Sphingosylphosphorylcholine induces cytosolic Ca(2+) elevation in endothelial cells in situ and causes endothelium-dependent relaxation through nitric oxide production in bovine coronary artery.
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Sphingosylphosphorylcholine (SPC) increased intracellular Ca(2+) concentration ([Ca(2+)]i) and nitric oxide (NO) production in endothelial cells in situ on bovine aortic valves, and induced endothelium-dependent relaxation of bovine coronary arteries precontracted with U-46619. The SPC-induced vasorelaxation was inhibited by N(omega)-monomethyl-L-arginine, an inhibitor of both constitutive and inducible NO synthase (NOS), but not by 1-(2-trifluoromethylphenyl) imidazole, an inhibitor of inducible NOS (iNOS). Immunoblotting revealed that endothelial constitutive NOS, but not iNOS, was present in endothelial cells in situ on the bovine aortic valves. We propose that SPC activates [Ca(2+)]i levels and NO production of endothelial cells in situ, thereby causing an endothelium-dependent vasorelaxation. (+info)
Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours.
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Doxorubicin pharmacokinetics were determined in 33 patients with solid tumours who received intravenous doses of 20-320 mg m(-2) HPMA copolymer bound doxorubicin (PK1) in a phase I study. Since assay constraints limited the data at lower doses, conventional analysis was not feasible and a 'population approach' was used. Bound concentrations were best described by a biexponential model and further analyses revealed a small influence of dose or weight on V1 but no identifiable effects of age, body surface area, renal or hepatic function. The final model was: clearance (Q) 0.194 I h(-1); central compartment volume (V1) 4.48 x (1+0.00074 x dose (mg)) I; peripheral compartment volume (V2) 7.94 I; intercompartmental clearance 0.685 I h(-1). Distribution and elimination half-lives had median estimates of 2.7 h and 49 h respectively. Free doxorubicin was present at most sampling times with concentrations around 1000 times lower than bound doxorubicin values. Data were best described using a biexponential model and the following parameters were estimated: apparent clearance 180 I h-(-1); apparent V1 (I) 1450 x (1+0.0013 x dose (mg)), apparent V2 (I) 21 300 x (1-0.0013 x dose (mg)) x (1+2.95 x height (m)) and apparent Q 6950 I h(-1). Distribution and elimination half-lives were 0.13 h and 85 h respectively. (+info)
Pharmacokinetics of PK1 and doxorubicin in experimental colon tumor models with differing responses to PK1.
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PK1 is a synthetic N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin (dox) conjugate currently undergoing Phase II evaluation in the United Kingdom. We have studied the activity of PK1 in three murine colon tumor models that differ in terms of morphology and vascularization in an attempt to determine which factors are most important in the tumor response to PK1. Vascular permeability was evaluated with Evans Blue, and pharmacokinetic studies in MAC15A and MAC26 used high-performance liquid chromatography to monitor both PK1 uptake and dox release in the tumors. Cathepsin B activity was assessed using a specific substrate. PK1 (40 mg x kg(-1) dox equivalent) was significantly more effective than dox alone (10 mg x kg(-1)) was against MAC15A tumors, which possess enhanced perfusion and retention, but not against MAC26 tumors, although MAC15A was also responsive to PK1 when grown as avascular micrometastatic deposits in the lung. Pharmacokinetic studies showed similar levels of PK1 in both tumors. Peak tumor levels of released dox were 7-fold greater in the responsive MAC15A tumor (53 microg x ml(-1)) compared with the less responsive MAC26 tumor (7.7 microg x ml(-1)) and more than 18-fold greater in MAC15A than when free dox was given. These differences in response correlated also with an increased lysosomal activity of cathepsin B. Calculated AUCs for intratumoral dox released were 431 microg x h x g(-1) and 775 microg x h x g(-1) for MAC15A and MAC26, respectively. These AUCs are 4-fold and 7-fold higher, respectively, than when dox is given alone. This study has shown that activity and the pharmacokinetics of PK1 and released dox are dependent on both the vascular properties and enzyme content of the tumors. These studies are likely to have clinical implications as aggressive tumors are known to have increased protease activity. (+info)
Limited exposure of the healthy distal colon to orally-dosed formulation is further exaggerated in active left-sided ulcerative colitis.
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BACKGROUND: Active distal ulcerative colitis is often resistant to topically acting oral formulations. We speculated that the left side of the colon is underexposed to orally-dosed topical agents in patients with active distal colitis. METHODS: Twenty-two healthy volunteers (12 males, aged 22-47 years), and 10 patients (6 males, aged 33-73 years) with active left-sided ulcerative colitis ingested a Eudragit-coated gelatine capsule containing 111In-labelled amberlite resin on four successive days. Regional colonic distribution, transit times and percentage of daily dose resident were calculated from the average of four serial gamma camera images on the 4th day. RESULTS: (mean [95% CI]). When compared to controls, patients with colitis had significantly faster total colon transit (24.3 h [9.5-39.1] vs. 51.7 h [41.1-62.3]) as well as faster proximal colon transit (18.7 h [9.1-28.3] vs. 36.7 [28.5-44.9]), and distal colon transit (3.1 h [-0.5 to 6.8] vs. 15.0 h [10.5-19.5]), respectively (all P < 0.01). Material was asymmetrically distributed in health (proximal colon 69% [63-76] vs. distal colon 31% [24-37]). This asymmetry was more extreme in colitis, with corresponding values of 91% [85-96] vs. 9% [4-15]. As a result colitics had less material in the left-sided colon (9% [4-15] vs. 31% [24-37]), P < 0. 001. Colitics had a significantly lower percentage of the daily dose resident within the left side of the colon compared to controls (13% [-2 to 28] vs. 63% [44-81]), P < 0.01. CONCLUSIONS: Delayed release oral formulation is asymmetrically distributed within the colon in health. This asymmetry is exaggerated in active left-sided ulcerative colitis and, together with faster colonic transit, results in reduced exposure of the distal colon to orally-dosed topical agents. (+info)
Development of metal-resin composite restorative material. Part 2. Effects of acid and heat treatments of silver-tin filler particles on flexural properties of metal-resin composite.
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The effects of acid and heat treatments of silver-tin filler particles on the flexural properties of metal-resin composite restorative materials were investigated. Five metal-resin composite restorative materials containing different silver-tin filler particles treated under different conditions were experimentally prepared. The conditions of the alloy particles were; 1) as atomized (NT), 2) 1.8% HCl acid-treated (AT), 3) heat-treated at 150 degrees C for 5 min after AT (A15), 4) heat-treated at 200 degrees C for 5 min after AT (A20) and 5) heat-treated at 250 degrees C for 5 min after AT (A25). The flexural strength and the flexural modulus of elasticity were measured for the five metal-resin composites to evaluate the effects of the acid and heat treatments. The flexural strength of the prepared composites was significantly influenced by the surface condition of the filler particles (p < 0.01), and increased significantly when the as atomized particles (NT) were acid-treated (AT) or acid- and heat-treated at 150 degrees C (A15), but then significantly decreased as the heat treatment temperature increased (A20 and A25). The strength of the A15 composite was significantly higher than those of the other composites, and exceeded that (about 60 MPa) of the previous composite with no treatment. No significant difference was found in the flexural modulus of the composites. (+info)
Evaluation of the amount of residual monomer on UDMA-based resins by FTIR.
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The purpose of this study was to establish a method using FTIR to evaluate the polymerization characteristics of UDMA-based resins. Three kinds of experimental UDMA-based resins were prepared with various molar fractions. IR spectra of the cured film specimens were measured with FTIR before and after extracting residual monomer from each specimen by MeOH. From the IR spectra, the changes in the number of double bonds were measured, with the NH absorbance peak as an internal standard, and the amounts of residual monomers (RM) were calculated. The MeOH-immersed specimens were analyzed by HPLC. The RM measured by FTIR were compared with those measured by HPLC. The RM measured by HPLC were more than those by FTIR. Since these differences could be due to the difference in the area measured, this FTIR estimation method of residual monomers in cured resins using the NH absorbance peak as an internal standard could be an appropriate method when the resin monomer does not contain aromatic compounds. (+info)
Interaction of antibodies and antigens conjugated with synthetic polyanions: on the way of creating an artificial chaperone.
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Recently we have initiated the use of synthetic polyelectrolytes to mimic the action of chaperones in living cells [Dainiak et al., Biochim. Biophys. Acta 1381 (1998) 279-285]. The next step in this direction is done by the synthesis of conjugates of poly(methacrylic acid) (PMAA) with antigen, denatured glyceraldehyde-3-phosphate dehydrogenase (dGAPDH), and with monoclonal antibodies specific for dGAPDH (but not for the native protein). The pH-dependent properties of the conjugates have been studied using turbidimetry and light scattering. The antibody-PMAA and dGAPDH-PMAA conjugates were shown to interact with free dGAPDH and antibodies respectively as well as with each other. Insoluble aggregates of dGAPDH with antibody-PMAA and of antibodies with dGAPDH-PMAA are formed in acidic media. The same situation occurs in the mixture of antibody-PMAA and dGAPDH-PMAA: precipitation takes place in acidic media, whereas soluble associates are formed in neutral solutions. The size of the soluble associates and the number of conjugates in the associate could be regulated by pH. The competition of free dGAPDH and dGAPDH-PMAA for binding with antibody-PMAA and the dynamic release of refolded GAPDH, with no affinity to antibody-PMAA, into solution could be used for simulating chaperone action. (+info)
Management of extensive carious lesions in permanent molars of a child with nonmetallic bonded restorations--a case report.
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The badly decayed molar teeth of a 12-year-old were restored using resin composite and ceramic restorations. The maxillary first left permanent molar, which had an extensive carious lesion that had destroyed most of the coronal hard tissues of the tooth, was restored to shape and function with a heat-treated resin composite onlay restoration. The restoration was followed up for two years. The mandibular right first molar had a failing large amalgam restoration with extensive recurrent caries. After a three-month period of pulp-capping, the tooth was restored with a bonded ceramic onlay restoration. A nine-month follow-up of this restoration is provided. The maxillary right first molar, which also had a failing large amalgam/resin composite restoration, was restored with a direct resin composite restoration. Under traditional treatment regimens, these extensive cavities would have been treated using more invasive procedures such as pin-retained restorations or elective root canal therapy, post placement, core build-up and crowning. Bonded non-metallic restorations avoid the trauma, time and cost that accompany such extensive procedures and offer a more conservative approach. (+info)