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Biomedical subjects

M G Lee

Publications and source records attributed to M G Lee.

At least 73 records · Page 4Linked to original sources
PubMed2000

Disposition of intravenous pyrimethamine in healthy volunteers.

A proportion of patients with AIDS and toxoplasmic encephalitis (TE) sustain low plasma pyrimethamine concentrations during oral treatment, possibly because of incomplete and variable bioavailability. We wanted to develop a safe, practicable intravenous (i.v.) formulation of pyrimethamine and characterize its disposition in healthy volunteers. A neutral, aqueous, sterile solution of pyrimethamine was produced and presented in sealed glass ampoules. Pyrimethamine (1 mg/kg) was given to eight healthy male volunteers by i.v. infusion over 2 h, and blood was sampled over a 2 week period. Pyrimethamine levels in plasma were measured by high-performance liquid chromatography. The drug was well tolerated by all volunteers, and there were no changes in vital signs, electrocardiogram, hematology, or biochemical parameters. The maximum pyrimethamine concentration of 2,089+/-565 ng ml(-1) (mean +/- standard deviation) was achieved shortly after the end of the infusion; thereafter, concentrations declined in a log-linear manner, with a half-life of 140+/-31 h.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Sequence requirements for trafficking of the CRAM transmembrane protein to the flagellar pocket of African trypanosomes.

CRAM is a cysteine-rich acidic transmembrane protein, highly expressed in the procyclic form of Trypanosoma brucei. Cell surface expression of CRAM is restricted to the flagellar pocket of trypanosomes, the only place where receptor mediated endocytosis takes place in the parasite. CRAM can function as a receptor and was hypothesized to be a lipoprotein receptor of trypanosomes. We study mechanisms involved in the presentation and routing of CRAM to the flagellar pocket of insect- and bloodstream-form trypanosomes. By deletional mutagenesis, we found that deleting up to four amino acids from the C terminus of CRAM did not affect the localization of CRAM at the flagellar pocket. Shortening the CRAM protein by 8 and 19 amino acids from the C terminus resulted in the distribution of the CRAM protein in the endoplasmic reticulum (ER) (the CRAM protein is no longer uniquely sequestered at the flagellar pocket). This result indicates that the truncation of the CRAM C terminus affected the transport efficiency of CRAM from the ER to the flagellar pocket. However, when CRAM was truncated between 29 and 40 amino acids from the C terminus, CRAM was not only distributed in the ER but also located to the flagellar pocket and spread to the cell surface and the flagellum. Replacing the CRAM transmembrane domain with the invariant surface glycoprotein 65-derived transmembrane region did not affect the flagellar pocket location of CRAM. These results indicate that the CRAM cytoplasmic extension may exhibit two functional domains: one domain near the C terminus is important for efficient export of CRAM from the ER, while the second domain is of importance for confining CRAM to the flagellar pocket membrane.

Amino Acid Sequence↗
PubMed2000

Na(+)-dependent transporters mediate HCO(3)(-) salvage across the luminal membrane of the main pancreatic duct.

To study the roles of Na(+)-dependent H(+) transporters, we characterized H(+) efflux mechanisms in the pancreatic duct in wild-type, NHE2(-/-), and NHE3(-/-) mice. The pancreatic duct expresses NHE1 in the basolateral membrane, and NHE2 and NHE3 in the luminal membrane, but does not contain NHE4 or NHE5. Basolateral Na(+)-dependent H(+) efflux in the microperfused duct was inhibited by 1.5 microM of the amiloride analogue HOE 694, consistent with expression of NHE1, whereas the luminal activity required 50 microM HOE 694 for effective inhibition, suggesting that the efflux might be mediated by NHE2. However, disruption of NHE2 had no effect on luminal transport, while disruption of the NHE3 gene reduced luminal Na(+)-dependent H(+) efflux by approximately 45%. Notably, the remaining luminal Na(+)-dependent H(+) efflux in ducts from NHE3(-/-) mice was inhibited by 50 microM HOE 694. Hence, approximately 55% of luminal H(+) efflux (or HCO(3)(-) influx) in the pancreatic duct is mediated by a novel, HOE 694-sensitive, Na(+)-dependent mechanism. H(+) transport by NHE3 and the novel transporter is inhibited by cAMP, albeit to different extents. We propose that multiple Na(+)-dependent mechanisms in the luminal membrane of the pancreatic duct absorb Na(+) and HCO(3)(-) to produce a pancreatic juice that is poor in HCO(3)(-) and rich in Cl(-) during basal secretion. Inhibition of the transporters during stimulated secretion aids in producing the HCO(3)(-)-rich pancreatic juice.

Animals↗
PubMed2000

Novel amiloride-sensitive sodium-dependent proton secretion in the mouse proximal convoluted tubule.

The proximal convoluted tubule (PCT) reabsorbs most of the filtered bicarbonate. Proton secretion is believed to be mediated predominantly by an apical membrane Na(+)/H(+) exchanger (NHE). Several NHE isoforms have been cloned, but only NHE3 and NHE2 are known to be present on the apical membrane of the PCT. Here we examined apical membrane PCT sodium-dependent proton secretion of wild-type (NHE3(+/+)/NHE2(+/+)), NHE3(-/-), NHE2(-/-), and double-knockout NHE3(-/-)/NHE2(-/-) mice to determine their relative contribution to luminal proton secretion. NHE2(-/-) and wild-type mice had comparable rates of sodium-dependent proton secretion. Sodium-dependent proton secretion in NHE3(-/-) mice was approximately 50% that of wild-type mice. The residual sodium-dependent proton secretion was inhibited by 100 microM 5-(N-ethyl-N-isopropyl) amiloride (EIPA). Luminal sodium-dependent proton secretion was the same in NHE3(-/-)/NHE2(-/-) as in NHE3(-/-) mice. These data point to a previously unrecognized Na(+)-dependent EIPA-sensitive proton secretory mechanism in the proximal tubule that may play an important role in acid-base homeostasis.

Amiloride↗
PubMed2000

Gastrointestinal first-pass effect of furosemide in rats.

The first-pass effect of furosemide was investigated in rats. Furosemide intravenous solution (20 mg kg(-1) Lasix), was administered via the jugular vein and the portal vein, orally, and instilled directly into the duodenum of rats. The first-pass effects of furosemide by lung, heart, and liver seemed to be negligible in rats. The absolute bioavailability of furosemide was 28.9 and 48.3% after oral and intraduodenal administration, respectively. Based on the gastrointestinal (GI) recovery study, 68.3 and 69.5% of furosemide were found to have disappeared mainly due to absorption and/or metabolism from rat GI tract after oral and intraduodenal administration, respectively. The results indicate that gastrointestinal and intestinal first-pass effects of furosemide were approximately 40% (68.3-28.9%) and 20% (69.5-48.3%) of the dose, respectively.

Administration, Oral↗
PubMed2000

Radiologic findings of abdominal polyarteritis nodosa.

OBJECTIVE: The purpose of this study was to evaluate the radiographic and imaging findings of seven patients with polyarteritis nodosa involving the abdomen. CONCLUSION: Vasculitis should be considered when multiple abdominal organs have abnormal radiologic findings; however, angiography is necessary to specifically diagnose polyarteritis nodosa.

Abdomen↗
PubMed2000

CT of patients with right-sided colon cancer and distal ileal thickening.

OBJECTIVE: The purpose of this study was to analyze the incidence and primary causes of distal ileal wall thickening in 131 patients with right-sided colon cancer. SUBJECTS AND METHODS: During a 2-year period, 131 patients underwent surgical resection for right-sided colon cancer. Of these patients, we analyzed 13 who had distal ileal wall thickening on CT before surgery and also had the cause determined at pathology. CT findings were analyzed with regard to the morphologic features of colonic tumors, bowel wall involvement patterns of the distal ileum, and changes in the pericolic space. RESULTS: Distal ileal wall thickening occurred in 13 (10%) of the 131 patients who had right-sided colon cancer. Three patients had polypoid colon cancer, whereas the other 10 had infiltrative colon cancer. The mean thickness of the involved colonic segments was 1.6 cm (range, 1.0-2.2 cm) with a mean length of 5.2 cm (range, 2.5-10.0 cm). Pericolic infiltration was mild in six patients and moderate in four patients. The mean length and thickness of the affected ileal segments were 3.2 cm (range, 1.5-6.0 cm) and 1.1 cm (range, 0.7-2.0 cm), respectively. On histopathologic examination, neoplastic processes involved the distal ileum in nine (69%) of the 13 patients. This involvement was caused by either direct tumor invasion in seven patients or lymphatic spread in two. In four patients (31%), nonneoplastic processes with edema and congestion involved the distal ileum. CONCLUSION: The distal ileum may be abnormally thickened in about 10% of patients with right-sided colon cancer; this thickening results from tumor extension (69%) or a nontumorous process (31%).

Adult↗
PubMed2000

Isolated splenic metastasis from colorectal carcinoma: a case report.

Isolated splenic metastasis arising from colorectal carcinoma is very rare and there has been only 6 cases reported in the English literature. A new case is presented, and its possible pathogenesis was considered with previously reported cases. A 65-year-old male patient had received a right hemicolectomy for ascending colon cancer 36 months earlier. He was followed up regularly with serial measurement of serum carcinoembryonic antigen (CEA). Rising serum CEA was discovered from 33 months postoperatively and CT revealed an isolated splenic metastasis. He therefore underwent splenectomy, which was proven to be a metastatic adenocarcinoma with similar histological feature to the original tumor. As all reported cases showed elevated serum CEA at the time of metastasis, isolated splenic metastasis might be associated with CEA in regard to its biological functions of immunosuppression and adhesion.

Adenocarcinoma↗
PubMed2000

Virulent Treponema pallidum 47 kDa antigen regulates the expression of cell adhesion molecules and binding of T-lymphocytes to cultured human dermal microvascular endothelial cells.

Perivasculitis and endothelial cell abnormalities are prominent histopathologic features of syphilis. Various cutaneous lesions are the main clinical features of syphilis. We examined whether Treponema pallidum 47 kDa antigen regulates the expression of cell adhesion molecules on human dermal microvascular endothelial cells (HDMEC) and the regulation of T-lymphocytes binding to HDMEC. Using immunofluorescence flow cytometry and enzyme-linked immunosorbent assay (ELISA), we demonstrated that T. pallidum upregulated the expression of adhesion molecules, including intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin. The 47 kDa antigen of T. pallidum also activated endothelium as measured by the upregulation of the expression of adhesion molecules on HDMEC, and it also promoted an increased adherence of T-lymphocytes to HDMEC. The expressions of ICAM-1 and VCAM-1 on HDMEC and the adherence of T-lymphocytes to HDMEC were inhibited by treatment with anti-TNF-alpha antibody or anti-IL-1alpha antibody. These results show that T. pallidum or T. pallidum-specific 47 kDa antigen are capable of stimulating HDMEC to increase the expression of ICAM-1, VCAM-1 and E-selectin and thereby, promote the adherence of T-lymphocytes. The whole process may play an important role in the immunopathogenesis of syphilis and it is likely that TNF-alpha and IL-1alpha are involved.

Antigens, Bacterial↗
PubMed2000

Analysis of methods for the generation of dendritic cells from human peripheral blood monocytes.

Dendritic cells (DC) are highly efficient antigen-presenting cells that initiate the primary immune response. Several laboratories have developed culture systems for human DC from peripheral blood monocytes. Most of these studies have used fetal calf serum (FCS) containing culture conditions that are inappropriate for human application. GM-CSF and IL-4 were used to make immature DC. The monocyte-conditioned medium (MCM) was used to induce the final maturation of DC. Using the previously described methods, the quality of MCM has unpredictable variations. Therefore using a defined cocktail of growth factors for the generation of mature DC would be advantageous for experimental as well as clinical purposes. In this study, it is suggested that combinations of both GM-CSF/IL-4 or GM-CSF/IL-13 could be used as the first-step culture to produce immature DC, and that cytokine cocktail (GM-CSF, IL-4, IL-1beta, TNF-alpha, IL-6, PGE2) was as efficient as MCM for the second step-culture to produce fully maturated DC. Here, we have generated an easily reproducible culture system for DC that allows for the generation of large amounts of immature and mature DC, and we also now have established the method in a FCS-free system that is suitable for clinical use.

Cell Division↗
PubMed2000

Bioequivalence assessment of closerin capsule to dura seromycin capsule of cycloserine after a single oral dose administration to healthy male volunteers.

AIM: A bioequivalence study of the closerin capsules to the dura seromycin capsules was conducted. PATIENTS AND METHODS: Twenty-four healthy male Korean volunteers received each medicine at the cycloserine dose of 250 mg in a 2 x 2 crossover study. There was a one-week washout period between the doses. Plasma concentrations of cycloserine were monitored by a high-performance liquid chromatography for over a period of 72 hours after the administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated by the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and Tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf and Cmax, and untransformed Tmax. RESULTS: There were no significant differences between the medications in AUCinf and Cmax. The point estimates and 90% confidence intervals for AUCinf (parametric) and Cmax (parametric) were, in point estimate (90% confidence interval), 0.992 (0.950 approximately 1.037) and 1.051 (0.965 approximatly 1.144), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value of Tmax was 0.000 (-0.250 approximatly 0.125). Moreover, the modified Pitman-Morgan's adjusted F test and equal variance test (one-sided) indicated that the 2 medications were comparable in intra- and inter-individual variability in cycloserine bioavailability. CONCLUSION: Therefore, these results indicate that the 2 medications of cycloserine are bioequivalent and, thus, may be prescribed interchangeably.

Administration, Oral↗
PubMed2000

Domestic and school violence among high school students in Jamaica.

This study determined the prevalence of domestic and school violence among high school students in Jamaica. A self-report questionnaire was administered to 3124 students (1467 boys and 1657 girls) from 34 randomly selected high schools in 13 of the 14 parishes in Jamaica. There were 1590 tenth graders (mean age 16 years) and 1534 eleventh graders (mean age 17 years). One thousand six hundred and seventeen students were from rural and 1507 from urban communities and 1642 and 1482 were children/wards of professionals and nonprofessionals, respectively. The results revealed that 78.5% of the students had witnessed violence in their communities, 60.8% in their schools, and 44.7% in their homes. Twenty-nine per cent of the students had caused injury to persons. Several weapons and techniques were used by the students during violent acts and these included the use of hands or feet 59.8%, nasty words 59.1%, kicks and punches 54.5%, blunt objects 26.5%, knives 18.4%, ice picks 9.3%, machetes 8.9%, scissors 8.5%, forks 7.5%, guns 6.9%, other weapons (e.g. bottles, dividers) 6.7%, acids 5.5%, and alkalis 4.9%. Significantly higher numbers of boys, 10th graders, and urban students indicated that they used more of the 14 weapons than girls, 11th graders and rural students, respectively. Effective programmes are urgently needed to address the high rate of violence recorded in this study among high school youths in Jamaica.

Adolescent↗
PubMed2000

No effect of water deprivation for 48 hours on the pharmacokiinetics of intravenous tacrolimus in rats.

Because the physiological changes that occur in patients with water deprivation could alter the pharmacokinetics of drugs, the pharmacokinetics of tacrolimus were investigated after 1-min intravenous administration of the drug (1 mg/kg) to control rats and rats with water deprivation for 48 h. In rats with dehydration, kidney function seemed to be impaired slightly. Kidney weight (0.800 versus 0.676% body weight) increased significantly and the renal tissue showed only total and mild tubular dilatation and flattening of tubular epithelial cells based on kidney microscopy. However, hepatic function seemed not to be impaired in rats with dehydration. After intravenous administration of tacrolimus, the pharmacokinetic parameters were not significantly different between two groups of rats and the results were expected since tacrolimus was almost completely metabolized in rats (impaired kidney function could not affect considerably the pharmacokinetics of tacrolimus) and hepatic function was not impaired in rats with dehydration.

Animals↗
PubMed2000

Factors influencing the protein binding of IQO4, a new isoquinolinedione derivative.

Various factors most likely to influence the plasma protein binding of IQO4, a new isoquinolinedione derivative, to 4% human serum albumin (HSA) were evaluated using an equilibrium dialysis technique at an initial IQO4 concentration of 5 microg/ml. It took approximately 12 h incubation to reach an equilibrium between 4% HSA and isotonic Sørensen phosphate buffer at pH 7.4 containing 3% dextran ('the buffer') using a Spectra/Por 2 membrane (molecular weight cut-off, 12000-14000) in a water-bath shaker kept at 37 degrees C and at a rate of 50 oscillations per min. IQO4 was stable both in 4% HSA and in 'the buffer' for up to 24 h incubation at 37 degrees C. The binding of IQO4 was constant (89.9 +/- 1.40%, mean +/- standard deviation) at IQO4 concentrations ranging from 1 to 100 microg/ml. However, the extent of binding was dependent on HSA concentrations. The values were 32.5, 62.0, 79.1, 84.9, 90.9, 91.2, and 91.7% at HSA concentrations of 0.5, 1, 2, 3, 4, 5, and 6%, respectively; on incubation temperature, 96.7, 93.8, and 91.0% when incubated at 4, 22, and 37 degrees C, respectively; and on the buffer pHs, 84.4, 87.2, 88.2, 90.9, and 92.3% for the buffer pHs of 5.8, 6.4, 7, 7.4, and 8, respectively. The free fraction of IQO4 increased with the addition of sulfisoxazole (0-300 microg/ml), and salicylic acid (0-300 microg/ml). The protein binding of IQO4 was independent of the quantity of alpha-1-acid glycoprotein (up to 0.32%), chloride ion (up to 0.546%) and heparin (up to 40 units/ml).

Buffers↗
PubMed2000

Effects of neostigmine on the pharmacokinetics of intravenous parathion in rats.

It was reported that the area under the plasma concentration-time curve from time zero to time infinity (AUC) of parathion was significantly smaller and the time-averaged total body clearance (CL) of parathion was significantly faster after intravenous administration of parathion to rats pretreated with dexamethasone than those in control rats. This was supported by significantly faster intrinsic clearance of parathion to form paraoxon in hepatic microsomal fraction of rats pretreated with dexamethasone. The above data suggested that parathion was metabolized to paraoxon by dexamethasone-inducible hepatic cytochrome P450 (CYP) 3A in rats. The purpose of this study is to explain the protective effects of neostigmine against paraoxon toxicity by suppressing CYP3A and hence decreasing formation of toxic metabolite, paraoxon by neostigmine. The pharmacokinetic changes of parathion and its active metabolite, paraoxon, were investigated after intravenous administration of parathion, 3 mg/kg, to control Sprague-Dawley rats and the rats pretreated with neostigmine (200 microg/kg, intraperitoneal injection 30 min before parathion administration). After 1-min intravenous infusion of parathion to rats pretreated with neostigmine, the AUC of parathion (65.1 versus 74.3 microg min/ml) was significantly greater and the CL of parathion (45.1 versus 40.4 ml/min/kg) was significantly slower than those in control rats. Based on in vitro hepatic microsomal studies, neostigmine inhibited significantly the erythromycin N-demethylase activity (1.03 versus 0.871 nmol/mg protein/min), mainly mediated by hepatic cytochrome P450 3A in rats. The above data suggested that the formation of paraoxon was inhibited in rats pretreated with neostigmine by inhibiting CYP3A.

Animals↗
PubMed2000

Pharmacokinetics, stability, and blood partition of DA-8159, a new phosphodiesterase V inhibitor.

The pharmacokinetics of DA-8159, a new phosphodiesterase V inhibitor, after 1 min intravenous, 30 mg/kg, and oral, 30 mg/kg, administration of the drug to rats, the stability of DA-8159 in various pH solutions ranging from 1 to 13, and human and rat plasma and urine, and the blood partition of DA-8159 between plasma and blood cells of rabbit were evaluated. After intravenous administration, DA-8159 was eliminated fast with the mean total body clearance of 126 ml/min/kg, and was almost completely metabolized in rats; 5.98% of intravenous dose of DA-8159 were excreted unchanged in 24-hr urine. The extent of absolute oral bioavailibility of DA-8159 was approximately 25%. The apparent volume of distribution at steady state was considerably large, 15048 ml/kg, suggesting that DA-8159 has a good affinity to rat tissues. DA-8159 was relatively stable in various pH solutions, and human and rat plasma and urine for up to 48 h incubation in a water-bath shaker kept at 37 degrees C and at a rate of 50 oscillations per min. DA-8159 reached equilibrium fast (within 30 sec mixing manually) between plasma and blood cells of rabbit blood and the plasma-to-blood cell concentration ratios were independent of initial blood concentrations of DA-8159, 1, 5, and 10 microg/ml, when the rabbit whole blood was incubated for up to 120 min; the ratios were in the range of 0.662-0.812. There was no in vitro 'blood storage effect' in the plasma concentration of DA-8159.

3',5'-Cyclic-GMP Phosphodiesterases↗