Biomedical subjects

K L Law

Publications and source records attributed to K L Law.

At least 19 recordsLinked to original sources

PubMed2001

Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic.

Multidrug resistance may be conferred by P-glycoprotein (Pgp, ABCB1) or the multidrug resistance associated protein (MRP). These membrane proteins are members of the ATP binding cassette transporter superfamily and are responsible for the removal from the cell of several anticancer agents including doxorubicin. Modulators can inhibit these transporters. LY335979 is among the most potent modulators of Pgp with a Ki of 59 nM. LY335979 is selective for Pgp, and does not modulate MRP-mediated resistance by MRP1 (ABCC1) and MRP2 (ABCC2). LY335979 significantly enhanced the survival of mice implanted with Pgp-expressing murine leukemia (P388/ADR) when administered in combination with either daunorubicin, doxorubicin or etoposide. Coadministration of LY335979 with paclitaxel compared to paclitaxel alone significantly reduced the tumor mass of the Pgp-expressing UCLA-P3.003VLB lung carcinoma in a xenograph model and delayed the development of tumors in mice implanted with the parental drug-sensitive UCLA-P3 tumor. LY335979 was without significant effect on the pharmacokinetics of these anticancer agents. This may be due impart to its poor inhibition of four major cytochrome P450 isozymes important in metabolizing doxorubicin and other oncolytics. The selectivity and potency of this modulator allows the clinical evaluation of the role of Pgp in multidrug resistance. LY335979 is currently in clinical trials.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed1999

Reversal of resistance in multidrug resistance protein (MRP1)-overexpressing cells by LY329146.

The benzothiophene LY329146 reverses the drug resistance phenotype in multidrug resistance protein (MRP1)-overexpressing cells when dosed in combination with MRP1-associated oncolytics doxorubicin and vincristine. Additionally, LY329146 inhibited MRP1-mediated uptake of the MRP1 substrate LTC4 into membrane vesicles prepared from MRP1-overexpressing cells.

ATP-Binding Cassette Transporters↗

PubMed1999

Sonography compared with radiography in revealing acute rib fracture.

OBJECTIVE: This study was undertaken to compare the sensitivities of sonography and radiography for revealing acute rib fracture. SUBJECTS AND METHODS: Chest radiography and rib sonography were performed on 50 patients with suspected rib fractures. Sonography was performed with a 9- or 12-MHz linear transducer. Fractures were identified by a disruption of the anterior margin of the rib, costochondral junction, or costal cartilage. The incidence, location, and degree of displacement of fractures revealed by radiography and sonography were compared. Sonography was performed again after 3 weeks in 37 subjects. RESULTS: At presentation, radiographs revealed eight rib fractures in six (12%) of 50 patients and sonography revealed 83 rib fractures in 39 (78%) of 50 patients. Seventy-four (89%) of the 83 sonographically detected fractures were located in the rib, four (5%) were located at the costochondral junction, and five (6%) in the costal cartilage. Repeated sonography after 3 weeks showed evidence of healing in all reexamined fractures. Combining sonography at presentation and after 3 weeks, 88% of subjects had sustained a fracture. CONCLUSION: Sonography reveals more fractures than does radiography and will reveal fractures in most patients presenting with suspected rib fracture. Further scientific studies are needed to clarify the appropriate role for sonography in rib fracture detection.

Adult↗

PubMed1999

Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P-450 activities.

Overexpression of ATP-dependent drug efflux pumps, P-glycoprotein (Pgp) or multidrug resistance-associated protein (MRP), confers multidrug resistance to tumor cells. Modulators of multidrug resistance block the action of these pumps, thereby sensitizing cells to oncolytics. A potent Pgp modulator is LY335979, which fully sensitizes Pgp-expressing cells at 0.1 microM in cytotoxicity assays and for which Pgp has an affinity of 59 nM. The present study examines its effect on MRP1-mediated drug resistance and cytochrome P-450 (CYP) activity and its ability to serve as a Pgp substrate. Drug resistance was examined with HL60/ADR and MRP1-transfected HeLa-T5 cells. Drug cytotoxicity was unaffected by 1 microM LY335979; leukotriene C4 uptake into HeLa-T5 membrane vesicles was unaffected. Because the substrate specificity of Pgp and CYP3A overlap, the effect of LY335979 on the 1'-hydroxylation of midazolam by CYP3A in human liver microsomes was examined. The apparent K(i) was 3.8 microM, approximately 60-fold higher than the affinity of Pgp for LY335979. The modulator's effect on Pgp was evaluated with Pgp-overexpressing CEM/vinblastine (VLB)(100) and parental CCRF-CEM cells. Both cell lines accumulated [(3)H]LY335979 equally well and did not efflux [(3)H]LY335979 during a 3-h incubation, indicating that it is not a substrate of Pgp. Equilibrium-binding studies with CEM/VLB(100) plasma membranes and [(3)H]LY335979 showed that Pgp had a K(d) of 73 nM, which is in good agreement with the previously determined K(i) value. Thus, LY335979 is an extremely potent Pgp, and not MRP1 or MRP2, modulator and has a significantly lower affinity for CYP3A than for Pgp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Pharmacological characterization of LY335979: a potent cyclopropyldibenzosuberane modulator of P-glycoprotein.

The above data indicate that LY335979 displays the following characteristics of an 'ideal modulator' of Pgp-mediated multidrug resistance: high affinity binding to Pgp, high potency for in vitro reversal of drug resistance, high therapeutic index (activity was demonstrated at doses ranging from 1-30 mg/kg) observed in in vivo antitumor efficacy experiments, and a lack of pharmacokinetic interactions that alter the plasma concentration of coadministered oncolytic agents. These desirable features strongly suggest that LY335979 is an exciting new clinical agent to test the hypothesis that inhibition of P-glycoprotein activity will result in reversal of multidrug resistance in human tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979.

Overexpression of P-glycoprotein (Pgp) by tumors results in multidrug resistance (MDR) to structurally unrelated oncolytics. MDR cells may be sensitized to these oncolytics when treated with a Pgp modulator. The present study evaluates LY335979 as a modulator both in vitro and in vivo. LY335979 (0.1 microM) fully restored sensitivity to vinblastine, doxorubicin (Dox), etoposide, and Taxol in CEM/VLB100 cells. LY335979 modulated Dox cytotoxicity even when LY335979 (0.5 microM) was removed 24 h prior to the cytotoxicity assay. LY335979 blocked [3H]azidopine photoaffinity labeling of the M(r) approximately 170,000 Pgp in CEM/VLB100 plasma membranes and competitively inhibited equilibrium binding of [3H]vinblastine to Pgp (Ki of approximately 0.06 microM). Treatment of mice bearing P388/ADR murine leukemia cells with LY335979 in combination with Dox or etoposide gave a significant increase in life span with no apparent alteration of pharmacokinetics. LY335979 also enhanced the antitumor activity of Taxol in a MDR human non-small cell lung carcinoma nude mouse xenograft model. Thus, LY335979 is an extremely potent, efficacious modulator that apparently lacks pharmacokinetic interactions with coadministered anticancer drugs and is, therefore, an exciting new agent for clinical evaluation for reversal of Pgp-associated MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Site-specific prodrug activation by antibody-beta-lactamase conjugates: regression and long-term growth inhibition of human colon carcinoma xenograft models.

Antibody-directed catalysis (ADC) is a two-step method for the delivery of chemotherapeutic agents in which enzyme-antibody conjugate, prelocalized to antigen-bearing tumor cells, catalyzes the site-specific conversion of prodrug to drug. An ADC system consisting of F(ab')-beta-lactamase conjugates and a cephalosporin derivative of the oncolytic agent 4-desacetylvinblastine-3-carboxhydrazide was investigated. The ability of the system to mediate antitumor activity was compared with that of free drug given alone and with covalent drug-antibody conjugates in LS174T and T380 colon carcinoma xenografts in nude mice. Efficacy increased from moderate tumor growth inhibition by using free 4-desacetylvinblastine-3-carboxhydrazide to tumor regression and long-term stabilization with the ADC system. Labile covalent drug-antibody conjugates prepared from the same antibodies were less effective than ADC and required much higher antibody doses. The antigens KS1/4, carcinoembryonic antigen, and tumor-associated glycoprotein-72, TAG-72, present on the model cell lines, were chosen to investigate the effect of differences in subcellular location and expression heterogeneity on the efficacy of ADC delivery. Response was equivalent with the three tumor antigens. Hence, heterogeneous expression and membrane shedding of carcinoembryonic antigen and TAG-72, did not diminish the suitability of these antigens as targets for ADC therapy. In contrast, drug-antibody conjugate efficacy was more sensitive to subcellular location and heterogeneity. Thus, ADC is a highly effective form of immunochemotherapy in preclinical models, with applicability toward a variety of antigen targets.

Animals↗

PubMed1993

Treatment of childhood acute lymphoblastic leukemia with protocol TCL-842 in Taiwan: the Taiwan Children's Cancer Study Group.

From March 1984 to May 1988, 212 children with acute lymphoblastic leukemia were enrolled on Protocol TCL-842. In all, 68 patients were classified as standard risk (SR), 56 as intermediate risk (IR), and 88 as high risk (HR) groups. Remission induction for all three groups consisted of vincristine (VCR), prednisolone (PRED) and L-asparaginase (L-Asp). One consolidation course with cyclophosphamide (CP) and cytarabine (AraC) was used for the SR and IR groups, and two courses were given to patients in the HR group. Central nervous system prophylaxis was randomized using either cranial irradiation 18 Gy + 5 intrathecal methotrexate (IT MTX) or triple IT with maintenance. Reinforcement cycles were employed periodically during maintenance therapy (basically 6-mercaptopurine+MTX) and varied among the three groups. Four-week oral PRED every 16 weeks was the sole reinforcement agent for SR. Two-week VCR+dexamethasone (DEX)+adriamycin CP cycles were used to reinforce IR and HR at different intervals. Five third-form cycles with VCR+DEX+AraC were used only for HR. Treatment was discontinued after three years in patients who achieved continuous complete remissions (CCR). Eight patients died during the induction phase and eight failed to achieve complete remission (CR). The CR rate for SR was 97%, for IR was 98% and for HR was 83.3%; the overall rate was 91.8%. As of 30 June 1991, 33 patients had dropped out, 12 had died during remission, and 52 had relapsed. Twenty-eight SR, 26 IR, and 29 HR patients remained in CCR with a median follow-up duration of 66 months (38-88 months).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1991

In vivo antitumor activity of a monoclonal antibody-Vinca alkaloid immunoconjugate directed against a solid tumor membrane antigen characterized by heterogeneous expression and noninternalization of antibody-antigen complexes.

It is widely believed that antigen heterogeneity and noninternalization of antigen-antibody complexes will severely limit the antitumor activity of monoclonal antibody-drug conjugates. The B72.3 monoclonal antibody binds to a tumor-associated antigen which is heterogeneously expressed in human carcinomas (J. Schlom, Cancer Res., 46: 3225-3238, 1986). We therefore performed studies to assess the degree of internalization of B72.3 antibody-antigen complexes and the level of in vivo antitumor activity that could be achieved with B72.3 conjugated to 4-desacetyl vinblastine-3-carboxhydrazide. Internalization studies were performed on LS174T colorectal carcinoma and OVCAR-3 ovarian carcinoma cells using iodinated B72.3 as well as an iodinated antibody that binds to the human transferrin receptor, IIB21. These data indicated that, in contrast to HB-21, the B72.3 antigen-antibody complex was not internalized. The B72.3-Vinca alkaloid immunoconjugate demonstrated significant antitumor activity against LS174T xenografts, although complete regressions of established tumors were not achieved. Immunohistochemical analyses indicated that the B72.3 antigen was heterogeneously expressed in the LS174T xenografts and that tumor cells which were not killed by high doses of B72.3-Vinca also expressed the B72.3 antigen. These studies indicated that significant antitumor activity may be achieved by monoclonal antibody-drug conjugates even when antigen heterogeneity and noninternalization of antigen-antibody complexes are encountered. The data also suggested that the formulation of antibody-drug conjugate cocktails to counteract antigen heterogeneity may not be sufficient to eradicate all malignant cells within a solid tumor mass.

Animals↗

PubMed1991

[Cyclosporin A for treatment in nephrotic syndrome of childhood--a preliminary report].

We treated five, three steroid resistant and 2 steroid dependent nephrotic syndrome with oral cyclosporin A and prednisolone. All children received more than eight weeks course of prednisolone, and were in a critically ill status from their nephrotic syndrome and by steroid-toxic side effects. Cyclosporin A was started at 7 mg/kg/day and titrated to maintain serum level of 150-250 ng/ml. Prednisolone was given initially at a dose of 1 mg/kg/day x 1 month, subsequently at a dose of 0.4 mg/kg/day x 1 month, then 0.2 mg/kg/day x 4 months. After a total course of six months, cyclosporin A was tapered to 3.5 mg/kg/day. Prednisolone was maintained at a dose of 0.2 mg/kg/day. Renal biopsies of the 3 steroid resistant children showed membranous glomerulonephritis with focal segmental glomerulosclerosis, focal segmental glomerulosclerosis and IgM nephropathy respectively. These three cases all went into complete remission within four weeks. Among them, one case relapsed twice within one year. Renal biopsies of the two steroid dependent children showed minimal change and focal segmental glomerulosclerosis respectively. These two cases went into complete remission within three weeks sustained up to a year. Side effects of cyclosporin A were observed in one patient with gum hypertrophy and two patients with hirsutism. Other side effects were not found. After cyclosporin A treatment for one year, the renal biopsy of the relapsing patient showed no interstitial fibrosis or tubular atrophy. In conclusion, cyclosporin A was found to be effective in steroid resistant and dependent patients. The duration of cyclosporin A treatment is so far unknown. It needs further evaluation in the future.

Child↗

PubMed1990

Continuous monitoring of intracranial pressure in Reye's syndrome--5 years experience.

Monitoring of intracranial pressure (ICP) and efforts to keep the ICP below the critical level are vital in the treatment of Reye's syndrome. Continuous monitoring of ICP was carried out in 21 cases of Reye's syndrome who were at or beyond stage III at the time of admission to the Veterans General Hospital, between January 1981 and August 1986. Seventeen had ICP ranging from 15 mmHg to 67 mmHg. Three patients died, 1 in stage V with an ICP of 67 mmHg received a craniectomy, and 2 others were in stage IV with ICP's of 66 mmHg and 25 mmHg, respectively. The fatality rate was 14% (3/21). Among 18 patients, 5 had moderate psychomotor retardation (PMR), 4 had severe PMR and 2 had mild PMR. The remaining 7 patients survived without sequelae. Blood exchange transfusion could further reduce ICP and seemed to improve neurologic outcome. Blood ammonia higher than 400 micrograms% is indicative of a bad prognosis. Hyperventilation was the most rapid and effective means of reducing moderate degrees of increased ICP. During intensive supportive care, we also found that coughing, endotracheal intubation, seizures, asynchronous respiration to an artificial respirator, suction of the airway and any painful stimulation caused further increases in ICP and worsened the situation. Care should be given to avoid these factors.

Ammonia↗

PubMed1990

[Retroperitoneal fibrosis in children].

A 13 year-old boy was hospitalized because of persisted fever had pallor for three months. Abdominal ultrasound, intravenous pyelogram, and abdominal computerized axial tomography scan disclosed a space occupying lesion located postero-superior to the bladder. Biopsies of the above lesion disclosed retroperitoneal fibrosis. Retroperitoneal fibrosis in children is very rare and has a wide variety of presentations and associated diseases. Treatment relief of obstruction when necessary.

Humans↗

PubMed1989

[Malignant fibrous histiocytoma of spleen. A case report and literature review].

A 11 year old girl who presented with malaise, poor appetite and flank mass was admitted in Sept. 1988. Abdominal x-ray, sonogram, Gallium scan and CT scan revealed a tumor mass in the spleen. Laparotomy confirmed a hugh mass measuring 15x15x10 cm in the spleen. The histologic study proved the tumor to be malignant fibrous histiocytoma, inflammatory type. Malignant fibrous histiocytoma occur mainly in late adult life, we report this case because the patient is young and the involvement of the spleen is rare.

Child↗

PubMed1989

[Childhood hypoplastic preleukemia].

Aplastic anemia preceeding acute leukemia is known as hypoplastic preleukemia, which tends to be more frequently evolved into acute lymphoblastic leukemia, whereas myelodysplastic preleukemia are specific for acute myelocytic leukemia. More than forty cases had been reported in the literatures. Here we report a 11-year-old boy who was initially diagnosed as aplastic anemia and treated with prednisolone and androgen with prompt response terminated into overt acute lymphoblastic leukemia.

Anemia, Aplastic↗

PubMed1989

[Acute peritoneal dialysis in low birth weight infants].

Between September 1986 and April 1988, five low birth weight infants weighing 950 gm to 2250 gm required acute peritoneal dialysis due to acute anuric renal failure. Severe hyaline membrane disease was the most common explanation for acute renal failure. All infants had severe electrolytes imbalance and fluid retention with generalized edema, which increased ventilation requirements and severely limited fluid intake. The volume of each exchange varied between 10-20 ml/kg. Four of five infants had good ultrafiltration (3.52 +/- 2.43 ml/kg/hr, mean +/- SD). Ultrafiltration was not achieved in one due to poor peripheral perfusion. Electrolytes imbalance were corrected in all patients. Although four infants died, one case given up further care after renal failure had improved, and one died of septic shock after renal function had recovered. Only one infant survived with complete recovery of renal function. We believe that early dialysis is likely to reduce both morbidity and mortality of acute renal failure in low birth weight infants.

Acute Kidney Injury↗

PubMed1989

[Urinary tract infection in children: clinical analysis and investigation].

The urinary tract is a common site for bacterial infection in childhood. The most important aspect of urinary tract infection in childhood is that it can lead to severe and progressive renal disease. From March 1983 to March 1987, 63 cases of suspected urinary tract infection were collected in Taichung VGH. Among them only 24 cases reached our diagnostic criteria. Eight cases were within 2 years old, which all are male. Sixteen cases were beyond 2 years old, which the ratio of male to female is 1:1. Eighteen cases presented pyuria. Ten cases had recurrent infections, among which eight cases had urinary abnormalities. The most common pathogenic organism was E. coli (44%), then Proteus (24%), Klebsiella (16%), Pseudomonas (12%). The antibiotics sensitivity test revealed 95.7% were sensitive to gentamicin and amikacin, 81% to cephalothin, 56. 5% to sulfamethoxazole-trimethoprim. Imaging studies revealed nine cases (37.5%) with urinary tract abnormalities, including vesicoureteral refluxes 6 cases, right multicystic kidney with left vesicoureteral reflux 1 case, horse-shoe kidney 1 case, atonic bladder 1 case. The ratio of male to female is 2:1. All seven cases of severe vesicoureteral refluxes received surgery. One case developed post-operative ureteral stricture. One case occurred unilateral chronic renal parenchymal disease one year later. Others were free of reflux and reinfection of urinary tract.

Anti-Bacterial Agents↗

PubMed1989

[Cerebrospinal fluid eosinophilia preceding central nervous system leukemia].

Cerebrospinal fluid eosinophilia are an uncommon finding that is most often the result of a helminthic infection of the central nervous system. Information from the recorded literature suggests the differential diagnosis of this clinical observation is relatively limited. This is a report of a girl with acute lymphoblastic leukemia who developed central nervous system relapse of leukemia following 3 years of remission. She showed marked eosinophilia in the cerebrospinal fluid 6 weeks preceding central nervous system leukemia. No cause for the eosinophilia was identified. The gradual accumulation of case reports of eosinophilia in the cerebrospinal fluid with or without blood eosinophilia in patient with leukemia suggests that this finding is of some importance.

Brain Neoplasms↗

PubMed1989

[Clinical observation of neonatal sepsis].

Sepsis remains a significant cause of morbidity and mortality in newborn infants. From January 1983 to April 1988, 166 cases of neonatal sepsis with positive blood cultures were collected at V.G.H.--Taichung. Among them 140 newborn babies were delivered at private clinic (outborn babies), 26 cases were inborn babies. Of the inborn babies, 20 cases (76.9%) were early onset sepsis (the onset of illness within 96 hours of life) and 6 cases (23.1%) were late onset sepsis (the onset of illness beyond 96 hours of life). Off the outborn babies, 64 cases (45.7%) were early onset sepsis and 76 cases (54.3%) were late onset sepsis. The Gram positive organism (51.9%) was more common than the Gram negative organism in the inborn babies, on contrary, the Gram negative organism (59.0%) was more common in the outborn babies. The most common pathogenic organism of the inborn babies was Enterococcus (22.2%) and E. coli (22.2%), followed by Pseudomonas spp (11.1%) and Staphylococcus aureus (11.1%). The most common pathogenic organism of the outborn babies was Enterococcus (17.4%), followed by E. coli (16.1%), Staphylococcus aureus (9.9%) and Klebsiella spp (8.1%). The antibiotics sensitivity tests to the pathogens didn't show any significant difference between these two group babies. In this clinical study, we found that the first choices of antibiotics were ampicillin plus aminoglycosides. The clinical symptoms and signs were nonspecific. The most common findings were lethargy, fever, hypothermia and poor feeding. Of the inborn babies, 17 cases (65.4%) had the predisposing factor(s). Of the outborn babies, 42 cases (30%) had the predisposing factor(s).(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗