Search PubMed⌕ Search

Biomedical subjects

T C Chou

Publications and source records attributed to T C Chou.

At least 91 records · Page 5Linked to original sources
PubMed1995

Antiplatelet actions of 2-(4-[1-(2-chlorophenyl) piperazinyl]) methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one compound.

The new quinazolinone derivative, 2-(4-[1-(2-chlorophenyl)piperazinyl]) methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one(CK53 ), inhibited platelet aggregation and ATP release induced by arachidonic acid, collagen, PAF and U46619 in washed rabbit platelets. In human platelet-rich plasma CK53 also significantly suppressed the platelet aggregation and ATP release challenged by epinephrine and ADP. The thromboxane B2 formation of rabbit washed platelets caused by collagen and thrombin was reduced by CK53 but that induced by arachidonic acid. CK53 inhibited the intracellular calcium increase stimulated by collagen and thrombin in quin-2/AM-loaded rabbit platelets. Phosphoinositides breakdown caused by collagen, U46619, PAF and thrombin was inhibited by CK53. CK53 also suppressed the aggregation of elastase-treated human platelets induced by fibrinogen but no alteration in platelet cyclic-AMP level. In conclusion, these data indicate that antiplatelet effect of CK53 may be mainly due to the direct inhibition of phosphoinositides breakdown.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

The synergistic effects of cyclosporine, sirolimus, and brequinar on heart allograft survival in mice.

The effects of cyclosporine (CsA), sirolimus (RAPA), and/or brequinar (BQR) were examined in a vascularized heterotopic heart transplant model in mice. Untreated C3H (H-2k) recipients reject C57 BL/10 (H-2b) heart allografts at a mean survival time (MST) of 7.7 +/- 1.4 days. A 7-d intravenous (i.v.) infusion by osmotic pump of CsA at doses of 5.0, 10.0, or 20.0 mg/kg extended heart allograft survival to 9.8 +/- 1.3 d (NS), 15.0 +/- 5.1 d (P < 0.01) or 15.0 +/- 1.9 d (P < 0.01), respectively. RAPA delivered i.v. for 7 d at a dose of 0.1 mg/kg produced an MST of 13.0 +/- 7.5 d; 0.2 mg/kg, 20.0 +/- 10.9 d; and 0.4 mg/kg, 15.8 +/- 4.1 d (all P < 0.01). A 7-d alternate-day (q.o.d.) course of oral gavage with BQR (0.5, 1.0, or 2.0 mg/kg) produced survivals of 12.0 +/- 2.4 d, 17.6 +/- 3.4 d, and 20.0 +/- 4.1 d, respectively (all P < 0.01). The combination of 2.5 mg/kg CsA with 0.05 mg/kg RAPA extended graft survival to 18.2 +/- 2.9 d (P < 0.01), and 5.0 mg/kg CsA with 0.1 mg/kg RAPA prolonged survival to 23.0 +/- 9.0 d (P < 0.01). These combinations represent synergistic interactions based upon combination index (CI) values of 0.1-0.6. Although 7-d courses of 0.5 mg/kg CsA (7.3 +/- 1.0 d; NS), 0.01 mg/kg RAPA (7.6 +/- 0.9 d; NS), or 0.125 mg/kg BQR (7.6 +/- 0.9 d; NS) were individually ineffective, the triple-drug combination prolonged the MST to 64.6 +/- 32.7 d (P < 0.005; CI = 0.001), with 2/5 grafts beating for more than 100 d. Similar results were produced by 14-day therapy in the BALB/c (H-2d) to C3H combination.

Animals↗
PubMed1995

Toxic effects of cholelitholytic solvents on gallbladder and liver. A piglet model study.

We evaluated the toxic effects of four currently used chemolytic solvents--dimethyl sulfoxide (DMSO, 99%), ethyl propionate (EP, 99%), tetrasodium ethyl-dimethyl tetraacetate (4Na-EDTA, 2%, pH 11), and methyl tert-butyl ether (MTBE, purity = 99.5%) in an animal model. Each solvent was tested in nine farm piglets (Landrace), weighing between 20 and 25 kg. A solvent-resistant catheter was inserted transhepatically into the gallbladder (GB) using sonographic guidance 24 hr prior to each experiment. Seventy-five milliliters of each solvent was infused over 3 hr into the gallbladder. The following day, a laparotomy was performed in order to assess for possible damage to the liver, GB, bile ducts (BD), or intestines. The GB and liver were resected and their histology examined. The following pathologic grades were assigned to GB, BD, and liver specimens to describe the tissue damage: normal (0), mild (1), moderate (2), and severe (3). We found that DMSO had the highest score on gallbladder and bile duct injury (49, 3), followed by EP (36, 2), EDTA (14, 1) and MTBE (16, 0), respectively; the difference in gallbladder damage was statistically significant. Very mild hepatocyte damage was present in the DMSO (2) and MTBE (2) groups. The administration of EP and EDTA resulted in no liver injury at all. Piglets within each treatment group suffered from varying degrees of tissue injury. No deaths were attributed to the administered solvents. We concluded that DMSO, EP, EDTA, and MTBE do not have serious local toxic effect on the GB, BD, and intestine; nor do they lead to severe hepatotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Synergistic interaction of 3 M KCl-extracted donor antigens (e-HAg) with cyclosporine or cyclosporine/sirolimus for prolongation of rat heart allograft survival.

Extracted donor histocompatibility antigens (e-HAg) may potentiate the effects of drugs to protect organ allografts from rejection. We examined the capacity of e-HAg when combined with cyclosporine (CsA) alone, sirolimus (rapamycin, RAPA) alone, or CsA/RAPA combinations to prolong heart allograft survival in rats. Wistar-Furth (WF; RT1u) rats that received CsA (10 mg/kg/day) by oral gavage for 3 (days 0, 1 and 2) or 7 (days 0, 1, 2, 3, 4, 5 and 6) consecutive days displayed modest prolongation of Brown Norway (BN; RT1n) heart allograft survival from a mean survival time of 7.2 +/- 0.8 days in untreated controls to 12.2 +/- 1.1 days and 18.6 +/- 2.7 days, respectively (p < 0.01). Although administration on the day of transplantation (day 0) of a single intravenous (i.v.) dose of BN e-HAg (5 mg/kg) failed to affect allograft survival, both three (days 0, 1 and 2) and five (days 0, 1, 2, 3 and 4) injections significantly potentiated the effect of a 3-day course of oral CsA (18.6 +/- 1.3 days (p < 0.01) and 20.0 +/- 1.4 days (p < 0.01), respectively) and of a 7-day course of oral CsA (25.3 +/- 4.4 days (p < 0.05) and 33.5 +/- 9.3 days (p < 0.01), respectively). Median-effect analysis confirmed a synergistic interaction between CsA (0.5 mg/kg x 7 days, i.v.) and e-HAg with combination index (CI) values less than 0.7 (CI = 1 shows additive interactions, CI < 1 synergistic, and CI > 1 antagonistic, interactions). In contrast, e-HAg failed to affect the immunosuppressive effect of RAPA. However, e-HAg (5.0 mg/kg x 3 days) significantly potentiated the effects of a 7-day or 14-day course of RAPA (0.01 mg/kg)/CsA (0.5 mg/kg) combination therapy, namely from 26.0 +/- 4.8 days with a 7-day treatment of CsA/RAPA alone to 32.6 +/- 3.6 days (p < 0.01) and from 28.2 +/- 2.7 days with a 14-day course of CsA/RAPA alone to 42.0 +/- 4.9 days (p < 0.05), respectively (CI = 0.2-0.5). Thus, e-HAg potentiates the immunosuppressive effects of CsA alone and of the CsA/RAPA combination, but not of sirolimus alone.

Animals↗
PubMed1995

2-Heteroaryl 2-substituted phenylketone derivatives and their inhibitory activity on platelet aggregation.

R 68070 and CV-4151 are two compounds possessing both thromboxane synthetase inhibitory activity and thromboxane receptor antagonist properties. 2-Heteroaryl 2-substituted phenylketone derivatives with a partial structural similarity to R 68070 and CV-4151, i.e. possessing a phenyl and a heteroaryl moiety, have been prepared and found to have antiplatelet activity. The compound 2-thienyl 2'-hydroxyphenyl ketone (4) was shown to completely inhibit platelet aggregation induced by arachidonic acid at a concentration of 5.0 microM. Structure-activity analysis indicated that the presence of a ketone group is an important requirement for this inhibitory activity. An o-hydroxyl substitution on the phenyl ring, and a 2-thienyl of heteroaryl ring might increase inhibitory activity.

Animals↗
PubMed1995

Paclitaxel in germ cell cancer.

The teratocarcinoma cell line 833K and its relatively cisplatin-resistant subline 833K/63CP 10 were used to assess the cytotoxicity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), cisplatin, and 4-hydroxyperoxycyclophosphamide quantitatively. The results showed that paclitaxel had marked cytotoxicity against teratocarcinoma, particularly in the cells that were relatively cisplatin resistant. These studies suggested synergy in cytotoxicity for paclitaxel, cisplatin, and 4-hydroxyperoxycyclophosphamide. A phase II trial of paclitaxel was conducted in patients with previously treated germ cell tumors with restricted prior treatment. The paclitaxel dose was 250 mg/m2 given by 24-hour continuous infusion. In 31 patients treated with paclitaxel, eight (26%) achieved a major (complete or partial) response. The antitumor activity of paclitaxel in the phase II trial has led us to further study it as a part of combination therapy. Since the in vitro studies showed synergistic cytotoxicity, combination studies of paclitaxel, ifosfamide, and platinum are under way as salvage treatment for patients with germ cell tumors.

Adolescent↗
PubMed1995

Comparison of amlodipine and quinapril on ambulatory blood pressure and platelet function in hypertension.

The effect of calcium channel blocker (CCB), amlodipine (5-10 mg/day) and angiotensin-converting enzyme (ACE) inhibitor, quinapril (10-40 mg/day) on ambulatory blood pressure (ABP), rheological and platelet function in hypertension were compared in this randomised double-blind placebo-controlled cross-over study. This study was preceded by 4 weeks placebo run-in period and the total duration of the study was 28 weeks. Casual and 24 h ABP, plasma renin activity (PRA) and plasma aldosterone (PA) concentration as well as metabolic and platelet function were determined before and at the end of each drug therapy. A total of 27 patients completed this study. Casual BP was significantly reduced after amlodipine or quinapril treatment, but there was no change in heart rate. Regarding the 24 h ABP, amlodipine produced a fall from 145 +/- 8/94 +/- 7 to 130 +/- 13/85 +/- 10 mm Hg (P < 0.001 for both SBP and DBP). Quinapril also caused a reduction from 144 +/- 10/94 +/- 7 to 134 +/- 12/88 +/- 8 mm Hg (P < 0.001 for both SBP and DBP). Neither amlodipine nor quinapril produce any significant change in heart rate. The level of 6-keto-prostaglandin Fl alpha (6-Keto-PGFl alpha) was increased from 36.8 +/- 4.4 to 45.1 +/- 2.5 pg/ml (P < 0.05) and no significant change of thromboxane B2(TXB2) was noted after amlodipine treatment. PRA was increased from 1.24 +/- 0.31 to 1.62 +/- 0.41 ng/ml/h (P < 0.05) after quinapril treatment. Other biochemical parameters were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design.

BACKGROUND: Cisplatin-based induction chemotherapy may achieve a complete response (i.e., no sign of tumor following treatment) in 70%-80% of patients with germ cell tumors. However, only a minority of patients in whom the firstline regimens fail are cured with the salvage regimens. PURPOSE: The aim of these studies was to identify new agents or new regimens for the treatment of germ cell tumors by carrying out quantitative assessment in vitro of two promising new antitumor agents (paclitaxel [Taxol] and topotecan) and three more established agents (cisplatin, vincristine, and etoposide). These agents were used singly or in two- and three-drug combinations and were selected because they represent five distinct categories of antineoplastic mechanisms. METHODS: The combination index-isobologram method, which is based on the median-effect principle developed by Chou and Talalay, was used for computerized data analysis. This method was selected because it takes into account both the potencies of each drug and combinations of these drugs and the shapes of their dose-effect curves. RESULTS: Synergism against the growth of teratocarcinoma cells resistant to cisplatin (833K/64CP10 cells) was greater than against the growth of parent 833K cells. The degrees of synergism were in the following order: cisplatin + topotecan > or = paclitaxel + cisplatin + topotecan > paclitaxel + topotecan > or = paclitaxel + etoposide > paclitaxel + cisplatin + etoposide > paclitaxel + cisplatin. All other combinations showed nearly additive effects or moderate antagonism. The degrees of antagonism were as follows: cisplatin + etoposide > or = paclitaxel + vincristine > paclitaxel + cisplatin + vincristine > cisplastin + vincristine. The combination of paclitaxel and cisplatin was synergistic against 833K/64CP10 cells and moderately antagonistic against 833K cells. Since the combination of paclitaxel, cisplatin, and topotecan and the two-component combinations of these drugs (cisplatin + topotecan and paclitaxel + topotecan) showed synergism stronger than that of other combinations, these three drugs were selected for illustrating detailed data analysis, using a computer software program developed in this institute. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that, as a result of synergy, the doses of these agents needed to achieve an antitumor effect may be reduced by twofold to eightfold when these agents are given in combination. The present quantitative data analyses for synergism or antagonism provide a basis for a rational design of clinical protocols for combination chemotherapy in patients with advanced germ cell tumors.

Antineoplastic Agents↗
PubMed1994

Synergistic immunosuppressive actions of cyclosporine with a mouse anti-rat alpha/beta-T cell receptor monoclonal antibody.

A mouse IgG1 mAb (R73) directed against the rat alpha/beta-TCR was documented not only to prolong the survival of allografts across major RT1 plus non-RT1 antigenic disparities, but also to display a synergistic immunosuppressive interaction with CsA. Heterotopic cardiac transplants from Buffalo (RT1b) rats survived significantly longer in Wistar-Furth (RT1u) hosts treated immediately after the operation with 0.25 mg/kg R73 i.v., with a mean survival time of 11.0 +/- 5.5 versus 6.8 +/- 1.2 days in the untreated group (P < 0.01). Administration of 0.5 or 5.0 mg/kg R73 displayed dose-dependent prolongation of survival to 17.0 +/- 8.3 days (P < 0.05) or 28.6 +/- 14.0 days (P < 0.01), respectively. One 0.5 mg/kg i.v. dose of R73 delivered to normal Wistar-Furth hosts produced peripheral T cell depletion that reversed after 16 days. Three injections of 0.5 mg/kg R73 on days 0, 2, and 4 prolonged allograft survival to 52.5 +/- 38.6 days compared with 17.0 +/- 8.3 days with a single dose (P < 0.01). Addition of 3 daily doses of 5 or 10 mg/kg CsA administered per oral gavage to a single dose of 0.05, 0.25, or 0.5 mg/kg R73 injected on day 0 produced a synergistic effect to prolong allograft survival, as determined by the rigorous median-effect analysis. The synergistic interaction, which may be explained by the inhibitory effect of CsA on Ca(2+)-dependent pathways triggered after activation of TCR, the target of R73, warrants clinical investigation in order to assess the potential impact of anti-alpha/beta-TCR mAb on CsA-based immunosuppressive regimens.

Animals↗
PubMed1994

Alternating versus continuous drug regimens in combination chemotherapy of human immunodeficiency virus type 1 infection in vitro.

We compared the in vitro efficacies of two-, three-, and four-drug combinations given continuously or in alternating regimens against a clinical isolate of human immunodeficiency virus type 1. In H9 cells and peripheral blood mononuclear cells, at the drug concentrations used in this study, there was greater suppression of human immunodeficiency virus type 1 infection as the number of drugs in the regimen was increased from one to four simultaneously administered agents. Although alternating drug regimens were effective, they were not better than continuous administration of either single drugs or combinations of agents and were less effective than giving all drugs of an alternating regimen simultaneously.

Antiviral Agents↗
PubMed1994

Are platelet cytosolic free calcium, serotonin concentration and blood viscosity different between hypertensive and normotensive subjects?

In this study, the platelet intracellular calcium and serotonin (5-HT) concentrations as well as the hemorheological properties were compared in 65 hypertensive (HT) and 25 age-matched normotensive (NT) subjects. The result showed that the platelet intracellular calcium concentration in the HT group was significantly higher than in the NT group (165.4 +/- 12.6 vs. 118.9 +/- 12.4 nM, p < 0.05). However, the platelet 5-HT content in the HT group was significantly lower than in the NT group (0.28 +2- 0.03 vs. 0.38 +/- 0.03 nmol/10(8) platelets, p < 0.05). Moreover, red cell flexibility, red cell deformability, hematocrit, fibrinogen concentration and plasma viscosity were all significantly increased in HT subjects. The whole blood viscosity was generally higher in the HT group. In conclusion, the higher platelet intracellular calcium and lower 5-HT level as well as abnormality of hemorheological properties may be important factors in the initiation and perpetuation of hypertension.

Aged↗
PubMed1994

Effect of intravenous calcitriol on platelet intracellular calcium in uremic hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: To investigate the effect of the reversal of hyperparathyroidism on platelet intracellular free calcium ([Ca2+]i) by pharmacological parathyroidectomy with intravenous calcitriol in uremic patients with secondary hyperparathyroidism (2 degrees HPT). METHODS: Serum concentrations of intact parathyroid hormone (I-PTH) were measured by two-site immunometric assay, and platelet [Ca2+]i was assessed using the fluorescent indicator fura-2. Fifteen hemodialysis patients with 2 degrees HPT and serum I-PTH 4 times greater than the normal upper limits, were selected for treatment with intravenous calcitriol 1 microgram thrice weekly for one month. RESULTS: An increase of serum I-PTH (449.17 +/- 52.35 vs 32.52 +/- 1.95 pg/ml) and elevated platelet [Ca2+]i (139.49 +/- 8.78 vs 74.70 +/- 6.48 nM/L) was observed in uremic patients with 2 degrees HPT. Serum I-PTH levels were significantly correlated with platelet [Ca2+]i in uremic patients with 2 degrees HPT (r = 0.736, p = 0.002). The serum I-PTH levels decreased from 449.17 +/- 52.35 to 221.27 +/- 35.66 pg/ml (p < 0.001) and platelet [Ca2+]i fell from 139.49 +/- 8.78 to 97.86 +/- 7.25 nM/L (p < 0.001) after treatment. Fall in platelet [Ca2+]i was related to concomitant reduction in PTH levels (r = 0.572, p = 0.026). CONCLUSIONS: It was concluded that an increase in cytosolic calcium in uremia may be at least in part induced by PTH. Besides, intravenous calcitriol can provide an effective way to suppress elevated serum I-PTH and attenuate platelet free calcium in uremia with 2 degrees HPT.

Adult↗
PubMed1994

Modulation of intrinsic in vitro resistance to carboplatin by edatrexate in the A549 human nonsmall cell lung cancer cell line.

Edatrexate (10-ethyl-deazaaminopterin) is a methotrexate analog that has been shown to have greater antitumor activity and improved therapeutic index compared to its parent compound in preclinical systems. We have evaluated the ability of edatrexate to modulate the intrinsic resistance of the lung adenocarcinoma A549 cell line to carboplatin. Concentration effects, exposure time and schedule dependence were assessed. Modulation of resistance was observed with edatrexate treatment (0.2 microM for 1 h) prior to carboplatin. The concentrations of carboplatin to achieve IC50 at the 1-, 3-, and 24-h IC50 were decreased by a mean of 16.8 times (12.2-22.2) with edatrexate preexposure. In contrast, there was little modulation observed of carboplatin resistance when carboplatin was administered prior to edatrexate. In addition, schedule dependency experiments were performed using the method described by Chou and Talalay, in which the ratio of carboplatin to edatrexate was constant or nonconstant, and both the potency of effects and the shapes of the concentration-effect curves were taken into account in a computerized analysis. These experiments also demonstrated schedule dependency. Although both treatments resulted in a reduced IC50 vs. carboplatin alone, the reduction was much greater when edatrexate was added first (12.59 vs. 2.59 times). We conclude that the combination of edatrexate and carboplatin demonstrates schedule-dependent modulation of intrinsic carboplatin resistance in this in vitro model at clinically achievable edatrexate plasma levels (0.01 to 10 microM). The greatest modulatory synergism was observed in the setting of edatrexate treatment before carboplatin. Our findings suggest a potentially useful schedule when combining edatrexate and carboplatin for the treatment of malignant disease.

Aminopterin↗
PubMed1994

Effects of long-acting propranolol and verapamil on blood pressure, platelet function, metabolic and rheological properties in hypertension.

The newly developed antihypertensive drugs, the long-acting beta-blocker propranolol and the sustained release calcium antagonist verapamil, are compared in their antihypertensive, platelet function, rheological properties and metabolic effects. The trial was a double-blind, randomised, placebo-controlled cross-over study. Thirty patients with mild to moderate hypertension received propranolol (40-120 mg) or verapamil (80-200 mg) once daily in two separate ten week courses. After ten weeks treatment both drugs had significantly reduced both SBP and DBP. Beta-thromboglobulin (beta-TG) concentration, reflecting the status of platelet activation in vivo, was significantly decreased after propranolol (129.6 +/- 13.5 vs. 77.9 +/- 8.6 ng/ml) and verapamil (129.6 +/- 13.5 vs. 90.7 +/- 10.1 ng/ml) treatments while platelet aggregation induced by ADP, collagen, arachidonic acid or adrenaline and the production of thromboxane B2 (TXB2), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and platelet cyclic 3'-5' adenosine monophosphate (C-AMP) concentration were not affected. Significant alterations in rheological parameters such as plasma and whole blood viscosity, fibrinogen level and red cell deformability were not found. Higher cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels were observed after propranolol treatment but not in verapamil treatment. Side-effects were mild, tolerated and no patient had to be withdrawn from the study. In conclusion, propranolol and verapamil are generally effective antihypertensive as well as rheologically safe drugs. Compared with the metabolic effect on serum lipid, verapamil may be a better choice. Both drugs possess the tendency to inhibit platelet properties which is desirable in hypertension treatment.

Adult↗