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Biomedical subjects

John Kim

Publications and source records attributed to John Kim.

At least 37 records · Page 2Linked to original sources
PubMed2005

In vitro investigation of the hepatic intrinsic clearance of apicidin, a histone deacetylase inhibitor, in mouse, rat, and human, with correction by nonspecific protein binding.

Apicidin is a potent histone deacetylase inhibitor exhibiting broad-spectrum antiprotozoal, antiproliferative, and antiangiogenic activities. This study was conducted to calculate the intrinsic hepatic clearance of apicidin in mouse, rat, and human. The microsomal stability was determined in pooled microsomes of mouse, rat, and human. The V(max) and K(m) were 680.4 ng/min/mg protein and 10,544.1 ng/ml for mouse, 745.0 ng/min/mg protein and 24,306.0 ng/ml for rat, and 927.0 ng/min/mg protein and 62,906.0 ng/ml for human, respectively. The f(u,plasma) was extremely low, 0.369 +/- 0.034% for mouse, 0.376 +/- 0.059% rat, and 1.042 +/- 0.114% human. The unbound fraction of apicidin in microsomes (f(u,mic)) was also low, 1.731 +/- 0.237% for mouse, 0.767 +/- 0.048% for rat, and 5.751 +/- 1.575% for human. The hepatic intrinsic clearance calculated by Michaelis kinetics was further corrected by nonspecific binding to microsomal proteins. The corrected intrinsic clearance of apicidin was 1.9, 8.6, and 284.2 ml/min for mouse, rat, and human, respectively. The allometric correlation was improved when the hepatic intrinsic clearance was corrected by the nonspecific protein binding.

Animals↗
PubMed2005

Pharmacokinetics of lithospermic acid B isolated from Salvia miltiorrhiza in rats.

The absorption and pharmacokinetics of an active component of Salvia miltiorrhiza, lithospermic acid B (LSB), was investigated after intravenous and oral administration of doses of 10 or 50 mg LSB/kg to rats. Concentrations of LSB were determined by a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay method. After intravenous administration of 50 mg/kg, dose-normalized (10 mg/kg) area under the curve (AUC) (993 microg.min/ml) was significantly greater than that at 10 mg/kg (702 microg.min/ml). The slower clearance Cl-at 50 mg/kg could be due to saturable metabolism of LSB in rats, and this could be supported by significantly slower Cl(NR) and significantly greater 24-h urinary excretion of LSB at 50 mg/kg than at 10 mg/kg. Following oral administration of LSB, the extent of LSB recovered from the entire gastrointestinal tract at 24 h ranged from 41.2% to 23.3%. Although LSB was not detected (limit of quantitation 10 ng/ml) in plasma after oral dose of 10 mg/kg, the absolute oral bioavailability at 50 mg/kg was 5%. Since LSB was shown to have low permeability through the Caco-2 cell monolayers, the low bioavailability of LSB could be due to poor absorption and metabolism.

Administration, Oral↗
PubMed2005

Preoperative radiation with concurrent chemotherapy for resectable rectal cancer: effect of dose escalation on pathologic complete response, local recurrence-free survival, disease-free survival, and overall survival.

PURPOSE: Three Phase II studies of preoperative radiotherapy and concurrent 5FU chemotherapy were undertaken. The primary endpoints were acute toxicity and pathologic complete response rate (pCR). Secondary endpoints were local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS). METHODS AND MATERIALS: A total of 134 patients with adenocarcinoma of the rectum (clinical T3/T4 or N1/N2) were treated. The initial cohort received 40 Gy in 20 fractions, the second 46 Gy in 23 fractions, and the third 50 Gy in 25 fractions. 5FU (225 mg/m2/day) was given continuously throughout radiotherapy. A total of 121 patients underwent surgical resection. RESULTS: Treatment was well tolerated. Grade 3/4 acute toxicity was observed in 13%, 4%, and 14% of patients in the 40 Gy, 46 Gy, and 50 Gy cohorts, respectively (p = 0.20). pCR was documented in 15%, 23%, and 33% of patients, respectively (p = 0.07). The 2-year actuarial LRFS was 72%, 90%, and 89% (p = 0.02); DFS was 62%, 84%, and 78% (p = 0.02); and OS was 72%, 94%, and 92%, respectively (p = 0.03). CONCLUSIONS: All treatment schedules were well tolerated. There was a trend toward increased pCR with higher doses. A statistically significant increase in LRFS, DFS, and OS was seen with radiation doses of 46 Gy and greater, but there was no difference between 46 Gy and 50 Gy.

Antimetabolites, Antineoplastic↗
PubMed2005

Primary radical external beam radiotherapy of rectal adenocarcinoma: long term outcome of 271 patients.

BACKGROUND AND PURPOSE: To assess local control, survival and toxicity following primary radical external beam radiotherapy of rectal adenocarcinoma treated between 1978 and 1997, and to compare practices and outcomes between the two decades of study. PATIENTS AND METHODS: A retrospective review of 271 patients who underwent primary radical external beam radiotherapy, without prior or concurrent chemotherapy, was conducted. All patients received radiation doses of at least 40 Gy. Most patients (82%) were followed until death. RESULTS: Tumor fixation was the only significant prognostic factor for complete response by multivariate analysis. Complete response rates for mobile, partially fixed and fixed tumors were 49, 22 and 9%, respectively. For patients with mobile, partially fixed and fixed tumors, overall 5 year survival was 48, 26 and 6%, respectively, and cancer specific 5 year survival was 59, 33 and 9%, respectively. On multivariate analysis, tumor fixation and CEA higher than 8.7 microg/L at presentation were associated with significantly shortened survival. Outcomes did not change significantly during the two decades of the study. RTOG grade 3 or higher acute (1.8%) and late (1.5%) toxicity occurred only in the first decade of study. CONCLUSIONS: Radical external beam radiotherapy is a reasonable treatment option for rectal carcinoma for patients who are not surgical candidates or refuse surgery. However in patients with fixed tumors in this study, the outcome is poor and treatment should be considered palliative. Severe radiation toxicity is infrequent with current schedules and techniques of radiotherapy.

Adenocarcinoma↗
PubMed2005

IMRT for adjuvant radiation in gastric cancer: a preferred plan?

PURPOSE: To assess the potential advantage of intensity-modulated radiotherapy (IMRT) over conformal planning for postoperative adjuvant radiotherapy in patients with gastric carcinoma. METHODS AND MATERIALS: Twenty patients who had undergone treatment planning with conformal beam arrangements for 4500 cGy adjuvant radiotherapy between 2000 and 2001 underwent repeat planning using IMRT techniques. Conformal five-field plans were compared with seven- to nine-field coplanar sliding-window IMRT plans. For each patient, the cumulative dose-volume histograms and organ-dose summaries (without distributions or digitally reconstructed radiographs) were provided to two independent, "blinded" GI radiation oncologists. The oncologists indicated which plan provided better planning target volume coverage and critical organ sparing, any safety concerns with either plan, and which plan they would choose to treat the patient. RESULTS: In 18 (90%) of 20 cases, both oncologists chose the same plan. Cases with disagreement were given to a third "blinded" reviewer. A "preferred plan" could be determined in 19 (95%) of 20 cases. IMRT was preferred in 17 (89%) of 19 cases. In 4 (20%) of 20 IMRT plans at least one radiation oncologist had safety concerns because of the spinal cord dose (3 cases) or small bowel dose (2 cases). Of 42 ratings, IMRT was thought to provide better planning target volume coverage in 36 (86%) and better sparing of the spinal cord in 31 (74%) of 42, kidneys in 29 (69%), liver in 30 (71%), and heart in 29 (69%) of 42 ratings. The median underdose volume (1.7 vs. 4.1 cm3), maximal dose to the spinal cord (36.85 vs. 45.65 Gy), and dose to 50% of the liver (17.29 vs. 27.97), heart (12.89 vs. 15.50 Gy), and left kidney (15.50 vs. 16.06 Gy) were lower with IMRT than with the conformal plans. CONCLUSION: Compared with the conformal plans, oncologists frequently preferred IMRT plans when using dose-volume histogram data. The advantages of IMRT plans include both improved planning target volume coverage and improved sparing of critical organs. We are currently studying organ motion in the upper abdomen as a prerequisite to using IMRT for actual patient treatment.

Adult↗
PubMed2005

Development of a liquid chromatography/electrospray tandem mass spectrometry assay for the quantification of apicidin, a novel histone deacetylase inhibitor, in rat serum: application to a pharmacokinetic study.

Apicidin, a fungal metabolite isolated from Fusarium pallidoroseum, is a cyclic tetrapeptide that exhibits potent anti-protozoal and anti-angiogenic activities. Although extensive studies have been recently conducted to examine the biological and pharmacological action, no information is available on the quantitative analysis of apicidin. To our knowledge, this study is the first to describe a rapid and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay method for the quantification of apicidin in rat serum. The method was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification (LLOQ), accuracy, and precision. The multiple reaction monitoring was based on the transitions m/z 624.7 --> 84.3 and 372.1 --> 176.1 for apicidin and trazodone, respectively. The assay utilized a single liquid-liquid extraction and isocratic elution, and the LLOQ was 0.5 ng/mL using 0.1 mL of rat serum. The assay was linear over a range from 0.5-1000 ng/mL, with correlation coefficients >0.9994. The mean intra- and inter-day assay accuracy ranged from 99.9-101.5% and 94.8-102.1%, respectively, and the mean intra- and inter-day precision was between 2.7-5.9% and 1.6-11.5%, respectively. The developed assay method was applied to a pharmacokinetic study after intravenous injection of apicidin in rats at a dose of 1 mg/kg.

Animals↗
PubMed2005

Doubly branched hexasaccharide epitope on the cell wall polysaccharide of group A streptococci recognized by human and rabbit antisera.

A number of epitope specificities associated with the cell wall polysaccharide antigen of group A streptococci were identified in a polyclonal rabbit antiserum induced in rabbits by whole group A streptococci and in polyclonal convalescent human antisera from children that had recovered from streptococcal A infections. The identification was achieved by using a series of synthetic oligosaccharides, glycoconjugates, and bacterial polysaccharide inhibitors to inhibit the binding of the group A helical polysaccharide to the polyclonal antisera. The exclusively dominant epitope expressed in the convalescent human antisera was the doubly branched extended helical hexasaccharide with the structure alpha-L-Rhap(1-->2)[beta-D-GlcpNAc(1-->3)]alpha-L-Rhap(1-->3)alpha-L-Rhap(1-->2)[beta-D-GlcpNAc(1-->3)]alpha-L-Rhap. The hexasaccharide epitope also bound with the highest immunoreactivity to the rabbit antiserum. In contrast, the human antisera did not show significant binding to the singly branched pentasaccharide with the structure alpha-L-Rhap(1-->2)alpha-L-Rhap(1-->3)alpha-L-Rhap(1-->2)[beta-D-GlcpNAc(1-->3)]alpha-L-Rhap or the branched trisaccharide alpha-L-Rhap(1-->2)[beta-D-GlcpNAc(1-->3)]alpha-l-Rhap, although both these haptens bound significantly to the same rabbit antiserum, albeit with less immunoreactivity than the hexasaccharide. Inhibition studies using streptococcal group A and B rabbit antisera and the inhibitors indicated above also suggested that the group A carbohydrate, unlike the group B streptococcal polysaccharide, does not contain the disaccharide alpha-L-Rhap(1-->2)alpha-L-Rhap motif at its nonreducing chain terminus, stressing the importance of mapping the determinant specificities of these two important streptococcal subcapsular group polysaccharides to fully understand the serological relationships between group A and group B streptococci.

Animals↗
PubMed2004

Tolerability of the Intergroup 0099 (INT 0099) regimen in locally advanced nasopharyngeal cancer with a focus on patients' nutritional status.

PURPOSE: The Intergroup 0099 trial (INT 0099) for locally advanced nasopharyngeal cancer (NPC) has set a standard of practice. This retrospective review documents our institutional experience with this regimen. METHODS AND MATERIALS: For all NPC patients treated between January 1998 and December 2002 with the INT 0099 regimen, compliance, toxicity, weight change, and feeding tube use were recorded. Patients were grouped by therapy completion status and by feeding tube status. RESULTS: Of 78 consecutive patients, 75 were evaluable. Compliance with radiotherapy was excellent. Only 43% and 61% of patients received all cycles of concurrent and adjuvant chemotherapy, respectively. Patients who successfully completed therapy had a higher average baseline weight and were more likely to have had a prophylactic feeding tube. Forty of 75 patients had a feeding tube inserted and were analyzed as two groups. Patients with prophylactic insertion (n = 23) had a more gradual drop in weight, and recovered to a greater degree at 1 year (93.6% vs. 87.2%), than those with a feeding tube inserted therapeutically during treatment (n = 17). CONCLUSIONS: The INT 0099 regimen was generally delivered with modifications to the chemotherapy component, as in the original trial. The prophylactic insertion of a feeding tube may facilitate therapy completion and weight recovery in some patients.

Adolescent↗
PubMed2004

An integrity assay for a meningococcal type B conjugate vaccine.

The development of an analytical procedure for the evaluation of a conjugate vaccine's structural wholeness or integrity is described. The principle component of the vaccine was the N-propionylated group B meningococcal polysaccharide (NPr-GBMP) covalently attached to a carrier protein. The goal of the procedure was to determine whether any whole polysaccharide, oligosaccharide, or monosaccharide, from minute to moderate levels, became detached off the conjugate. Free saccharide was isolated from the formulation, which included an aluminum hydroxide adjuvant for analysis. Due to its linkage, the NPr-GBMP did not release sialic acid efficiently with acid hydrolysis to the extent necessary for accurate quantitation. To accomplish depolymerization, the NPr-GBMP was subjected to methanolysis, 3N hydrochloric acid in methanol for 16h at 80 degrees C. The main product of the methanolysis reaction was a de-N-acylated methyl glycoside of sialic acid. N-acetylneuraminic acid oligomers and colominic acid were used to confirm the methanolysis depolymerization efficiency of the alpha(2 --> 8) saccharides; with the treatment all oligomers produced a common methyl glycoside. For this determination anion exchange chromatography and size exclusion chromatography were both interfaced to an integrated pulsed amperometric detector. Sensitivity and linearity were demonstrated to be sufficient for the application with vaccine dose formulations with low total saccharide concentrations.

Bacterial Capsules↗
PubMed2004

Is expert breast pathology assessment necessary for the management of ductal carcinoma in situ ?

BACKGROUND: Current guidelines include a recommendation that a pathologist with expertise in breast disease review all ductal carcinoma in situ (DCIS) specimens due to the presence of significant variability in pathologic reporting of DCIS. The objective of this study was to evaluate the completeness and accuracy of pathologic reporting of DCIS over the past decade and to determine the current impact of expert breast pathology assessment on the management of DCIS. METHODS: All patients with a diagnosis of DCIS referred to a single regional cancer centre between 1982 and 2000 have been reviewed. Inter-observer variability between initial and secondary reports has been evaluated using kappa statistics. For each case, the Van Nuys Prognostic Index (VNPI) using pathologic data obtained from the initial and reviewed pathology reports were compared. The impact of expert breast pathology on risk assessment and treatment was determined. RESULTS: 481 individuals with DCIS were referred and pathology review was performed on 350 patients (73%). Inter-observer agreement was high for the main pathologic features of DCIS. From 1996 to 2000, secondary pathology assessments lead to a change in the assessment of local recurrence risk in 100 cases (29%) and contributed to a change in treatment recommendation in 93 (43%) cases. CONCLUSION: Expert breast pathology assessments continue to be necessary in the management of DCIS.

Adult↗
PubMed2004

Amniotic band sequence: the use of bone grafting and distraction osteogenesis.

Distraction has proven to be a useful technique in cases of severe bone deficiency in the craniofacial skeleton. This is a report of its use in the treatment of a child affected by amniotic band sequence. This 5 year old Hispanic female presented with transverse deficiences of one lower extremity and both upper extremities. Additionally, she was missing the mandible and overlying soft tissue from ramus to ramus. Although free fibula transfer was a possibility, due to the presence of only one lower extremity, it was elected to utilize the technique of distraction. After preliminary bone grafting to unite these two hemimanibles, the bone graft was distracted bilaterally to create a neomandible. Following consolidation and removal of the distraction devices, the child was markedly improved despite what appeared to be a pathologic fracture in the region of the mandibular angle. Repeat distraction was planned.

Amniotic Band Syndrome↗
PubMed2004

Rhinoplasty with advancing age.

Rhinoplasty in the aging patient poses a unique set of challenges to the plastic surgeon. Aging patients usually have different expectations and motivations than their younger counterparts; therefore, open communication and frank discussions are paramount to define realistic goals. Anatomically, changes in skin quality, cartilage characteristics, underlying bony framework, and the nasal airways mandate special considerations to optimize the functional and aesthetic results. This review will present a practical approach to the management of the nose in the aging patient.

Aged↗
PubMed2004

Stereoselective pharmacokinetics of fluoxetine and norfluoxetine enantiomers in pregnant sheep.

We examined the stereoselective disposition of fluoxetine (FX) and its metabolite norfluoxetine (NFX) in five pregnant sheep. Racemic FX was administered i.v. to the ewe (50 mg) and the fetus (10 mg) on separate occasions. Maternal and fetal blood, maternal urine, and fetal amniotic and tracheal fluid samples were collected for 72 h. FX and NFX isomers were quantified by gas chromatography-mass spectrometry. They rapidly crossed the placenta [maternal to fetal area under the plasma concentration versus time curve (AUC) ratios 0.59 and 0.65, respectively]. There was significant FX stereoselectivity with S/R FX AUC ratios averaging 1.65 +/- 0.33 and 1.73 +/- 0.29 in ewe and fetus, respectively, after maternal dosing. The maternal clearance and volume of distribution were also higher for (R)-fluoxetine than for (S)-fluoxetine. FX, NFX, and their glucuronides were present in maternal urine but accounted for only 3.4% of maternal drug elimination. In contrast, NFX was not detected in the fetus after fetal FX administration, which is consistent with the absence of measurable fetal nonplacental clearance of the drug and the lack of NFX formation in fetal hepatic microsomal incubations. There was also no fetal production of FX and NFX glucuronides in vivo. Both FX and NFX were extensively and stereoselectively bound in maternal and fetal plasma, with the free fraction S/R FX ratio averaging 0.46 +/- 0.06 and 0.58 +/- 0.10 in ewe and fetus, respectively. Thus, FX exhibits extensive stereoselective disposition, which is likely due to differential plasma protein binding of the FX isomers, and there is no detectable fetal formation of NFX, FX, and NFX glucuronides.

Animals↗
PubMed2003

Identification of many microRNAs that copurify with polyribosomes in mammalian neurons.

Localized translation in mammalian dendrites may play a role in synaptic plasticity and contribute to the molecular basis for learning and memory. The regulatory mechanisms that control localized translation in neurons are not well understood. We propose a role for microRNAs (miRNAs), a class of noncoding RNAs, as mediators of neuronal translational regulation. We have identified 86 miRNAs expressed in mammalian neurons, of which 40 have not previously been reported. A subset of these miRNAs exhibits temporally regulated expression in cortical cultures. Moreover, all of the miRNAs that were tested cofractionate with polyribosomes, the sites of active translation. These findings indicate that a large, diverse population of miRNAs may function to regulate translation in mammalian neurons.

Animals↗
PubMed2003

An innovative technique of vertebral body stapling for the treatment of patients with adolescent idiopathic scoliosis: a feasibility, safety, and utility study.

STUDY DESIGN: Retrospective review. OBJECTIVES: To report the feasibility, safety, and utility of vertebral body stapling without fusion as an alternative treatment for adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: The success rate of brace treatment of adolescent idiopathic scoliosis ranges from 50% to 82%. However, poor self-image and brace compliance are issues for the patient. An alternative method of treatment such as a motion-preserving vertebral body stapling to provide curve stability would be desirable. METHODS: We retrospectively reviewed 21 patients (27 curves) with adolescent idiopathic scoliosis treated with vertebral body stapling. Patients were immature as defined by Risser sign or=6 degrees or beyond 50 degrees was considered a failure of treatment. Of these 10 patients, 6 (60%) remained stable or improved and 4 (40%) progressed. One of 10 (10%) in the stapling group had progressed beyond 50 degrees and went on to fusion. Six patients required stapling of a second curve, three as part of the primary surgery, and three as a second stage, because a second untreated curve progressed. The results need to be considered with caution, as the follow-up is still short. CONCLUSIONS: The data demonstrate that vertebral body stapling for the treatment of scoliosis in the adolescent was feasible and safe in this group of 21 patients. In the short-term, stapling appears to have utility in stabilizing curves of progressive adolescent idiopathic scoliosis.

Adolescent↗
PubMed2003

Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents.

PURPOSE: Molecular targeted agents have been combined with radiotherapy (RT) in recent clinical trials in an effort to optimize the therapeutic index of RT. The appeal of this strategy lies in their potential target specificity and clinically acceptable toxicity. DESIGN: This article integrates the salient, published research findings into the underlying molecular mechanisms, preclinical efficacy, and clinical applicability of combining RT with molecular targeted agents. These agents include inhibitors of intracellular signal transduction molecules, modulators of apoptosis, inhibitors of cell cycle checkpoints control, antiangiogenic agents, and cyclo-oxygenase-2 inhibitors. RESULTS: Molecular targeted agents can have direct effects on the cytoprotective and cytotoxic pathways implicated in the cellular response to ionizing radiation (IR). These pathways involve cellular proliferation, DNA repair, cell cycle progression, nuclear transcription, tumor angiogenesis, and prostanoid-associated inflammation. These pathways can also converge to alter RT-induced apoptosis, terminal growth arrest, and reproductive cell death. Pharmacologic modulation of these pathways may potentially enhance tumor response to RT though inhibition of tumor repopulation, improvement of tumor oxygenation, redistribution during the cell cycle, and alteration of intrinsic tumor radiosensitivity. CONCLUSION: Combining RT and molecular targeted agents is a rational approach in the treatment of solid tumors. Translation of this approach from promising preclinical data to clinical trials is actively underway.

Angiogenesis Inhibitors↗
PubMed2003

Simultaneous determination of sildenafil and its active metabolite UK-103,320 in human plasma using liquid chromatography-tandem mass spectrometry.

A liquid chromatography-tandem mass spectrometric method for the simultaneous determination of sildenafil and its active N-demethylated metabolite, UK-103,320 in human plasma was developed. Sildenafil, UK-103,320 and the internal standard (DA-8159) were extracted from human plasma with dichloromethane at basic pH. A reverse-phase LC separation was performed on Luna phenylhexyl column with the mixture of acetonitrile-ammonium formate (10 mM, pH 6.0) (60:40, v/v) as mobile phase. The detection of analytes was performed using an electrospray ionization tandem mass spectrometry in the multiple reaction-monitoring mode. The lower limits of quantification for sildenafil and UK-103,320 were 2.0 ng/ml. The method showed a satisfactory sensitivity, precision, accuracy, recovery and selectivity.

Gas Chromatography-Mass Spectrometry↗