Biomedical subjects
Publications and source records attributed to S J Chung.
Of 67 consecutive patients with spontaneous CSF hypovolemia (SCH), 11 (16.4%) had subdural hematoma (SDH). Patients with SDH were older (p = 0.005), more likely to be male (p = 0.035), and displayed longer time to diagnosis of SCH (p = 0.019) than those without SDH. All patients with SDH showed the findings of pseudo-subarachnoid hemorrhage on CT and responded favorably to epidural blood patches and neurosurgical drainage.
We studied the administration method during a transition period from continuous intravenous (i.v.) infusion to oral administration of cyclosporin A (CsA). Thirty-two pediatric hematopoietic stem cell transplant (HSCT) recipients, between the ages of 8 months and 15.6 years (median 7.1 years) participated in this study. The pharmacokinetic properties of CsA was evaluated during the transition period from i.v. to oral CsA. The daily oral dose of CsA was three times higher than the i.v. dose. Oral dosing began immediately after the continuous infusion was discontinued. Whole-blood CsA concentrations were measured by a monoclonal fluorescence polarization immunoassay (FPIA). The mean+/-s.d. value of bioavailability (F), maximum concentration (C(max)), half-life (t(1/2)) of CsA were 43.1+/-14.4%, 1135.3+/-340.6 ng/ml and 3.1+/-1.2 h, respectively. Mean clearance (CL)+/-s.d. was 480.9+/-103.7, 414.9+/-137.1 and 320+/-51.8 ml/h/kg in patients <20, 20-40 and >40 kg of body weight, respectively. The CsA CL of younger children was significantly greater than for older children (P=0.044). CsA trough levels were maintained within the therapeutic range throughout the transition period. Therefore, our findings suggest that the immediate administration of an oral formulation, after discontinuation of the continuous infusion, would be practical and effective for routine clinical use.
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AIM: We recently succeeded in preparing soft gelatin capsules containing a new self-nanoemulsifying formulation consisting of cyclosporin A (CsA), triacetin, polyoxyl 40 hydrogenated castor oil, polysorbate 20, medium chain triglycerides and medium chain mono- and diglycerides. The soft capsules containing the new formulation exhibited a significantly improved physical stability in terms of the appearance of the gelatin capsule shells and the composition of the fill mass during long-term storage, compared to commercially available soft capsules containing CsA, in which ethanol was employed as a cosolvent of CsA. In the present study, the influence of a fat-rich meal on the bioavailability of CsA from the soft capsule containing the new formulation (test drug) was evaluated and the results compared to those obtained with a representative soft capsule of CsA. VOLUNTEERS AND METHODS: A randomized, open-label, 3-way crossover study was performed in the test capsules and reference soft capsules, in a fasted state or after a fat-rich breakfast. 18 healthy male volunteers received a single dose of the reference formulation (Neoral, Novartis AG, Basel, Switzerland) or test formulation (2 capsules each, 200 mg as CsA) with 240 ml of water with a 1-week washout period between the treatments, after a fat-rich (670 kcal, 45 g fat) breakfast (for the test drug, Treatment A; for the reference drug, Treatment B) or a 12-h fasting (for the test drug, Treatment C). Serial blood samples, collected over a 24-h period after the administration, were assayed for blood CsA concentrations using a specific monoclonal radioimmunoassay. RESULTS: The differences in bioavailability parameters (i.e., AUC(0-24h), AUC(0-infinity) and C(max)) between the treatments were within the range of 80-125% of the reference treatment. An analysis of variance (ANOVA) revealed no significant differences (p > 0.05) between subjects, formulations or periods. The 90% confidence intervals (CI) indicated that the differences between the treatments (Treatments A and B, Treatments A and C) were also within the criteria. CONCLUSION: These results indicate that the bioavailability of CsA from the test drug is equivalent to reference in the fed state, and is likely to be less influenced by a fat-rich meal. Therefore, the new formulation of CsA using triacetin appears to have an advantage over the commercial soft capsules of CsA using a volatile cosolvent such as ethanol.
Characteristic tissue fluorescence is associated with advanced glycation end product (AGE) accumulation in experimental diabetes models, but its utility in patients with type 1 diabetes remains to be established. We studied 148 patients with type 1 diabetes and 77 healthy age-matched control subjects. Low-molecular weight (LMW) fluorophore levels were estimated in plasma samples obtained after an overnight fast. Intra- and interassay coefficients of variation were 4.7% and 6.4%, respectively. LMW fluorophore levels were significantly higher in patients with diabetes than in control subjects (6.3 +/- 0.6 AU/mL vs. 4.1 +/- 0.3; P = 0.007). However, all of this difference came from patients with microvascular complications (n = 67, 7.5 +/- 1.3). There was no significant difference in LMW fluorescence between complication-free patients (4.4 +/- 0.2) and control subjects (P > 0.05). On multivariate analysis, LMW fluorophores correlated with measures of renal function (P < 0.05) but not with diabetes per se. In addition, there was no correlation between LMW fluorophores and the markers of oxidative stress or systemic inflammation. Longitudinal and interventional studies are required to determine whether the association between LMW fluorophores and nephropathy is cause or effect.
In ophthalmic drug delivery, a major problem is retaining an adequate concentration of a therapeutic agent in the pre-corneal area. Polycarboxylic acid carriers such as polyacrylic acid and polyitaconic acid in sub-colloidal, nanoparticulate hydrogel form have a strong potential for sustained release of a drug in ocular delivery. Formulations have been prepared of brimonidine loaded in polycarboxylic (polyacrylic and polyitaconic) acid nanoparticles for potential ophthalmic delivery. These particles were prepared by a reverse micro-emulsion polymerization technique with sizes in the range of 50 nm. The loading efficiencies of the drug brimonidine in the particles were shown to be between 80-85% for polyacrylic acid nanoparticles and between 65-70% for polyitaconic nanoparticles. The loading efficiency was also found to be pH dependent. In a preliminary biocompatibility test, human corneal epithelial cells incubated with polyacrylic acid nanoparticles were found to retain their viability, whereas polyitaconic acid nanoparticles were found to be toxic. Two-photon laser scanning microscopic studies of the fluorescently labelled polyacrylic acid nanoparticles and human cornea shows that they are adhesive on the corneal surface. The polyacrylic acid nanoparticles demonstrated a controlled release of the opthalmological drug (Brimonidine) through the human cornea as compared to that of the commercial formulation, Alphagan.
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Pharmacokinetics of nicotine was studied in rats following intravenous (i.v.) administration of nicotine base (NB) and nicotine hydrogen tartarate salt (NS) at a nicotine dose of 1 mg/kg. The area under the plasma concentration-time curve (AUC), mean residence time (MRT), systemic clearance (CL), distribution volume at steady state (V(ss)) and terminal plasma half-life (T(1/2,beta)) of nicotine were compared between NB and NS. Compared to NS, NB exhibited higher and sustained plasma nicotine levels, thereby yielding significantly (P<0.05) larger AUC (66.3 vs. 27.7 microg ml/min), MRT (165.7 vs. 58.3 min), T(1/2,beta) (144.2 vs. 51.4 min) and a lower CL (18.3 vs. 46.3 ml/min per kg). The V(ss) was comparable between the two compounds. The metabolic conversion to cotinine from NS was threefold larger than that from NB. The plasma protein binding and distribution to blood cells were comparable between the compounds. The apparent partition coefficient (APC) of NS decreased as a function of its concentration, while that of NB remained nearly constant. Particles of different mean sizes were observed for the 1% (w/v) aqueous solutions of NS (388.6 nm) and NB (123.8 nm). Different metabolism and/or elimination between NB and NS appear to be mainly responsible for their different pharmacokinetics.
The effects of cysteine on the pharmacokinetics of phenytoin and one of its metabolites, 5-(p-hydroxyphenyl)-5-phenylhydantoin (pHPPH) were investigated after intravenous administration of phenytoin, 25 mg/kg, to control rats (4-week fed on 23% casein diet) and rats with PCM (protein-calorie malnutrition, 4-week fed on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily starting from the fourth week). In rats with PCM and PCMC, the phenytoin hydroxylation (to form pHPPH) activities were significantly smaller (164, 103 and 95.3 pmol/min per mg protein for the control rats, and rats with PCM and PCMC, respectively) than that in control rats. In rats with PCMC, the intrinsic clearance of phenytoin, CL(int) was significantly slower than those in control rats and rats with PCM (0.175, 0.131 and 0.044 ml/min). The above data suggested that the formation of pHPPH could be reduced in rats with PCM and PCMC. This was supported by significantly smaller 24-h urinary excretion of pHPPH (54.7, 35.6 and 32.5% of intravenous dose of phenytoin) in rats with PCM and PCMC than that in control rats. In rats with PCM, the maximum velocity (0.344, 0.203 and 0.196 microg/min), apparent volume of distribution in central compartment (44.4, 65.4 and 72.2 ml/kg) of phenytoin, and total area under the plasma concentration-time curve from time zero to time infinity (609, 714 and 1210 microg min/ml), renal clearance (20.5, 13.4 and 4.67 ml/min per kg) and 24-h urinary excretion (54.7, 35.6 and 32.5% of intravenous dose of phenytoin) of pHPPH were not returned to control levels by cysteine supplementation (rats with PCMC). This could be mainly due to the fact that the phenytoin hydroxylation activity in rats with PCMC was not returned to control level.
On the basis of the active site topology and enzymic catalytic mechanism of carboxypeptidase A (CPA), a prototypical zinc-containing proteolytic enzyme, alpha-benzyl-2-oxo-1,3-oxazolidine-4-acetic acid (1), was designed as a novel type of mechanism-based inactivator of the enzyme. All four possible stereoisomers of the inhibitor were synthesized in an enantiomerically pure form starting with optically active aspartic acid, and their CPA inhibitory activities were evaluated to find that surprisingly all of the four stereoisomers inhibit CPA in a time dependent manner. The inhibited enzyme did not regain its enzymic activity upon dialysis. The inactivations were prevented by 2-benzylsuccinic acid, a competitive inhibitor that is known to bind the active site of the enzyme. These kinetic results strongly support that the inactivators attach covalently to the enzyme at the active site. The analysis of ESI mass spectral data of the inactivated CPA ascertained the conclusion from the kinetic results. The values of second-order inhibitory rate constants (k(obs)/[I](o)) fall in the range of 1.7-3.6 M(-1) min(-1). The lack of stereospecificity shown in the inactivation led us to propose that the ring cleavage occurs by the nucleophilic attack at the 2-position rather than at the 5-position and the ring opening takes place in an addition-elimination mechanism. The tetrahedral transition state that would be generated in this pathway is thought to be stabilized by the active site zinc ion, which was supported by the PM3 semiemprical calculations. In addition, alpha-benzyl-2-oxo-1,3-oxazolidine-5-acetic acid (18), a structural isomer of 1 was also found to inactivate CPA in an irreversible manner, reinforcing the nucleophilic addition-elimination mechanism. The present study demonstrates that the transition state for the inactivation pathway plays a critical role in determining stereochemistry of the inactivation.
Prevention of cyclosporin A (CsA) adsorption onto the inner surface of Transwell during transport experiments, by the addition of human plasma to the receiver compartment (basolateral side), was investigated. The addition of plasma to a level of 50% (v/v) of the transport medium led to a reduction in the adsorption of CsA (0.1 microM) down to a level of 5%. As a result, the apical to basolateral flux of CsA across the Caco-2 cell monolayer in the presence of 50% (v/v) plasma was estimated to be 2.7-fold higher than that obtained in the absence of plasma. Thus, the adsorption problem can be overcome simply by the addition of an appropriate volume of human plasma to the transport medium. This method appears to be applicable to the routine estimation of CsA flux across epithelial cell monolayers using Transwell.
Isopropryl 2-(1-3-dithiethane-2-ylidene)-2[N-(4-methyl-thiazole-2-yl) carbamoyl] acetate (YH439) is currently under phase II clinical trials by the Yuhan Research Center for use as a hepatoprotective agent. Unfortunately, the oral bioavailbility of YH439, which is sparingly soluble in water (i.e., 0.3 microg/ml or 0.91 microM at room temperature), reportedly, is negligible regardless of the dose administered to rats in the 10-300 mg/kg range. The bioavailability of the compound increased up to 24%, when administered in the form of a micellar solution (700 microg/ml or 2.1 mM for YH439) at a dose of 10 mg/kg, suggesting that its limited solubility is associated with its negligible bioavailability. In order to obtain additional information concerning the bioavailability of YH439, the mechanism(s) involved in gastrointestinal (GI) absorption were investigated in the present study. For this purpose, the transport of YH430 across a Caco-2 cell monolayer was measured in a Transwell. A permeability of 4.07 x 10(-5) cm/s was obtained for the absorptive (i.e., apical to basolateral direction) transport of 0.42 pM YH439, implicating that the in vivo GI absorption is nearly complete. The absorptive transport exhibited a slight concentration-dependency with an intrinsic clearance (CLi) of 0.38 microLL/cm2/sec, which accounted for 28.1% of the total intrinsic clearance (i.e., CLi plus the intrinsic clearance for the linear component) of the transport. Thus, saturation of the absorption process appears to be a minor factor in limiting the bioavailability of the compound. The apparent permeability of YH439 from the basolateral to the apical direction (i.e., efflux, 6.67 x 10(-5) cm/s) was comparable to that for absorptive transport, but, interestingly, a more distinct concentration-dependency was observed for this transport. However, the efflux does not appear to influence the bioavailability of the compound, as evidenced by the sufficiently high permeability in the absorption direction. Rather, a reportedly extensive first-pass hepatic metabolism appears to be a principal factor in limiting the bioavailability. In this respect, reducing the first-pass metabolism by some means would lead to a higher bioavailability of the compound. Thus, elevation of the absorption rate of YH439 becomes a necessity. From a practical point of view, increasing the concentration of YH439 in the GI fluid appears to be a feasible way to increase the absorption rate, because the compound is primarily absorbed via a linear mechanism. In summary, the solubilization of YH439, as previously demonstrated for a micellar solution of the compound, appears to be a practical way to increase the oral bioavailability of YH439.
Nasal absorption of procyclidine, a synthetic anticholinergic compound, was investigated in Wistar rats and Beagle dogs. The dosing solution was prepared by dissolving 14C-procyclidine in 50% ethanolic saline. The dosing solution was administered intravenously and intranasally to rats at a dose of 0.6 mg/kg (i.e., 60 microl/kg in the form of a 1% w/v solution), and intravenously, orally and intranasally to dogs at a dose of 0.3 mg/kg (i.e., 6 microl/kg in the form of a 5% w/v solution). Blood samples were taken from an artery of the animals through the catheter for periods of 1200 (for rats) and 1,440 min (for dogs), and the radioactivity in the samples was determined by liquid scintillation counting. The nasal bioavailability of procyclidine in rats and dogs, based on the radioactivity, was calculated to be 81.1 and 98.6%, respectively. In both rats and dogs, the plasma profiles of procyclidine following nasal administration were very close to those following intravenous administration, leading to nearly superimposable profiles between the two protocols. In dogs, nasal administration resulted in significantly higher plasma concentrations during the first 30 min period compared to oral administration, suggesting the superiority of the nasal route over the oral route in terms of a prompt expression of the pharmacological effect of the drug. The results obtained in this study indicate that procyclidine is rapidly and nearly completely absorbed via the nasal route. In conclusion, nasal administration represents a viable alternative to intravenous administration in the case of procyclidine.
DA-5018, a recently synthesized capsaicin analog, appears to possess potent analgesic activity when administered topically. The objective of this study is to test the feasibility of the topical administration of this compound. Specifically, our goal was to identify vehicle system that permit a reasonable transdermal permeation of the compound in mice. Among the vehicles examined, isopropyl myristate (IPM) showed the largest in vitro permeability across the intact skin (83.6 +/- 5.42 microl/cm2/h). However, due to the limited solubility of DA-5018 in IPM (0.53 mg/ml), the maximal flux from the IPM medium remained at only 44.3 +/- 2.87 microg/cm2/hr. In order to increase the flux, addition of better solvents for DA-5018 was attempted, under the assumption that flux is the result of both solubility and permeability. Ethoxydiglycol (EG) and oleic acid (OA) were selected as examples of good solvents. The addition of EG or OA to IPM at a 1:1 volume ratio resulted in a comparable increase in the solubility of the compound (i.e., to 61.1 and 50.2 mg/ml for EG and OA, respectively). However, the addition of EG at a 1:1 volume ratio, for example, increased the flux 6.3 fold (i.e., 279 microg/cm2/hr), while OA, at a 1:1 volume ratio, decreased the flux 5 fold (i.e., 9.26 microg/cm2/hr). The mechanism of this discrepancy between EG and OA was investigated by measuring the permeabilty of DA-5018 across the stratum corneum-removed skin of the mouse, under the hypothesis that the viable skin layer may serve as a barrier for the permeation of lipophilic substances such as DA 5018. The permeability of DA-5018, from the medium of EG or OA, across the viable skin differed greatly for EG (0.41 microl/cm2/hr) and OA (0.086 microl/cm2/hr), suggesting that a higher permeability across the viable skin layer is needed for the second solvents. The maximum flux across the intact skin was achieved for DA-5018 when EG was added to IPM at a 1:1 volume ratio. Thus, the use of a binary system appears to be the bes approach for realizing the transdermal delivery of DA-5018 at a reasonable rate.
A simple, reliable HPLC-UV detection method was developed for the simultaneous determination of loxoprofen and its metabolites (i.e. trans- and cis-alcohol metabolites), in human plasma and urine samples. The method involves the addition of a ketoprofen (internal standard) solution in methanol, zinc sulfate solution and acetonitrile to plasma and urine samples, followed by centrifugation. An aliquot of the supernatant was evaporated to dryness, and the residue reconstituted in a mobile phase (acetonitrile:water=35:65 v/v, pH 3.0). An aliquot of the solution was then directly injected into the HPLC system. Separations were performed on octadecylsilica column (250x4.5 mm, 5 microm) with a guard column (3.2x1.5 cm, 7 microm) at ambient temperature. Loxoprofen and the metabolites in the eluent were monitored at 220 nm (a.u.f.s. 0.005). Coefficients of variations (CV%) and recoveries for loxoprofen and its metabolites were below 10 and over 96%, respectively, in the 200 approximately 15000 ng ml(-1) range for plasma and 500 approximately 50000 ng ml(-1) range for urine. Calibration curves for all the compounds in the plasma and urine were linear over the above-mentioned concentration ranges with a common correlation coefficient of 0.999. The detection limit of the present method was 100 ng for all the compounds. These results indicate that the present method is very simple and readily applicable to routine bioavailability studies of these compounds with an acceptable sensitivity.
N-(Hydroxyaminocarbonyl)phenylalanine (1) was designed rationally as a new type of inhibitor for carboxypeptidase A (CPA). The designed inhibitor was readily prepared from phenylalnine benzyl ester in two steps and evaluated to find that rac-1 inhibits CPA in a competitive fashion with the Ki value of 2.09 microM. Surprisingly, inhibitor 1 having the D-configuration is more potent (Ki = 1.54 microM) than its antipode by about 3-fold. A possible explanation for the stereochemistry observed in the inhibition of CPA with 1 is presented.
In the hydrogen peroxide (H2O2) apoptosis model of the murine thymocyte, redox reactant and antioxidant pyruvate prevents programmed cell death. We tested the hypothesis that such protection was mediated, at least in part, via pyruvate handling by mitochondrial metabolism. Cultured bovine pulmonary artery endothelial cells were incubated for 30 min with 0.5 mM H2O2 in the absence and presence of 0.5 mM alpha-cyano-3-hydroxycinnamate, as a selective inhibitor of the mitochondrial pyruvate transporter. In controls H2O2 decreased cell viability by 30% within 24 h; this was associated with apoptosis-like bodies, nuclear condensation, and biochemical DNA damage consistent with programmed cell death. Pyruvate (0.1-20 mM) enhanced cell viability in a dose-dependent manner, with > or = 85% viable cells at > or = 3 mM and no DNA laddering, no positive nick-end labeling (TUNEL), and no detectable Annexin V or propidium iodide staining. In contrast, using > or = 5 mM L-lactate as a cytosolic reductant or acetate as a redox-neutral substrate, cell death increased to approximately 40%, which was associated with intense DNA laddering, positive TUNEL and Hoechst 33258 assays. Alpha-cyano-3-hydroxycinnamate alone did not significantly decrease endothelial viability but reduced viability from 85+/-3 to 71+/-4% (p = 0.023) in presence of 3 mM pyruvate plus H2O2; pathological cell morphology and DNA laddering under the same conditions suggested loss of pyruvate protection against apoptosis. Since alpha-cyano-3-hydroxycinnamate re-distributed medium pyruvate and L-lactate consistent with selective blockade of pyruvate uptake into the mitochondria, the findings support the hypothesis that pyruvate protection against H2O2 apoptosis is mediated in part via the mitochondrial matrix compartment. Possible mediators include anti-apoptotic bcl-2 and/or products of mitochondrial pyruvate metabolism such as citrate that affect metabolic regulation and anti-oxidant status in the cytoplasm.