm) or apamin (1 mM) did not, however, have the same antagonistic effect.
These results suggest that progesterone's selective suppression of rat portal vein contractility is mediated by the opening of BKCa channels.
Effect of Aegle marmelos on Biotransformation Enzyme Systems and Protection Against Free-radical-mediated Damage in Mice
Authors: Singh R P , Banerjee S , Rao A Ramesha 
Published: July 2003

Abstract
The effect of hydroalcoholic (80% ethanol, 20% water) extract of leaves of Aegle marmelos was examined on carcinogen-metabolizing phase-I and phase-II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation, using two doses of dried extract (50 and 100 mg kg−1 daily for 14 days), in the liver of mice. The modulatory effect of the extract was also examined on extrahepatic organs (lung, kidney and fore-stomach) for effects on the activity of glutathione S-transferase, DT-diaphorase, superoxide dismutase and catalase.
Extract treatment significantly increased the basal levels of acid-soluble sulphydryl (–SH) content, cytochrome P450, NADPH-cytochrome P450 reductase, cytochrome b5, NADH-cytochrome b5 reductase, glutathione S-transferase, DT-diaphorase, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in the liver. Aegle acted as a bifunctional inducer since it induced both phase-I and phase-II enzyme systems. Both doses significantly decreased the activity of lactate dehydrogenase and formation of malondialdehyde in liver, suggesting a role in cytoprotection as well as protection against pro-oxidant-induced membrane damage. Butylated hydroxyanisole (positive control) induced almost all the antioxidative parameters measured in this study. The extract was effective in inducing glutathione S-transferase, DT-diaphorase, superoxide dismutase and catalase in lung, glutathione S-transferase, DT-diaphorase and superoxide dismutase in fore-stomach, and DT-diaphorase and superoxide dismutase in lung.
These significant changes in the levels of drug-metabolizing enzymes and antioxidative profiles are strongly indicative of the chemopreventive potential of this plant, especially against chemical carcinogenesis.
The Effect of Acute Ethanol Exposure on the Chronotropic and Inotropic Function of the Rat Right Atrium
Authors: Campbell Patrick H , Barker Louis A , McDonough Kathleen H 
Published: July 2003

Abstract
Consumption of ethanol (CH2CH3OH), both acutely and chronically, is known to affect cardiac function and may alter the autonomic control of the heart. This study investigated the effects of two modes of acute exposure to ethanol on the chronotropy and inotropy of the rat right atrium with emphasis on alterations in the adrenergic responses.
Atria from rats infused with an anesthetizing level of ethanol for 21 h showed a tendency for a greater increase of the unstimulated beating rate with isoproterenol (ISO), while both unstimulated inotropy and the inotropic response to ISO were significantly decreased compared with the control. Right atria in the presence of ethanol in-vitro demonstrated decreased basal active tension development and decreased inotropic responses to ISO. No alteration of the chronotropic response to ISO was evident with any concentration of ethanol.
These results demonstrate both an immediate as well as a persistent effect of ethanol on right atrial chronotropy and inotropy. Alterations in the G-stimulatory subunit of the adenylate cyclase system and alterations in myofilament binding of Ca2+ are consistent with these observed ethanol effects.