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Biomedical subjects

J Chang

Publications and source records attributed to J Chang.

At least 505 records · Page 28Linked to original sources
PubMed1984

Human platelet activation by bacterial phospholipase C is mediated by phosphatidylinositol hydrolysis but not generation of phosphatidic acid: inhibition by a selective inhibitor of phospholipase C.

We have shown earlier that phospholipase C (PLC) from Clostridium perfringens causes human platelet aggregation and secretion in a concentration dependent manner. The present study was undertaken to further characterize the specificity of the effects of PLC and to better understand the mechanism of the action of this inducer. A methylene-dioxybenzazepine (MDBA) analog of trimetoquinol was synthesized and tested for antiplatelet activity. MDBA (3-30 microM) inhibited PLC-induced aggregation in a concentration dependent manner. Whereas up to 200 microM MDBA did not inhibit aggregation induced by either thrombin, arachidonic acid, or U46619. Effects of PLC (0.05 U/ml) on hydrolysis of phosphatidylinositol, production of phosphatidic acid and thromboxane B2 (TXB2) synthesis were investigated using [32P]-phosphate and [14C]-arachidonic acid labeled platelets. PLC (0.05 U/ml) caused a time dependent decrease in platelet phosphatidylinositol. Up to 50% of labeled phosphatidylinositol was lost from platelets in five minutes. MDBA (3-30 microM) inhibited PLC-induced loss of phosphatidylinositol in a concentration dependent manner. An increase in phosphatidic acid was also observed in PLC-stimulated platelets. Up to 100 microM MDBA did not inhibit production of phosphatidic acid. PLC-treated platelets did not produce any TXB2. In other experiments possible protease contamination of PLC preparations was tested by incubating PLC (0.03-0.5 U/ml) with [14C]-casein. PLC in concentrations up to ten times higher than the concentrations used in aggregation studies did not cause hydrolysis of [14C]-casein, whereas more than 30% of [14C]-casein was hydrolyzed by trypsin. PLC-induced aggregation was not inhibited by up to 300 microM adenosine or ATP. In other experiments, platelet aggregation by ADP was inhibited by adenosine and ATP in a concentration dependent manner. The addition of calcium (0.5- 2.0 mM) increased aggregation by PLC in a concentration dependent manner. These findings suggest that PLC-induced activation of platelets is: (a) dependent on phosphatidylinositol hydrolysis but not on the production of phosphatidic acid, TXB2 or secretion of ADP; (b) not caused by protease contaminants; (c) calcium dependent; and (d) MDBA inhibits PLC-induced aggregation by blocking phosphatidylinositol hydrolysis.

Adenosine↗
PubMed1984

Differential effects of putative lipoxygenase inhibitors on arachidonic acid metabolism in cell-free and intact cell preparations.

The effects of nordihydroguairetic acid (NDGA), 3-amino-1-trifluoromethyl-)-phenyl-2-pyrazoline (BW755c), eicostatetraynoic acid (ETYA), phenidone, quercetin, and indomethacin (INDO) on the synthesis of 15-hydroxyeicosatatetraenoic acid (15-HETE) from soybean 15-lipoxygenase, leukotriene B4 (LTB4) from 5-lipoxygenase, and prostaglandin E2 (PGE2) from cyclooxygenase enzymes of rat neutrophils and mouse peritoneal macrophages were investigated. All of the drugs caused a dose-related inhibition of increased oxygen consumption by soybean 15-lipoxygenase in the presence of arachidonic acid and the rank order of potency was phenidone greater than or equal to BW755c greater than ETYA greater than quercetin greater than NDGA greater than indomethacin. The reduction in oxygen consumption correlated with a reduction of 15-HETE formation as identified by high-performance liquid chromatography. Apart from indomethacin, these drugs were also effective against the rat neutrophil 5-lipoxygenase, although the rank order of potency did not correlate with that obtained with soybean 15-lipoxygenase. Furthermore, in both A23187-activated rat neutrophils and zymosan-activated mouse peritoneal macrophages the synthesis of prostaglandins was inhibited by all of these drugs. In the neutrophils, the rank order of potency was INDO greater than ETYA greater than BW755c greater than quercetin greater than NDGA greater than phenidone, whereas in mouse peritoneal macrophages, the order was INDO greater than ETYA greater than BW755c greater than NDGA greater than quercetin greater than phenidone. These results suggest that putative lipoxygenase inhibitors exhibit both qualitative and quantitative differences in their effects on both lipoxygenases and cyclooxygenases.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

The effects of antiallergic and bronchodilator drugs on platelet-activating factor (PAF-acether) induced bronchospasm and platelet aggregation.

Platelet activating factor (PAF-acether) is a potential mediator of asthma and inflammation. Recently, the suggestion was made that inhibition of PAF-acether by disodium cromoglycate (DSCG) might be partly responsible for the effectiveness of DSCG in asthma. We have extended these studies and examined the effects of antiallergic and bronchodilator drugs on PAF-acether induced bronchospasm after i.v. administration in guinea pigs and in vitro platelet aggregation in rabbits. Neither DSCG nor Wy-41,195, a potent orally effective antiallergic, altered either of the PAF-acether responses. Furthermore, aerosolized ipratropium, promethazine, ketotifen and FPL 55712 failed to affect the PAF-acether-induced bronchospasm. The same drugs were also ineffective against platelet aggregation induced by PAF-acether. In contrast, aerosolized thiazinamium chloride inhibited the bronchospasm and also inhibited PAF-acether-induced platelet aggregation. Thiazinamium chloride possessed weak antiaggregatory effects against ADP and was without effect against arachidonic acid-induced platelet aggregation. Both lipoxygenase and cyclooxygenase products of arachidonic acid metabolism appear to be involved in PAF-acether bronchospasm since i.v. administered lipoxygenase inhibitors (phenidone, BW755c and NDGA) and indomethacin independently inhibited this in vivo response. However, these drugs failed to alter platelet aggregation to PAF-acether. Thiazinamium chloride may be capable of directly antagonizing the PAF-acether-induced platelet aggregatory response and, in addition, inhibiting the synthesis and/or effects of bronchoconstrictor amines and endogenously generated arachidonic acid metabolites.

Animals↗
PubMed1984

A comparative study of the antiinflammatory activity of fentiazac and its major metabolite, p-hydroxy fentiazac.

Wy-25,110, the p-OH metabolite of fentiazac was approximately 100 times less potent than fentiazac after oral administration in rat carrageenan edema and 100-130 times less potent as an inhibitor of prostaglandin synthesis by mouse peritoneal macrophages. In addition, Wy-25,110 was one twelfth as active as fentiazac against immunologic-induced inflammation on day 16 in rat adjuvant arthritis. Wy-25,110 was also much less potent than fentiazac when administered intravenously, suggesting that inadequate oral absorption does not account for its lack of potency. Thus it seems unlikely that the p-OH metabolite contributes greatly to the antiinflammatory properties of fentiazac.

Acetates↗
PubMed1984

The antiinflammatory profile of (5H-dibenzo[a,d]-cyclohepten-5-ylidene)acetic acid (WY-41,770), an agent possessing weak prostaglandin synthetase inhibitory activity that is devoid of gastric side effects.

Wy-41,770 [(5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid], a novel acrylic acid, was compared to indomethacin and aspirin in standard antiinflammatory, analgesic and antipyretic animal models. The acute antiinflammatory, analgesic and antipyretic activity of Wy-41,770 (oral ED50S 50-170 mg/kg) was similar to aspirin; however, it was considerably more potent orally in adjuvant arthritis in the rat (ED50, 16 mg/kg) and urate-induced synovitis in the dog (ED50, 4.5 mg/kg). Wy-41,770 was a weak inhibitor of prostaglandin biosynthesis and did not inhibit either 5- or 15-lipoxygenase. Furthermore, the cellular migration characteristic of carrageenan pleurisy was not affected by Wy-41,770. Unlike a majority of NSAIDs, it produced no gastric irritation in rats after either acute or chronic oral administration over the range 400-800 mg/kg. The major mechanism of action of Wy-41,770 has yet to be identified but does not seem to involve interference of arachidonic acid metabolism.

Acetates↗
PubMed1984

Effect of gold salts, D-penicillamine and benoxaprofen on type II collagen-induced arthritis in rats.

We investigated the therapeutic effect of two gold salts, gold sodium thiomalate (GST, i.m.) and auranofin (p.o.), D-penicillamine (p.o.) and benoxaprofen (p.o.) in rat collagen-induced arthritis using type II collagen from fetal bovine articular cartilage. GST, but not auranofin, reduced hind paw edema and bone pathology. However, auranofin reduced serum copper and zymosan-induced prostaglandin production from peritoneal macrophages. In contrast, GST increased both serum copper and macrophage prostaglandin production by zymosan. Benoxaprofen reduced both hind paw edema and pathology, whereas D-penicillamine was without effect. None of these treatments influenced the circulating level of antibody to type II collagen.

Animals↗
PubMed1983

Rabies induced in a cat by high-egg-passage Flury strain vaccine.

An adult male domestic short-hair cat developed posterior paralysis 22 days after being vaccinated for rabies with a high-egg-passage Flury strain vaccine currently approved for use in cats. A diagnosis of rabies was confirmed by mouse inoculations, and viral typing using a panel of monoclonal antibodies demonstrated that it was vaccine induced.

Animals↗
PubMed1983

Effects of thiazinamium chloride, promethazine and chlorpromazine on thromboxane B2 synthesis, phagocytosis and respiratory burst by rat alveolar macrophages.

The effects of three phenothiazines, promethazine, thiazinamium chloride and chlorpromazine, on macrophage function were investigated in rat alveolar macrophages. The study focused on thromboxane B2 (TxB2) synthesis, zymosan phagocytosis, and hexosemonophosphate (HMP) shunt activity in these phagocytes. TxB2 synthesis by resting macrophages was inhibited by thiazinamium chloride and promethazine in a dose-dependent manner. However, chlorpromazine was inhibitory only at 10(-3) M. Promethazine treatment of zymosan-activated macrophages led to a concomitant reduction in both phagocytosis and TxB2 synthesis. Thiazinamium chloride inhibited TxB2 synthesis but had no effect on the ingestion of zymosan particles. In contrast, chlorpromazine inhibited phagocytosis but not TxB2 synthesis except at 10(-3) M. The effects of these agents on the formation of TxB2 synthesis from exogenous arachidonic acid were also investigated. Under these conditions where indomethacin, a known cyclooxygenase inhibitor, was inhibitory, promethazine but not thiazinamium chloride inhibited TxB2 synthesis from exogenous arachidonic acid. Treatment of macrophages with promethazine and chlorpromazine but not thiazinamium chloride results in a reduction in the oxidative burst during phagocytosis. The results suggest that the phenothiazines used in this study differ from one another in their actions on macrophage function. Furthermore, the ability of thiazinamium chloride to selectively inhibit arachidonic acid metabolism may contribute to its bronchodilator/antiallergic activity.

Animals↗
PubMed1983

Characterization of a high-affinity receptor for phorbol esters in rat alveolar macrophages.

Macrophages display varied responses to the tumor promoter, TPA. In this study, a high-affinity receptor for phorbol ester is characterized in a viable alveolar macrophage population. The binding assay is performed using tritiated PDBu and specific binding is demonstrated to be temperature-sensitive. At 37 degrees C, the level of bound ligand reaches maximal binding within 2-5 min but rapidly decays to within 30% of the original specific binding. Equilibrium, however, can be established when the assay is carried out at 4 degrees C. The data indicate that at this temperature maximal binding is reached within 2 h and remains constant thereafter. Scatchard analysis shows that the receptor has an apparent Kd of 21 nM and each macrophage possesses 2 X 10(5) binding sites. Active phorbol derivatives such as TPA and PDBu compete with the labeled ligand for the receptor, whereas the inactive phorbol alcohol does not modulate the specific binding. Mezerein, a related diterpene which has been shown to share some of the properties of phorbol esters, also competes for the binding site. The high-affinity receptor is not affected by zymosan or EIgG phagocytosis. Inflammatory mediators such as prostaglandins E2 and F2 alpha and platelet-activating factor do not compete for the receptor.

Animals↗
PubMed1983

The Toronto Western Hospital catheter in a pediatric dialysis program.

Following multiple technical problems with Tenckhoff catheters in children commencing prolonged dwell peritoneal dialysis, we have recently used the Toronto Western Hospital (TWH) catheter with considerable success. Six of the TWH catheters were inserted in children who had experienced either obstruction or leakage with prior use of 1-4 Tenckhoff catheters. Overall, we have used 15 TWH catheters in 12 children and have compared the results to 23 Tenckhoff catheters in 9 children. The rate of obstruction with TWH (7%) has been much less than with the Tenckhoff catheter (45%). We conclude that the TWH catheter represents a significant advance in peritoneal dialysis catheter technology for end-stage renal disease (ESRD) children starting continuous ambulatory peritoneal dialysis (CAPD) or continuous cycling peritoneal dialysis (CCPD).

Catheters, Indwelling↗
PubMed1983

Cerebral blood flow and cerebrovascular CO2 reactivity in stroke-age normal controls.

We used the noninvasive 133-xenon inhalation technique to determine cerebral hemodynamics in 55 normal volunteers aged 18 to 88. Values for cerebral blood flow and cerebrovascular CO2 reactivity in fast-clearing tissue (flow gray) and slow-clearing tissue (flow white) were examined as functions of age and in relation to hematocrit, blood pressure, and evidence of extracranial vascular disease. Flow gray declined linearly with age, but no corresponding change was found in flow white or in CO2 reactivity. The data suggest that the progressive fall in flow gray is due to a physiologic aging process.

Adolescent↗
PubMed1982

Acrolein: a potent modulator of lung macrophage arachidonic acid metabolism.

Resting rat pulmonary alveolar macrophages exposed to acrolein were stimulated to synthesize and release thromboxane B2 and prostaglandin E2 in a dose-dependent manner. Zymosan-activated pulmonary alveolar macrophages released approximately twice as much prostaglandin E2 as thromboxane B2, whereas acrolein-activated pulmonary alveolar macrophages released 4-5 times less prostaglandin E2 than thromboxane B2. In the zymosan-stimulated pulmonary alveolar macrophages, acrolein also induced a reversal in the relative amounts of prostaglandin E2 and thromboxane B2 synthesized and released into the culture medium. This reversal was achieved by a dose-dependent reduction in prostaglandin E2 synthesis. Although phagocytosis was also inhibited in a dose-dependent manner, the reduction in prostaglandin E2 appeared to be partially independent of particle ingestion since thromboxane B2 synthesis was not affected by low doses of acrolein. In fact, high doses induced a slight enhancement in thromboxane B2 synthesis. These results suggest that acrolein selectively inhibited the enzyme, prostaglandin endoperoxide E isomerase, necessary for the conversion of the endoperoxide to prostaglandin E2. Sulfhydryl reagents such as N-ethylmaleimide and 5,5'-dithiobis (2-nitrobenzoic acid) mimicked acrolein's effects, and reduced glutathione afforded protection against the effects of acrolein. These results indicated the possible involvement of acrolein's sulfhydryl reactivity in the inhibition of the isomerase enzyme. Propionaldehyde had no effect on macrophage arachidonic acid metabolism whereas crotonaldehyde mimicked the effects of acrolein. Pulmonary macrophages were unable to reverse the acrolein effects on arachidonate metabolite synthesis after 6 h in an acrolein-free environment. These data indicated the necessity of the unsaturated carbon bond for the acrolein effects on arachidonic acid metabolism and the relative irreversibility of acrolein's reaction with the macrophage.

Acrolein↗
PubMed1982

Investigation of the effects of phospholipase C on human platelets: evidence that aggregation induced by phospholipase C is independent of prostaglandin generation, released ADP and is modulated by cyclic AMP.

Effects and the mechanism of action of phospholipase C (PLC), from Clostridium perfringens, on washed human platelets were examined to better understand the role of PLC in platelet function. PLC caused aggregation and secretion of [14C]-5HT, without concomitant loss of cytoplasmic, LDH, in a concentration dependent manner. P-nitrophenylphosphorylcholine, a substrate for PLC, blocked these responses in a concentration dependent manner. In other experiments hirudin, alpha-1-antitrypsin and soybean trypsin inhibitor did not inhibit PLC-induced activation of human platelets. PLC-induced aggregation and [14C]-5HT secretion was not inhibited by aspirin, a known inhibitor of prostaglandin biosynthesis. PLC-induced aggregation was selectively inhibited by analogs of 7,8-dihydroxybenzazepine and 7,8-methylenedioxybenzazepine in a concentration dependent manner. These two agents had no effect on arachidonic acid-induced aggregation. PLC-induced aggregation was not inhibited by apyrase, an enzyme which hydrolyzes ADP. In other experiments, PLC-treated platelets did not exhibit any platelet activating factor-like activity. Prostaglandin E1 and trifluoperazine showed concentration dependent inhibitor effects on PLC-mediated aggregation and secretion of [14C]-5HT. These findings indicate that: a) PLC is capable of inducing aggregation and specific secretion of [14C]-5HT without causing lysis of platelets; b) mechanism of PLC-induced activation of platelets is independent of prostaglandin generation or action, released ADP, and PAF; and c) cyclic AMP plays a modulatory role in PLC-mediated secretion and aggregation of human platelets.

Adenosine Diphosphate↗
PubMed1982

Bronchoselective actions of a new series of trimetoquinol analogues.

In selected beta 1- (guinea pig atrial) and beta 2- (guinea pig trachea and lung parenchyma) adrenoceptor systems, we have examined the interaction of isoproterenol (ISO), trimetoquinol (TMQ), erythro- and threo-diastereoisomers of 1-(3,4,5-trimethoxy-alpha-methylbenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (alpha-methylTMQ), alpha-dimethylTMQ, N-methylTMQ and N-[2-methyl-2-(3,4,5-trimethoxyphenyl)propyl]dopamine (open chain dimethylTMQ analogue). The rank order of potency for agonists in trachea was threo-alpha-methylTMQ greater than (+/-)-TMQ greater than ISO greater than erythro-alpha-methylTMQ greater than N-methylTMQ greater than alpha-dimethylTMQ. Only N-methylTMQ gave an intrinsic activity similar to ISO, whereas the alpha-methylated TMQ analogues were partial agonists in this beta 2-system. In atria, the rank order of beta 1-potency was ISO greater than (+/-)-TMQ greater than threo-alpha-methylTMQ greater than N-methylTMQ = erythro-alpha-methylTMQ. Maximal chronotropic effects of all compounds, with the exception of threo-alpha-methylTMQ, were similar to ISO in this preparation. Both alpha-dimethylTMQ and open chain dimethylTMQ analogues were inactive as agonists in this beta 1-system. The ratio of beta 2 : beta 1 selectivity (trachea vs. atria), relative to ISO for threo-alpha-methylTMQ, erythro-alpha-methylTMQ, TMQ and N-methylTMQ was 106.5, 27, 7 and 5.8, respectively. Whereas the rank order of potency for selected compounds in lung parenchyma was ISO greater than threo-alpha-methylTMQ = TMQ greater than erythro-alpha-methylTMQ, the comparative beta 2-selectivity (lung parenchyma vs. atria) relative to ISO, for erythro-alpha-methylTMQ, threo-alpha-methylTMQ and TMQ was 2.5, 1.9 and 0.24, respectively. It is concluded that lipophilic substitutions on the alpha-carbon of the 1-(3,4,5-trimethoxybenzyl)-substituent of TMQ can generate compounds which are potent bronchoselective adrenoceptor agonists. Threo-alpha-methylTMQ and erythro-alpha-methylTMQ were more beta 2-selective than (+/-)-TMQ.

Animals↗
PubMed1982

Bone marrow involvement in adult soft tissue sarcomas.

Bone marrow biopsy was performed as part of the initial assessment in 74 patients with soft tissue sarcoma. Infiltration of the marrow by tumour was present in four cases, all from the group of 56 patients who had other evidence of metastatic disease, giving an overall incidence of 7%. The histological subtypes were pleomorphic rhabdomyosarcoma, angiosarcoma, synovial sarcoma and myxoid liposarcoma, of which the first three were high-grade tumours. Although it was not possible to determine whether response to chemotherapy was influenced by marrow involvement, haematological toxicity seemed excessive.

Adolescent↗
PubMed1982

Positron brain imaging--normal patterns and asymmetries.

Regional brain physiology was investigated in 11 normal resting right-handed subjects using positron emission tomography. Cerebral blood flow was studied in all subjects. Cerebral oxygen metabolism was studied in six subjects, and cerebral glucose metabolism was also studied in one subject. In five subjects, physiological activity was higher in left frontotemporal regions than right. These findings may be related to structural cerebral asymmetries or to activation of brain language centers.

Adult↗