bluuebunny/crossref_metadata_2025_split huggingface dataset:
Colon Delivery Efficiencies of Intestinal Pressure-controlled Colon Delivery Capsules Prepared by a Coating Machine in Human Subjects
Authors: Hu Zhaopeng , Mawatari Shunsuke , Shimokawa Tatsuharu , Kimura Go , Yoshikawa Yukako , Shibata Nubuhito , Takada Kanji 
Published: July 2003

Abstract
Large quantities of pressure-controlled colon delivery capsules (PCDCs) were prepared by a Hicoater-mini pharmaceutical coating machine and colon delivery efficiencies were evaluated in man. Caffeine powder as a model drug was suspended with a polyethylene glycol (PEG) 1000 suppository base at 50°C, and was hardened in no. 0- and no. 2-sized capsular shapes. The capsule-shaped suppositories were coated with 5% w/v ethanolic ethylcellulose (7G grade) solution using the coating machine.
By increasing the coating weight of ethylcellulose from 28.6 ± 1.1 mg to 45.3 ± 0.2 mg, the mean coating thickness of no. 0 PCDCs increased from 56 ± 1 μm to 64 ± 1 μm. With no. 2 PCDCs, the mean coating thickness increased from 50 ± 1 μm to 57 ± 1 μm by increasing the coating weight of ethylcellulose from 8.1 ± 0.5 mg to 11.2 ± 0.3 mg. The no. 0 PCDCs, having a mean ethylcellulose coating membrane thicknesses of 56± 1 μm (type 1) and 64 ± 1 μm (type 2), as well as no. 2 PCDCs, having thicknesses of 50 ± 1 μm (type 3) and 57 ± 1 μm (type 4), were used for in-vivo evaluation in man. After oral administration of test preparations containing 75 mg of caffeine, saliva samples were obtained and salivary caffeine levels were measured by an HPLC method. The first appearance time, Ti, of caffeine in the saliva was used as a parameter for the estimation of the release time of caffeine from PCDCs in the gastrointestinal tract. The mean Ti values of no. 0 PCDCs were 3.3 ± 0.3 h for type-1 and 5.3 ± 0.3 h for type-2 preparations while the mean Ti values of no. 2 PCDCs were 4.3 ± 0.5 h for type 3 and 5.3 ± 0.3 h for type 4. There were good correlations between ethylcellulose coating membrane thicknesses and in-vivo Ti values. A colon arrival time of 5 h was reported in our subjects by gastrointestinal magnetomarkergraphy.
PCDCs having a mean coating thickness of 64± 1 μm for no. 0 capsules and of 57 ± 1 μm for no. 2 capsules were thought to deliver caffeine to the human colon efficiently.
Biodegradable Microparticles with Different Release Profiles: Effect on the Immune Response After a Single Administration via Intranasal and Intramuscular Routes
Authors: Spiers Ian D , Eyles Jim E , Baillie Les W J , Diane Williamson E , Alpar H O 
Published: July 2003

Abstract
In the development of single-dose microparticulate vaccines, identification of the type of protein release profile required to elicit high and sustainable immune responses is important. Microparticles exhibiting different protein release profiles (continuous, pulsatile and plateau) were made by solvent evaporation or solvent extraction methods from biodegradable polymers encapsulating the model antigen, bovine serum albumin (BSA). The immune responses obtained after a single intranasal or intramuscular administration of microparticles were determined, and also after a subcutaneous boost after 11 months.
Microparticles were manufactured with acceptable protein loading and average volume size ranging from 1 to 10 μm. The integrity of BSA extracted and released from microparticles after 2 months incubation was retained. Microparticulate preparations administered by either intranasal or intramuscular routes, evoked rapid, high titre and long-lived (up to 11 months after priming) specific serum IgG responses which were significantly greater than for free BSA. The type of protein release from microparticles had no significant effect on the systemic immune responses. Interestingly, a formulation exhibiting a plateau-release profile was the only microparticulate system capable of inducing significantly greater IgA responses than free BSA after intranasal immunization.
This study shows the benefit of microencapsulation in inducing high and long-lasting systemic immune responses after a single dose by both parenteral and mucosal delivery. We conclude that of the microparticles tested, the longevity and magnitude of humoral responses was not effected by the type of in-vitro protein release profile.
Mitigation of Surfactant Erythrocyte Toxicity by Egg Phosphatidylcholine
Authors: Gould Larissa A , Lansley Alison B , Brown Marc B , Forbes Ben , Martin Gary P 
Published: July 2003

AbstractPolyoxyethylene alkyl ether surfactants have been shown to have excellent penetration enhancing abilities although they are associated with a high level of local toxicity. We have compared the toxicity of a range of polyoxyethylene alkyl ethers (Brij 96, Brij 76, Brij 56, 10 lauryl ether and 9 lauryl ether) to an anionic surfactant (sodium dodecyl sulphate (SDS)), an ampholytic surfactant (lysophosphatidylcholine) and a cationic surfactant (tetradecyltrimethylammonium bromide (TTAB)), in the presence and absence of egg phosphatidylcholine.The toxicity of the surfactants or phospholipid/surfactant mixtures was assessed by measuring haemolytic activity. The test samples were incubated with a suspension of red blood cells for 30 min and Drabkin's reagent was used to indicate the amount of haemoglobin released.All of the polyoxyethylene alkyl ethers, SDS, TTAB and lysophosphatidylcholine exhibited haemolytic activity at concentrations between 0.10 and 0.25 mM. The addition of egg phosphatidylcholine reduced the toxicity for all of the surfactants, with the toxicity of Brij 96 being mitigated to a greater extent than the toxicity of the other polyoxyethylene surfactants examined. The rate of haemolysis induced by Brij 96 or 10 lauryl ether was also reduced by increasing concentrations of phosphatidylcholine. As the phosphatidylcholine content of a mixed surfactant system comprising egg phosphatidylcholine: Brij 96 was replaced by lysophosphatidylcholine and fatty acid, the haemolytic action of the mixture increased markedly.The results from this study show that the toxicity of surfactants to erythrocytes can be mitigated by the addition of egg phosphatidylcholine. Synthetic surfactants combined with phosphatidylcholine may generate drug delivery systems worthy of more extensive investigation.
The Effects of Carrier Size and Morphology on the Dispersion of Salbutamol Sulphate after Aerosolization at Different Flow Rates
Authors: Zeng Xian Ming , Martin Gary Peter , Marriott Christopher , Pritchard John 
Published: July 2003

Abstract
We have investigated the interdependence of various factors (particle size, surface smoothness, carrier particle shape, inhalation flow rate) on the deposition of a model drug (salbutamol sulphate) after aerosolization from a model inhaler device (Rotahaler).
Different batches of α-lactose monohydrate were prepared to have different particle size, particle shape and surface smoothness. Each batch of lactose was then mixed separately with salbutamol sulphate in a ratio of 67.5:1 (w/w), under similar conditions. Drug deposition from each formulation was investigated using a 4-stage liquid impinger after aerosolization at 28.3, 60.0 and 96.0 L min−1 via a Rotahaler.
At a flow rate of 28.3 L min−1, a large portion of drug particles was not emitted from the inhaler, the % emission varying from 29.6% to 66.6% for all formulations investigated. Drug emission tended to increase with particle size of the carrier whilst fine particle fraction, fine particle dose and dispersibility appeared to increase with decreasing particle size but increasing elongation ratio of the carrier particles. Increasing the flow rate to ***60.0 L min−1 was shown to increase drug emission since &gt;75% total dose was found to be emitted from the inhaler. Again, smaller or more elongated lactose particles resulted in a higher fine particle dose or fine particle fraction of salbutamol sulphate than the coarser carrier, although they produced a similar (analysis of variance P&gt;0.05) drug emission. Increasing the flow rate to 96.0 L min−1 did not increase drug emission. Increasing the flow rate resulted in an increase in the fine particle fraction and fine particle dose of salbutamol sulphate from all formulations. The flow rate of the airstream appeared to play the most important role, followed by particle size and elongation ratio of the carrier particles, with the surface smoothness relatively less significant in determining the deposition of salbutamol sulphate from the Rotahaler.
The Use of a Capillary Rheometer to Determine the Shear and Extensional Flow Behaviour of Nasal Spray Suspensions
Authors: Eccleston Gillian M , Hudson Nick E 
Published: July 2003

Abstract
The rheological profiles of four commercial nasal spray suspensions (Beconase, Flixonase, Nasacort and Nasonex) were compared using rotational viscometry. Two of the nasal sprays (Beconase and Nasonex) were further examined in both shear and extension using a capillary rheometer under conditions similar to those experienced at the spray nozzle (i.e. extremely high shear rates with significant stretching or extensional flow).
In rotation, the shear viscosity fell rapidly with increase in shear rate. Plots of the viscosity derived at the lower shear rates in rotation were extrapolated to include the high-shear rate capillary values. At very high shear rates, the shear viscosity of Beconase was higher than that of Nasonex with the cross-over occurring in the extrapolated region at approximately 10 000 s−1. In the transition region between laminar and turbulent flow (shear rate 6–8 times 104 s−1) there was a minimum in the shear viscosity to less than that of water for Nasonex and similar to water for Beconase, and a plateau region in extensional viscosity for Beconase but not Nasonex. These anomalies were due to the extensive aeration of both samples when sprayed. Whereas Beconase had de-aerated within 30 min of the experiment, Nasonex had not de-aerated completely after six weeks. The very low viscosity at the shear rates at the nozzle imply that it is unlikely that the low viscosity of the spray on delivery to the nose is a key factor in prolonging its residence time.
The extensional viscosity for these rather fluid samples was over 1000-times the shear viscosity (not 3-times as with Newtonian fluids) and both sprays exhibited strain hardening over the range covered. The high extensional stress in the nozzle enables the fluid to form as reasonably sized droplets rather than fine atomized droplets, which rather than settling in the nose, would be prone to redistribution through the normal respiratory function. Both sprays resisted degradation despite the high shear rates and extensional stresses experienced.
Effects of Dosing Time and Schedule on Cisplatin-Induced Nephrotoxicity in Rats
Authors: Kobayashi Minoru , To Hideto , Yuzawa Masayuki , Hakamata Yoji , Higuchi Shun , Tokue Akihiko , Fujimura Akio , Kobayashi Eiji 
Published: July 2003

AbstractRenal dysfunction induced by a single injection of cisplatin depends on the timing of the dose. However, the effects of repeated administration of cisplatin on time-dependent toxicity have not been evaluated despite the fact that in clinical practice high doses are repeatedly injected at intervals or low doses are administered daily. We studied chrono-nephrotoxicity in rats after weekly or daily cisplatin injections.Weekly high doses (5 mg kg−1) or daily low doses (1.2 mg kg−1) of cisplatin were injected at four time points (3, 9, 15 and 21 h after the light was turned on (HALO)) for 3 weeks. Changes in body weight after weekly cisplatin administration were independent of the timing of the doses. In the group that received daily cisplatin, the loss in body weight in the 3 HALO group was smaller than in animals receiving injections at 15 and 21 HALO (P &lt; 0.05 and 0.001, respectively). The blood urea nitrogen and serum creatinine levels in the control rats showed a significant circadian change (peak at 15 HALO and trough at 9 HALO), but these parameters were markedly elevated in both trials and their circadian variations were disturbed. In conclusion, cisplatin-induced nephrotoxicity was the lowest at 3HALO compared with other time points of both dose regimens.
Pharmacokinetic Interactions between HIV-1 Protease Inhibitors in Rats: Study on Combinations of Two Kinds of HIV-1 Protease Inhibitors
Authors: Shibata Nobuhito , Matsumura Yasuhiro , Okamoto Hiroyuki , Kawaguchi Yuko , Ohtani Akiko , Yoshikawa Yukako , Takada Kanji 
Published: July 2003

Abstract
The drug interactions between four human immune deficiency virus (HIV-1) protease inhibitors have been characterized by in-vitro metabolic studies using rat liver microsomal fractions and in-vivo oral administration. In this study, a new HPLC analytical method developed by us was used for the simultaneous determination of saquinavir and nelfinavir in rat plasma and microsomes.
The metabolic clearance rates (Vmax/Km) of saquinavir, nelfinavir, and indinavir were 170.9 ± 10.9, 126.1 ± 4.4, and 73.0 ± 2.0 μL min−1 (mg protein)−1, respectively. Ritonavir was the strongest inhibitor with inhibition constants (Ki) of 1.64 μM for saquinavir, 0.95 μM for indinavir, and 1.01 μM for nelfinavir. Nelfinavir was the second strongest inhibitor with Ki's of 2.35 μM for saquinavir and 2.14 μM for indinavir. Indinavir was the third strongest inhibitor with Ki's of 2.76 μm for nelfinavir and 3.55 μM for saquinavir. Saquinavir was the weakest inhibitor for the other three HIV-1 protease inhibitors. After oral co-administration in combination with another HIV-1 protease inhibitor, the AUCs of saquinavir, indinavir, and nelfinavir were significantly increased compared with mono-treatment. The AUCs of saquinavir were increased about 10.1-, 3.1- and 45.9-fold in the presence of indinavir, nelfinavir and ritonavir, respectively. The AUCs of indinavir were increased about 6.8-, 5.9- and 9.4-fold in the presence of nelfinavir, saquinavir and ritonavir, respectively. The AUCs of nelfinavir were increased about 2.2-, 6.6- and 8.5-fold in the presence of indinavir, saquinavir and ritonavir, respectively.
The in-vivo effects observed after co-administration of two kinds of HIV-1 protease inhibitor were not always expected from in-vitro data, suggesting the presence of other interaction processes besides metabolism in the liver. These results provide useful information for the treatment of AIDS patients receiving combination therapy with two HIV-1 protease inhibitors.
Synthesis and in-vitro anticancer evaluation of bistacrine congeners
Authors: Hu Ming-Kuan 
Published: July 2003

Abstract
In the search for potential new anticancer drugs, an efficient synthesis of bis-tetrahydroaminoacridine (bis-tacrine) and its congeners was accomplished by bis-amination of 9-chlorotetrahydroacridine and its congeners under heated conditions.
The critical chlorides were efficiently prepared from o-aminoaromatic acids and cycloketones in-situ in the presence of phosphorus oxychloride. In-vitro cytotoxic evaluation of the compounds was carried out against a panel of 60 human cancer cell lines. Among them, butyllinked bis-tacrine (5b) exhibited the strongest cytotoxic profile with GI50 (concentration causing 50% growth inhibition) values of approximately 0.04-0.08 μM against breast, colon, melanoma and non-small lung cancer cells. Congeners bearing a longer alkyl chain were on average 30- to 100-fold less cytotoxic against these cancer cells. Shorter connecting alkyl chains of bis-tacrine or its congeners dramatically decreased the cytotoxic effects.
Compound 5b has been selected for further biological evaluation of its anticancer profile.
Potential transition state phosphoramidate inhibitors of β-tubulin as antifilarial agents
Authors: Anderson R J , Bendell D J , Hooper M , Cairns D , Mackay S P , Hiremath S P , Jivanagi A S , Badami S , Biradar J S , Townson S 
Published: July 2003

Abstract
Transition state phosphoramidate inhibitors of β-tubulin were designed as potential antifilarial agents.
The reactionof 2-aminobenzimidazole with diisopropyl phosphite and carbon tetrachloride at a low temperature gave the unexpected 1-diisopropoxyphosphoryl-2-aminobenzimidazole, which on heating gave the novel benzimidazole derivative, 2-(diisopropoxyphosphoryl)-aminobenzimidazole. Both products were fully characterized and the synthetic procedure to both compounds was optimized. The procedure was used to prepare the related 5-benzoyl-2-(diisopropoxyphosphoryl)aminobenzimidazole and 5-benzoyl-2-(diethoxyphosphoryl)amino-benzimidazole (1d). In a preliminary trial against Brugia pahangi compound 1d was found to have no antifilarial activity. This lack of activity may be attributed to its extreme insolubility and thus low bioavailability. The synthesis of analogous, more soluble, phosphorothioate-substituted benzimidazoles using the same methods may yield compounds with greater antifilarial activity.
A near-infrared method for the assay of cineole in eucalyptus oil as an alternative to the official BP method
Authors: Wilson Nicola D , Watt Robert A , Moffat Anthony C 
Published: July 2003

Abstract
Eucalyptus oil of British Pharmacopoeia (BP) and European Pharmacopoeia standard must contain not less than 70.0% w/w 1,8-cineole (eucalyptol). The official assay is a freezing-point method which involves the addition of o-cresol to the eucalyptus oil, whereupon the o-cresol and the 1,8-cineole form a solid complex. The assay has several disadvantages and we aim to show that near-infrared (NIR) spectroscopy is an attractive alternative to this method, in that it is simple to use, requires no sample preparation and is potentially as accurate as the traditional method.
Thirty different eucalyptus oil samples were scanned on the FOSS NIRSystems 6500 Rapid Content Sampler using a reflectance vessel as sample presentation method. The cineole content of each sample was determined by the BP method and these reference data were used to construct two calibration equations for cineole content in the oils using Vision software. The mean accuracy for the NIR method differed by 1.01% or less, and the mean bias by ±0.33% or less, compared with the BP method. Calculation of the 95% confidence intervals for the slope and intercept of plots of NIR predicted values against BP method reference values showed that there was no evidence of fixed or relative systematic errors. Tests for short-term and intermediate repeatability were conducted. The standard deviation was 0.83% w/w or less and the coefficient of variation was 1.11% or less. The confidence intervals for both short-term and intermediate repeatability overlapped with that for the BP method, suggesting that there was no evidence for a difference in values obtained by the BP and NIR methods. The range of cineole contents used in the calibrations was extended by incorporating five samples of eucalyptus oil spiked with cineole, and five samples of two essential oils known to have a lower cineole content than eucalyptus oil, to give a range of 52.5 to 99.0% w/w. The mean accuracy decreased to an error of 1.26% or less and the bias to ±0.50% or less. Again, confidence intervals suggested there was no evidence for fixed or systematic errors in the NIR calibrations.
We propose that NIR spectroscopy could be used as an alternative method for the determination of cineole content in eucalyptus oils.
Antagonistic effects of selective α1-adrenoceptor antagonists MDL73005EF and tamsulosin and partial agonists clonidine and tizanidine in rat thoracic aorta and rabbit iliac artery
Authors: Satoh Mitsutoshi , Enomoto Keisuke , Koike Katsuo 
Published: July 2003

Abstract
The antagonistic effects of MDL73005EF and tamsulosin and partial agonists clonidine and tizanidineat rat thoracic aorta and rabbit iliac artery α1-adrenoceptors were investigated in this study.
Selective α1-adrenoceptor antagonists MDL73005EF and tamsulosin dose-dependently shifted the concentration-response curves for noradrenaline to the right. Schild plots of the results obtained from the inhibition by MDL73005EF (pA2 8.30 ± 0.04) and tamsulosin (pA2 10.51 ± 0.06) of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta. The slopes of Schild plots obtained from the inhibition by MDL73005EF and tamsulosin of noradrenaline were significantly different from unity in rabbit iliac artery. Schild plots of the results obtained from the inhibition by clonidine and tizanidine of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta (pA2 7.08 ± 0.04 and 7.32 ± 0.04, respectively).
These results suggest that α1D-adrenoceptors play a significant role in the α1-adrenoceptor-agonist-induced contraction of rat thoracic aorta and rabbit iliac artery, and that clonidine and tizanidine interact with the α1D-adrenoceptor subtype as competitive antagonists in rat thoracic aorta.
Enhanced nasal retention of hydrophobically modified polyelectrolytes
Authors: Bromberg L E 
Published: July 2003

Abstract
Hydrophobically modified polyelectrolytes (HMP) are polymers with a high content of ionizable groups bonded to hydrophobic groups. Copolymers of poly(acrylic acid) and Pluronic surfactants constitute a special class of HMP whereby poly(propylene oxide) segments act as hydrophobes. The poly(propylene oxide) segments possess temperature-dependent aqueous solubility and the solutions of the Pluronic-poly(acrylic acid) copolymers (MW &gt; 3000000) undergo a sol-gel transition when kept at body temperature. Due to the presence of the poly(acrylic acid) segments, the Pluronic-poly(acrylic acid) copolymers are bioadhesive. We have examined the hypothesis that the in-situ gelling polymer formulations of Pluronic-poly(acrylic acid) copolymers may have an enhanced retention in the nasal cavity. The effects of putative bioadhesive (Carbomer 934P) and thermogelling (Pluronic F127) polymers on nasal clearance were compared with Pluronic-poly(acrylic acid) copolymers using a rat model.
The enhancement of the residence time of fluorescent labels by the Pluronic-poly(acrylic acid) copolymers was shown to be 5–8-fold that of Carbomer, and 3–6-fold that of Pluronic F127. The results unequivocally demonstrate the superior retention of the HMP that combines bioadhesive and thermogelling capabilities over either a bioadhesive polyelectrolyte or a polymer of a low molecular weight that undergoes a sol-gel transition.
Reduction of structural perturbations in bovine serum albumin by non-aqueous microencapsulation
Authors: Carrasquillo Karen G , Carro Juan Carlos Aponte , Alejandro Adriana , Toro Diana Diaz , Griebenow Kai 
Published: July 2003

Abstract
Protein stability is a factor limiting the use of sustained-release devices in medical applications. The aim of this study was to reduce structural perturbations occurring in the frequently used model protein, bovine serum albumin (BSA), upon microencapsulation in poly(D,L-lactide-co-glycolide) (PLG) microspheres.
Spray freeze-dried BSA was encapsulated into PLG microspheres by a completely nonaqueous oil-in-oil encapsulation procedure. FTIR spectroscopy was used as a non-invasive method to quantify procedure-induced structural perturbations in BSA. Spray-freeze drying of BSA caused significant structural perturbations that were minimized by co-spray freeze-drying BSA with trehalose. BSA-containing microspheres were produced by suspension of the powder by homogenization in methylene chloride containing PLG, followed by formation of coacervate droplets by the addition of silicon oil and hardening using the solvent heptane. Resulting microspheres had dimensions of approximately 100 μm and the encapsulation efficiency for BSA was &gt; 90 %. FTIR data showed that the structure of the BSA-trehalose formulation encapsulated into PLG microspheres was less perturbed than that of BSA obtained from buffer alone.
The results demonstrate that the structure-guided encapsulation approach introduced for non-aqueous casting encapsulation procedures can be extended to the non-aqueous production of pharmaceutically relevant PLG microspheres involving a complex encapsulation procedure.