Biomedical subjects

C L Chen

Publications and source records attributed to C L Chen.

At least 55 records · Page 3Linked to original sources

PubMed2001

Reappearance of HBsAg with compartmentalized different HBV strains in allograft versus PBMC of the recipient.

A woman who was positive for anti-hepatitis B surface antigen (anti-HBs) and anti-hepatitis B core antigen (anti-HBc) received an orthotopic liver transplantation from an anti-HBc-seropositive donor in November 1985. Reappearance of hepatitis B surface antigen (HBsAg) was noted 5 months after the transplantation, but it was not associated with significant liver inflammation. Ten years after the transplantation, results of serum hepatitis B virus (HBV) DNA study, by nested polymerase chain reaction, were negative. However, HBV DNA was detected in the transplanted liver tissues and peripheral blood mononuclear cells. Different strains were identified in these two organs. An adw strain was found in the transplanted liver, whereas an adr strain with long segment deletions in the core gene was found in the peripheral blood mononuclear cells. Covalently closed circular HBV DNA was not detected in any of the tissues examined. Occult HBV infection in the donor as well as the recipient is common in HBV endemic areas. The recipient in this case had reappearance of hepatitis B surface antigen (HBsAg) in the serum after transplantation. Nevertheless, 10 years later, two different strains of HBV were identified in different organs, without cross infection. The present case demonstrates that HBsAg reappearance was not associated with reactivation of the virus and liver inflammation. This type of HBsAg reappearance did not appear to produce a significant hazard to the transplanted liver.

Adult↗

PubMed2001

Electron microscopic observations of a marine fish iridovirus isolated from brown-spotted grouper, Epinephelus tauvina.

The morphogenesis and the ultrastructure of a marine fish iridovirus isolated from diseased grouper, Epinephelus tauvina were studied by electron microscopy. The virus was grown on a marine fish cell line (GP) at 25 degrees C. After appearance of advanced cytopathic effect (CPE), various morphogenetic stages of virus amplification, maturation and assembly were detected in the cytoplasm of virus-infected cells. The matured nucleocapsids were probably formed by insertion of electron-dense core material into a partly forming empty capsid just before completely sealed. The nucleocapsids were located at the assembly sites as pseudocrystalline arrays or scattered individually. In the late phase of infection, the nucleocapsids were enveloped and released by budding from the plasma membrane. The budding virus particles could directly enter neighbouring cells by endocytosis to start the next round infection. Ultrastructure of the grouper iridovirus was studied using the methods of enzymatic digestions and detergent degradations. The purified iridovirus particles showed a three-layered membrane including an external lipoprotein envelope, an inner periodic protein capsid and a lipid-containing membrane. The regular array of surface capsid subunits was observed after degradation with detergent.

Animals↗

PubMed2001

Assessment of the myocardial changes in heart transplant recipients without evident acute myocardial rejection by integrated backscatter: comparison with simultaneous dobutamine stress echocardiography and (201)thallium spect.

Cardiomyocyte hypertrophy and interstitial fibrin deposition develop in cardiac allografts and contribute to the functional changes of transplanted hearts. We hypothesized that integrated backscatter (IBS) can detect these myocardial changes. A total of 32 heart transplant recipients with either no or mild acute rejection (International Society of Heart and Lung Transplantation grade IA) were enrolled in this study. IBS data of myocardium were collected immediately before simultaneous dobutamine stress echocardiography (DSE) and (201)thallium imaging. Coronary angiography and endomyocardial biopsy were also performed. Coronary angiography showed diffuse narrowing in 1 patient who also had abnormal results of IBS, DSE, and thallium results. In the other 31 patients with patent coronary arteries, there were 3 patients (10%) with abnormal DSE results, 19 patients (61%) with abnormal IBS patterns, and 16 patients (52%) with reversible thallium perfusion defects. Of the patients, 44% had cardiomyocyte hypertrophy and 56% interstitial fibrin deposition. There were significant differences in the prevalence of (201)thallium perfusion defects and serum cyclosporine levels between patients with and without abnormal IBS patterns. Pathologic changes were also associated with abnormal IBS patterns (p = 0.01). However, there was no association between abnormal IBS and DSE results. By multiple logistic regression analysis, the abnormal IBS patterns were associated inversely with serum cyclosporine level (p = 0.028). In conclusion, abnormal IBS patterns are associated significantly with perfusion heterogeneity and pathologic changes in heart transplant recipients without evident acute myocardial rejection. There is no association between abnormal IBS patterns and dobutamine-induced dyssynergy in these patients. IBS provides a noninvasive approach for detection of myocardial changes in transplanted hearts without evident acute rejection.

Cardiac Catheterization↗

PubMed2001

The role of age and salivation in acid clearance in symptomatic patients with gastro-oesophageal reflux disease.

BACKGROUND: Cisapride has been shown to have not only prokinetic effects, but also salivary stimulating effects. Both of these mechanisms play an important role in the acid clearance of the oesophagus. AIM: To access the efficacy of cisapride in facilitating acid clearance in patients with symptomatic gastro-oesophageal reflux disease. METHODS: Fifteen older adults and 15 younger adults with symptomatic gastro-oesophageal reflux disease completed the study. The acid clearance test was accomplished by infusing 15 mL of 0.1 N HCl into the distal oesophagus, and the number of swallows was determined to achieve an oesophageal pH of 4.0. This was accomplished under baseline conditions and salivary stimulation with a peppermint lozenge. After 1 week of treatment with cisapride (10 mg, q.d.s.), the acid clearance test was repeated. RESULTS: The lozenge produced a significant decrease in the number of swallows compared to baseline in both groups (P < 0.01). There was a significant decrease in the number of swallows after the treatment with cisapride compared to baseline in both groups (P < 0.01). No significant difference was found in the number of swallows when comparing cisapride with lozenge. CONCLUSIONS: Cholinergic stimulation of salivation is an effective means of facilitating oesophageal acid clearance. Drugs, such as 5 hydroxytriptamine (5-HT)4-receptor agonists, should be considered as potentially important compounds in the treatment of gastro-oesophageal reflux disease.

Aged↗

PubMed2001

Acute oxalate nephropathy after ingestion of star fruit.

Acute oxalate nephropathy associated with ingestion of star fruit (carambola) has not been reported before. We report the first two cases. These patients developed nausea, vomiting, abdominal pain, and backache within hours of ingesting large quantities of sour carambola juice; then acute renal failure followed. Both patients needed hemodialysis for oliguric acute renal failure, and pathologic examinations showed typical changes of acute oxalate nephropathy. The renal function recovered 4 weeks later without specific treatment. Sour carambola juice is a popular beverage in Taiwan. The popularity of star fruit juice is not compatible with the rare discovery of star fruit-associated acute oxalate nephropathy. Commercial carambola juice usually is prepared by pickling and dilution processes that reduce oxalate content markedly, whereas pure fresh juice or mild diluted postpickled juice for traditional remedies, as used in our cases, contain high quantities of oxalate. An empty stomach and dehydrated state may pose an additional risk for development of renal injury. To avoid acute oxalate nephropathy, pure sour carambola juice or mild diluted postpickled juice should not be consumed in large amounts, especially on an empty stomach or in a dehydrated state.

Acute Kidney Injury↗

PubMed2001

Acute oxalate nephropathy induced by star fruit in rats.

In this study, we intend to establish a connection between star fruit and acute oxalate nephropathy and also investigate predisposing factors for its development. Male Sprague-Dawley rats of 180 to 200 g were assigned to four groups; namely, control, experimental, fasting, and water-deprivation groups. The former two groups were subjected to both fasting and water deprivation, whereas the latter two groups were subjected to either fasting or water deprivation, respectively. Except for tap water for controls, the remaining groups were administered 4 mL/100 g of body weight of sour star fruit juice with an oxalate concentration of 2.46 g/dL. After these procedures, serial measurement of serum creatinine levels and kidney pathological examination were performed. Peak serum creatinine levels in the control, experimental, fasting, and water-deprivation groups were 0.50 +/- 0.04, 1.46 +/- 0.26, 0.68 +/- 0.20, and 0.52 +/- 0.08 mg/dL, respectively. The experimental group had a greater peak serum creatinine level (P < 0.05). Mean serum creatinine levels of the experimental group days 0, 1, 2, 3, 4, and 5 were 0.43 +/- 0.03, 1.11 +/- 0.18, 1.31 +/- 0.27, 1.16 +/- 0.28, 0.8 +/- 0.26, and 0.82 +/- 0.28 mg/dL, respectively. Mean serum creatinine levels days 1 to 3 were greater than that day 0 (P < 0.05). Pearson's correlation analysis of peak serum creatinine level and kidney weight for the experimental group showed a significant correlation (R = 0.75; P < 0.05; n = 9). In addition to typical changes of oxalate nephropathy, kidney pathological examination showed many refractile oxalate crystals with all rainbow colors under polarized light microscopy in the experimental group. In conclusion, sour star fruit with abundant oxalate contents could cause acute oxalate nephropathy in rats under the conditions of fasting and water deprivation.

Acute Kidney Injury↗

PubMed2001

Temporal stride and force analysis of cane-assisted gait in people with hemiplegic stroke.

OBJECTIVE: To understand the underlying biomechanics of temporal stride and force in people with hemiplegic stroke during cane-assisted walking. DESIGN: Three forceplates, 6 cameras, and an instrumented cane were integrated to analyze the cane-assisted gait of people with hemiplegic stroke. Temporal-stride parameters, and peak vertical, anterior (propulsive), posterior (braking), and lateral shear forces, as well as propulsive-breaking impulses were analyzed. SETTING: Chang Gung Memorial Hospital, Medical Center, Taiwan. PARTICIPANTS: Twenty people with hemiplegic stroke. MAIN OUTCOME MEASURES: Temporal-stride and force parameters. RESULTS: All patients walked at a relatively slow speed, ranging from 4.2 to 35.8cm/s. The triple and double support occupied most of the gait cycle (GC), whereas the single support occupied only 10% of GC. The applied vertical, propulsive, braking, and lateral shear forces on either foot and the cane were 89.7% to 97.6%, 2.2% to 4.8%, 2.9% to 3.9%, and 5.5% to 6.7% body weight (BW), respectively. Patients applied less than 25% BW of peak vertical forces on the cane. They applied greater peak propulsive forces and impulses on the sound foot, while applying greater peak braking forces and impulses on the affected foot and cane. CONCLUSIONS: The cane provided support and a braking function for people with hemiplegic stroke. People with stroke walking with cane assistance rely mostly on the sound limb for propulsion, while using the affected limb and cane for braking. Data provided could be useful in assessing the nature of cane assistance and in planning therapeutic strategies for people with stroke.

Adult↗

PubMed2001

Expression of multidrug resistance 1 and glutathione-S-transferase-Pi protein in nasopharyngeal carcinoma.

Radiotherapy is the modality of choice for the treatment of nasopharyngeal carcinoma (NPC). However, systemic chemotherapy has recently been found to play an increasing role in the treatment of advanced or metastatic disease. The status of drug resistance gene expression that has crucial impact on chemotherapy has not been fully addressed for patients with NPC. In this study, we examined the expression of multidrug resistance 1 (MDR-1) and glutathione-S-transferase-Pi (GST-Pi) in primary, recurrent, and metastatic NPC using results of immunohistochemical examinations. The results were correlated with the expression of Epstein-Barr virus (EBV) latent protein, latent membrane protein 1 (LMP1), and clinicopathologic features, including stage, histopathologic types, and survival rates. MDR-1 protein expression was detected in 18 (12.6%) of 143 patients with primary NPC, 14 (32.6%) of 43 with recurrent NPC, and O (0%) of 20 with metastatic NPC, whereas 83 (58%) of 143 patients with primary NPC, 30 (69.8%) of 43 with recurrent NPC, and 13 (65%) of 20 with metastatic NPC expressed GST-Pi. EBV-LMP1 was expressed in 59 (41.3%) of 143 patients with primary NPC, 23 (53.5%) of 43 with recurrent NPC, and 9 (45%) of 20 with metastatic NPC. Simultaneous expression of MDR1 and GST-Pi was observed in 13 (72.2%) of 18 patients with primary NPC and 12 (85.7%) of 14 with recurrent NPC. The expression of LMP1 was detected in only 6 of the 13 patients with primary NPC and 6 of the 12 with recurrent NPC. We concluded that the expression of GST-Pi was more frequent in NPC tumor tissues than the expression of MDR-1. The expression of MDR-1 correlated with clinicopathologic features of primary NPC, including the histopathologic types and survival rates, but not with disease stage. The expression of GST-Pi did not correlate with clinicopathologic features. The expression of MDR-1 and GST-Pi did not correlate with expression of EBV-LMP1 for patients with NPC.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Clinical features of familial gout and effects of probable genetic association between gout and its related disorders.

We examined whether the age at onset, gender, arthritic manifestations, and tophus formation in familial gout are different from those in nonfamilial gout, and we also examined the contributory effect of genetic association to the concurrence of hypertriglyceridemia, hypercholesterolemia, type 2 diabetes mellitus (DM), hypertension, obesity, and renal insufficiency with gout in Taiwan. A total of 21,373 gout patients' data from Ho-Ping Gout database were analyzed in this study retrospectively. The clinical and laboratory data were compared between familial and nonfamilial gout. Mean age at onset of gout in familial subjects was significantly 7.5 years lower than that of nonfamilial subjects (40.9 +/- 13.4 v 48.4 +/- 14.2 years, P =.0001), while gender, arthritic severity, and tophus formation were not significantly different between these 2 groups. Familial gout had lower serum triglyceride (TG), total cholesterol (TC), and percentage of hypertension than nonfamilial gout (182.4 +/- 125.3 v 195.9 +/- 135.8 mg/dL, P =.0001; 207.5 +/- 42.5 v 210.4 +/- 48.8 mg/dL, P =.0003; and 19.57% v 22.56%, P <.0001, respectively). Their serum creatinine, body mass index (BMI), and percentage of type 2 DM were not significantly different. Our results demonstrate that familial gout is associated with precocious onset. Furthermore, the contributory effect of genetic association to the concurrence of hyperlipidemia and hypertension with gout is less than that of environmental factors, while the effect of genetic association to the concurrence of obesity, type 2 DM, and renal insufficiency with gout is equivalent to that of environmental factors.

Age of Onset↗

PubMed2001

In vivo toxicity, pharmacokinetic features and tissue distribution of N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236), a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase.

N-[2-(2,5-Dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236, CAS 233271-65-3) possesses potent anti-viral activity against zidovudine-sensitive as well as multidrug-resistant HIV-1 (human immunodeficiency virus) strains. The purpose of the present study was to examine in vivo toxicity, pharmacokinetic features and tissue distribution of HI-236 in mice. HI-236 had an elimination half-life of 85.8 min after i.v. administration and 86.6 min after i.p. administration. The systemic clearance of HI-236 was 4337 ml/h/kg after i.v. administration and 10,130 ml/h/kg after i.p. administration. Following i.v. injection, HI-236 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in lung, adipose tissue, skin, urinary bladder, adrenal gland and uterus + ovary. The concentration of HI-236 in brain tissue was comparable to that in the plasma, indicating that HI-236 easily crosses the blood-brain barrier. Following i.p. injection, HI-236 was rapidly absorbed with a tmax values of 5.6 min and showed linear pharmacokinetics within the dose range of 10-80 mg/kg. Following oral administration, HI-236 was absorbed with a tmax of 5.8 min. The intraperitoneal bioavailability was estimated at 42.9%, while the oral bioavailability was only 2.2%. The pharmacokinetic study described herein provides the basis for advanced pharmacodynamic study of HI-236.

Animals↗

PubMed2001

Nuclear factor-kappaB (NF-kappaB) regulates proliferation and branching in mouse mammary epithelium.

The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types. Although recent studies have demonstrated aberrant expression or activity of NF-kappaB in human breast cancer cell lines and tumors, little is known regarding the precise role of NF-kappaB in normal proliferation and development of the mammary epithelium. We investigated the function of NF-kappaB during murine early postnatal mammary gland development by observing the consequences of increased NF-kappaB activity in mouse mammary epithelium lacking the gene encoding IkappaBalpha, a major inhibitor of NF-kappaB. Mammary tissue containing epithelium from inhibitor kappaBalpha (IkappaBalpha)-deficient female donors was transplanted into the gland-free mammary stroma of wild-type mice, resulting in an increase in lateral ductal branching and pervasive intraductal hyperplasia. A two- to threefold increase in epithelial cell number was observed in IkappaBalpha-deficient epithelium compared with controls. Epithelial cell proliferation was strikingly increased in IkappaBalpha-deficient epithelium, and no alteration in apoptosis was detected. The extracellular matrix adjacent to IkappaBalpha-deficient epithelium was reduced. Consistent with in vivo data, a fourfold increase in epithelial branching was also observed in purified IkappaBalpha-deficient primary epithelial cells in three-dimensional culture. These data demonstrate that NF-kappaB positively regulates mammary epithelial proliferation, branching, and functions in maintenance of normal epithelial architecture during early postnatal development.

Animals↗

PubMed2001

Lymphoepithelioma-like cholangiocarcinoma: an Epstein-Barr virus-associated tumor.

Epstein-Barr virus (EBV) has been linked to carcinomas of several body sites, especially of the nasopharynx, salivary gland, lung, and stomach. We present five cases of lymphoepithelioma-like cholangiocarcinoma, including one that had been previously reported. Two patients were men and three were women. Their ages ranged from 42 to 66 years. Histologically, all five tumors were composed of variable proportions of undifferentiated epithelial cells and glandular components in a lymphocyte-rich stroma. EBV was detected in all five tumors by in situ hybridization for EBER-1 in both lymphoepithelioma-like carcinoma (LELC) and glandular parts, but not in 36 cases of cholangiocarcinoma without the LELC component. Taken together, these observations indicate that lymphoepithelioma-like cholangiocarcinoma is strongly linked to EBV. The LELC type of cholangiocarcinoma, like LELC of other body sites, may be more common in areas with endemic EBV infection.

Adult↗

PubMed2001

Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin.

Adiponectin, an adipose tissue-specific plasma protein, was recently revealed to have anti-inflammatory effects on the cellular components of vascular wall. Its plasma levels were significantly lower in men than in women and lower in human subjects with obesity, type 2 diabetes mellitus, or coronary artery disease. Therefore, it may provide a biological link between obesity and obesity-related disorders such as atherosclerosis, against which it may confer protection. In this study, we observed the changes of plasma adiponectin levels with body weight reduction among 22 obese patients who received gastric partition surgery. A 46% increase of mean plasma adiponectin level was accompanied by a 21% reduction in mean body mass index. The change in plasma adiponectin levels was significantly correlated with the changes in body mass index (r = -0.5, P = 0.01), waist (r = -0.4, P = 0.04) and hip (r = -0.6, P = 0.0007) circumferences, and steady state plasma glucose levels (r = -0.5, P = 0.04). In multivariate linear regression models, the increase in adiponectin as a dependent variable was significantly related to the decrease in hip circumference (beta = -0.16, P = 0.028), after adjusting body mass index and waist circumference. The change in steady state plasma glucose levels as a dependent variable was related to the increase of adiponectin with a marginal significance (beta = -0.92, P = 0.053), after adjusting body mass index and waist and hip circumferences. In conclusion, body weight reduction increased the plasma levels of a protective adipocytokine, adiponectin. In addition, the increase in plasma adiponectin despite the reduction of the only tissue of its own synthesis suggests that the expression of adiponectin is under feedback inhibition in obesity.

Adiponectin↗

PubMed2001

Risk for occupational injury of handicapped workers in Taiwan.

The current study investigated occupational risk of handicapped workers relative to nonhandicapped workers and used the standardized mortality ratio as an index that handicapped workers were at elevated risk for occupational injury. A total of 6,327 records of disabling occupational injuries beyond first aid treatment from January to December, 1999 were collected and analyzed. The ratio of the standardized mortality ratio of the handicapped vs nonhandicapped workers indicated that occupational injury risk of handicapped workers must be seriously examined for the reasons for this unexpectedly high occupational risk.

Adult↗

PubMed2001

Bioavailability and pharmacokinetic features of etoposide in childhood acute lymphoblastic leukemia patients.

The bioavailability and pharmacokinetic characteristics of etoposide were studied in 12 relapsed B-lineage acute lymphoblastic leukemia (ALL) patients after both intravenous (i.v.) infusion and oral administration. Following a 1 hour i.v. infusion of 50 mg/m2 etoposide, the elimination half-life ranged from 49.8 min to 509.4 min (mean +/- SD = 218.6 +/- 134.7 min), the MRT ranged from 71.8 to 734.9 min (mean +/- SD = 315.4 +/- 194.3 min) and the systemic clearance of etoposide ranged from 15.7 to 38.0 ml/min/m2 (mean +/- SD = 24.1 +/- 7.0 ml/min/m2). The AUC ranged from 2234.9 to 5427.0 microM.min) (mean +/- SD = 3827.8 +/- 1069.5 microM.min) and Vc ranged from 2026.9 to 13,505.2 ml/m2 (mean +/- SD = 6825.4 +/- 3278.5 ml/m2). The maximum plasma etoposide levels ranged from 6.0 to 28.4 microM (mean +/- SD = 13.6 +/- 6.3 microM). The bioavailability of oral etoposide was determined by comparing the AUC following i.v. infusion to the AUC following oral administration in the same patient. The overall bioavailability (mean +/- SD) was 60.6 +/- 22.4% (ranged from 17.6% to 91.2%). The elimination half-life following oral administration (mean +/- SD) was 209.8 +/- 196.3 min (ranged from 51.0 to 794.2 min). The time required to reach the maximum plasma etoposide concentration was 145.4 +/- 118.7 min (ranged from 23.7 to 396.9 min). To our knowledge, this is the first report concerning the bioavailability of etoposide in pediatric leukemia patients. All of the other pharmacokinetic properties of etoposide in pediatric B-lineage ALL leukemia patients reported here were similar to those described previously.

Administration, Oral↗

PubMed2001

Biliary complications in living related liver transplantation.

BACKGROUND: Biliary tract reconstruction has long been considered the Achilles' heel of liver transplantation as biliary complications can increase morbidity and mortality especially in partial liver graft transplantation. METHODS: Thirty-four living related liver transplants were performed at Chang Gung Memorial Hospital in Kaohsiung for 33 children and 1 adolescent during a 5.5-year period. All potential donors underwent a detailed preoperative imaging study of the vascular and biliary anatomy, including three-dimensional helical computed tomographic cholangiography (n = 20), magnetic resonance cholangiography (n = 14), and intra-operative cholangiography (n = 31) before graft retrieval. All hepatic artery anastomoses were performed in the standard microsurgery fashion and their patency was confirmed intra-operatively using Doppler ultrasound. RESULTS: The biliary complication rate was 8.8% (3/34), including multiple intrahepatic biliary stenosis of unknown origin (n = 1), bile leakage from the Roux-en-Y loop (n = 1), and a missed biliary radicle (n = 1) which were treated via interventional radiological and surgical procedures. The overall graft and patient survival rates were 100%. CONCLUSION: The biliary complication rate in this series was low compared to those of other experienced centers. Complete study of the variations of intrahepatic duct ramification pre-and-intra-operatively provided adequate information on the appropriate transection plane. Furthermore, intra-operative Doppler ultrasound verification of vessel patency helps prevent vascular complications, which has been identified as a cause of biliary complications.

Adolescent↗

PubMed2001

In vivo pharmacokinetics and metabolism of anti-human immunodeficiency virus agent D4T-5'-[p-bromophenyl methoxyalaninyl phosphate] (SAMPIDINE) in mice.

d4T-5'-[p-Sampidine, bromophenyl methoxyalaninyl phosphate] (HI-113), a novel aryl phosphate derivative of stavudine (d4T), exhibits substantially more potent anti-human immunodeficiency virus activity than d4T. The purpose of the present study was to investigate the in vivo pharmacokinetics and metabolism of this promising new anti-HIV agent in mice. Here, we report that HI-113 forms two active metabolites with favorable pharmacokinetics after systemic administration. Plasma HI-113 concentrations were measured by analytical high-performance liquid chromatography and the pharmacokinetic parameters were estimated using the WinNonlin program. After intravenous administration, the elimination half-life (t(1/2)) of HI-113 was 3.6 min with a systemic clearance of 174.5 ml/min/kg. HI-113 was converted to the active metabolites alaninyl-d4T-monophosphate (ala-d4T-MP) and d4T. The T(max) values for ala-d4T-MP and d4T derived from intravenously administered HI-113 were 5.1 and 17.4 min, respectively. The elimination half-life for synthetic ala-d4T-MP was 38.9 min after intravenous administration. Ala-d4T-MP was metabolized to form d4T (T(max) = 5.0 min). The elimination half-life of d4T derived from intravenously administered ala-d4T-MP (32.4 min) was similar to the elimination half-life of intravenously administered d4T (26.6 min). In contrast, the elimination half-life of d4T derived from HI-113 was substantially longer (116.2 min). Similarly, the elimination half-life of ala-d4T-MP derived from HI-113 (138.8 min) was markedly longer than the elimination half-life of ala-d4T-MP given intravenously (38.9 min). Following oral administration of HI-113, the elimination half-lives of ala-d4T-MP (56.1 min) and d4T (102.6 min) were also prolonged.

Animals↗

PubMed2001

In vivo antitumor activity of bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (METVAN [VO(SO4)(Me2-Phen)2]).

The compound bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (METVAN [VO(SO4)(Me2-Phen)2]), exhibits potent cytotoxicity against human cancer cells at low micromolar concentrations. At concentrations > or = 1 microM, METVAN treatment was associated with a nearly complete loss of the adhesive, migratory, and invasive properties of the treated tumor cell populations. METVAN did not cause acute or subacute toxicity in mice at dose levels ranging from 12.5 mg/kg to 100 mg/kg. Therapeutic plasma concentrations > or = 5 microM were rapidly achieved and maintained in mice for at least 24 h after i.p. bolus injection of a single 10 mg/kg nontoxic dose of METVAN. At this dose level, the maximum plasma METVAN concentration was 37.0 microM, which was achieved with a t(max) of 21.4 min. Plasma samples (diluted 1:16) from METVAN-treated mice killed 85% of human breast cancer cells in vitro. METVAN was slowly eliminated with an apparent plasma t(1/2) of 17.5 h and systemic clearance of 42.1 ml/h/kg. In accordance with its potent in vitro activity and favorable in vivo pharmacokinetics, METVAN exhibited significant antitumor activity and delayed tumor progression in CB.17 severe combined immunodeficient (SCID) mouse xenograft models of human glioblastoma and breast cancer. In these experiments, METVAN was administered in daily injections of a single nontoxic 10 mg/kg i.p. dose on 5 consecutive days per week for 4 consecutive weeks beginning the day after the s.c. inoculation of U87 glioblastoma or MDA-MB-231 breast cancer cells. At 40 days after the inoculation of tumor cells, the U87 tumor xenografts in the vehicle-treated control SCID mice were much larger than those of the mice treated with METVAN (4560 +/- 654 mm(3) versus 1688 +/- 571 mm(3); P = 0.003). Similarly, the MDA-MB-231 tumors in SCID mice treated with METVAN were much smaller 40 days after tumor cell inoculation than those of the vehicle-treated control SCID mice (174 +/- 29 mm(3) versus 487 +/- 82 mm(3); P = 0.002). The favorable in vivo pharmacodynamic features and antitumor activity of METVAN warrants further development of this novel oxovanadium compound as a potential new anticancer agent.

Animals↗