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Biomedical subjects

D A Handley

Publications and source records attributed to D A Handley.

At least 37 records · Page 2Linked to original sources
PubMed1995

Preclinical pharmacology and possible mechanism of action of the novel antitumor agent 5-(4'-piperidinomethylphenyl)-2,3-dihydroimidazo [2,1-a]isoquinoline.

SDZ 62-434 (CAS 115621-95-9, 5-(4'-piperidinomethylphenyl)-2,3-dihydroimidazo [2,1-a]isoquinoline dihydrochloride), a member of a novel class of antitumor agents, exhibited direct and macrophage-induced cytotoxicity against a variety of murine tumor cell lines. It is more effective than edelfosine in increasing survivors and reducing tumor volume in the oral mouse Meth A fibrosarcoma model. Preliminary studies suggest that an undefined cytotoxic effect, macrophage activation and possible effects on signal transduction may account for its antitumor mechanism of action. SDZ 62-434 is currently in Phase I clinical trials as a potential antitumor agent.

Allantoin↗
PubMed1994

Antitumor activity of a piperidine phospholipid.

A piperidine phospholipid ((+/-)-2-[hydroxy] [1-octadecyloxycarbonylpiperidin-3-yl]methoxy-phosphinyl] oxy]-N,N,N, trimethylethaniminium hydroxide inner salt, SDZ 62-826) has been prepared that exhibited weak direct cytotoxicity and strong macrophage-induced cytotoxicity in vitro against a variety of murine and one human tumor cell lines. This compound was found to be as effective as ET-18-OCH3 and SRI 62-834, phospholipids with both strong direct and macrophage-induced cytotoxicity, in increasing survivors and reducing tumor volume when given either orally or intravenously in the mouse MethA fibrosarcoma model. These findings suggest that the macrophage-induced cytotoxicity exhibited by ET-18-OCH3 and other phospholipids may play an important role in this tumor model.

Animals↗
PubMed1993

Structural modification of 5-aryl-2,3-dihydroimidazo[2,1-a]isoquinoline platelet activating factor receptor antagonists.

In an effort to determine the effect of modification of the imidazo[2,1-a]isoquinoline portion of the PAF-receptor antagonist SDZ 64-412 (1), several new analogs were prepared and evaluated in vitro and in vivo. One of these, 5-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenyl]-2,3-dihydroimidazo [1,2-a]thieno[2,3-c]pyridine (6) was 4-5 times more potent than 1 in inhibiting PAF-induced bronchoconstriction and hemoconcentration when administered po to the guinea pig.

Animals↗
PubMed1992

Induction by aerosol allergen of sustained and nonspecific IgE-mediated airway hyperreactivity in the guinea pig.

Described is a guinea pig model of allergic asthma, in which animals are sensitized by intraperitoneal injections of ovalbumin complexed with aluminum hydroxide to elicit an IgE response. Aerosol exposure to ovalbumin induces acute bronchoconstriction and nonspecific airways hyperreactivity, evaluated by intravenous challenges of histamine or acetylcholine. This model mimics the hallmark features of human asthma, is induced by respired allergen and is pharmacologically modulated by prophylactic drugs (methyl prednisolone, ketotifen, theophylline) and the competitive PAF receptor antagonist SDZ 264-412.

Acetylcholine↗
PubMed1990

Prevention of non-specific airway hyperreactivity after allergen challenge in guinea-pigs by the PAF receptor antagonist SDZ 64-412.

1. Allergen challenge by aerosol in sensitized guinea-pigs elicited non-specific airway hyperreactivity assessed by reactivity to i.v. histamine or acetylcholine. Airway hyperreactivity to histamine persisted for at least 48 h and was accompanied by pulmonary eosinophilia as determined by bronchoalveolar lavage cell analysis. 2. Airway hyperreactivity was independent of vagal reflex mechanisms since it was not abrogated by bilateral vagotomy. 3. The novel platelet-activating factor (PAF) receptor antagonist SDZ 64-412 inhibited the development of airway hyperreactivity, as measured 24 h after aerosol allergen challenge, when given as a single treatment orally 2 h before allergen challenge. The PAF receptor antagonist WEB 2086 as well as methylprednisolone and ketotifen also showed efficacy in preventing development of airway hyperreactivity. 4. Neither the two PAF antagonists nor ketotifen had any effect on bronchoalveolar lavage (BAL) eosinophil numbers. Methylprednisolone was the only substance which readily prevented eosinophil recruitment in addition to airway hyperreactivity. 5. We conclude that allergen-induced airway hyperreactivity in guinea-pigs is inhibited by prophylactic anti-asthma drugs and specific PAF receptor antagonists, thus demonstrating a pivotal role of PAF in this response. There was a lack of correlation between airway hyperreactivity and the presence of BAL eosinophils.

Allergens↗
PubMed1989

Effects of combined receptor antagonists of leukotriene D4 (LTD4) and platelet-activating factor (PAF) on rhesus airway responses to LTD4, PAF and antigen.

Rhesus monkeys with IgE-mediated asthmatic-type responses to Ascaris suum antigen were pretreated with a combination of 2 receptor antagonists to leukotriene D4 (LTD4) and platelet-activating factor (PAF). This combination of anti-LTD4 and anti-PAF was shown to inhibit airway responses to either LTD4 or PAF in separate experiments in these Ascaris airway-reactive animals. When the same combination of LTD4 and PAF receptor antagonists was used to pretreat the same animal prior to aerosol challenge with Ascaris antigen we could not demonstrate inhibition of the antigen-induced airway response. Thus, combined receptor blockade for LTD4 and PAF did not alter IgE-mediated acute airway responses to antigen in this species. We review the current status of rhesus asthma and LTD4 and PAF receptor antagonist activity in this model.

Animals↗
PubMed1989

Terbinafine inhibits the mitogenic response to platelet-derived growth factor in vitro and neointimal proliferation in vivo.

Terbinafine [(E)-N(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthale nemethanamine], an antimycotic agent that inhibits fungal squalene epoxidase activity, was examined for its effects on platelet-derived growth factor (PDGF)-stimulated aortic smooth muscle cell DNA synthesis in vitro and neointimal proliferation in vivo. Exposure of bovine aortic smooth muscle cells to 0.25 to 25 microM terbinafine resulted in a concentration-dependent inhibition of PDGF-induced mitogenesis as determined by [3H]thymidine incorporation into DNA or cell number. The IC50 for inhibition of PDGF-stimulated smooth muscle cell DNA synthesis was approximately 5 microM. Micromolar concentrations of terbinafine also suppressed the mitogenic response to PDGF in fibroblasts. Neither the binding of [125I]PDGF to its plasma membrane receptors nor the uptake of [3H]thymidine or [3H]uridine was affected significantly by terbinafine. Oral administration of terbinafine (200 mg/kg/day) to rats for 2 days before and 14 days after balloon catheter injury to the carotid artery was associated with a 40% decrease in the area of the neointimal lesion. These observations indicate that terbinafine is both a potent in vitro antagonist of the smooth muscle cell mitogenic response to PDGF and an effective, well-tolerated p.o. active inhibitor of neointimal proliferation in vivo.

Animals↗
PubMed1988

Membrane-bound lipoprotein lipase on human monocyte-derived macrophages: localization by immunocolloidal gold technique.

Macrophages from both rodent and human sources have been shown to produce lipoprotein lipase (LPL), the enzyme activity of which can be measured in culture media and in cellular homogenates. The studies reported here show the presence of LPL on the surface of human monocyte-derived macrophages. An inhibitory monoclonal antibody to human LPL was used for cellular and immunoelectron microscopy studies. This antibody is a competitive inhibitor of LPL hydrolysis of triacylglycerol but does not inhibit LPL hydrolysis of a water-soluble substrate, p-nitrophenyl acetate. Furthermore, when postheparin plasma was mixed with monoclonal antibody prior to gel filtration on 6% agarose, the LPL activity eluted with the lipoproteins and was not inhibited by the antibody. These studies suggest that the antibody recognized the lipid/lipoprotein binding site of the LPL molecule. Membrane-bound LPL was demonstrated on human monocyte-derived macrophages using colloidal gold-protein A to detect the monoclonal antibody to LPL. The surface colloidal gold was randomly distributed with a surface density of 56,700 gold particles per cell. Control cells cultured in heparin-containing media (10 units/ml) or cells reacted with anti-hepatic triacylglycerol lipase monoclonal IgG or nonimmune mouse IgG did not exhibit membrane binding of protein A-gold. Macrophages were incubated with control and monoclonal anti-LPL IgGs and 125I-labeled anti-mouse IgG F(ab')2. Heparin-releasable membrane-bound anti-LPL antibody was demonstrated. These studies demonstrate the presence of LPL on the surface of human monocyte-derived macrophages, such that the LPL is oriented with its lipid-binding portion (recognized by this antibody) exposed. Membrane-associated LPL may be important in the interaction and subsequent uptake of lipid and lipoproteins by macrophages and in the generation of atherosclerotic foam cells.

Antibodies, Monoclonal↗
PubMed1988

Biological effects of the orally active platelet activating factor receptor antagonist SDZ 64-412.

SDZ 64-412 is a trimethoxyphenylethylphenyl imidazo[2,1-a] isoquinoline molecule that displays marked in vitro inhibition of platelet activating factor (PAF)-induced human platelet aggregation (IC50 = 60 nM) but is without inhibition (at 100 microM) of epinephrine-, ADP- or collagen-induced aggregation. SDZ 64-412 antagonized receptor binding of radiolabeled PAF to human platelet membranes with an IC50 = 60 nM. In the rat, SDZ 64-412 inhibited 100 ng kg-1 PAF-induced hypotension when given i.v. (ED50 = 0.23 mg kg-1) or p.o. (ED50 = 13 mg kg-1). In the guinea pig, SDZ 64-412 inhibited 50 ng kg-1 PAF-induced bronchoconstriction (ED50 = 4.2 mg kg-1 p.o.) and hemoconcentration (ED50 = 5.0 mg kg-1 p.o.). SDZ 64-412 exhibited oral activity in the dog against 1.5 micrograms kg-1 PAF-induced hypotension (ED50 = 5.1 mg kg-1 p.o.) and hemoconcentration (ED50 = 4.9 mg kg-1) and 3.5 micrograms kg-1 PAF-induced hemoconcentration in the cebus primate (ED50 = 12.8 mg kg-1 p.o.). SDZ 64-412 protected in a dose-dependent manner against PAF-induced lethality (LD75 = 75 micrograms kg-1 i.v.) in mice, where 20 mg kg-1 p.o. improved survival from 25 +/- 4% to 77 +/- 8%. SDZ 64-412 afforded complete protection against endotoxin-induced lethality (LD90 = 7.5 mg kg-1 endotoxin i.v.) where the ED50 was 45 mg kg-1 twice predose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1987

Inhibition by SRI 63-072 and SRI 63-119 of PAF-acether and immune complex effects in the guinea pig.

We have examined two PAF-acether receptor antagonists, SRI 63-072 and SRI 63-119, for their ability to inhibit PAF-acether and immune complex effects in the guinea pig. Both compounds exhibited dose-dependent inhibition of bronchoconstriction and hemoconcentration induced by 0.1 micrograms kg-1 PAF-acether, where the ED50 values of SRI 63-072 were 0.3/0.4 mg kg-1 i.a. and 0.14/0.17 mg kg-1 i.a. for SRI 63-119 for each response, respectively. The d and 1 chiral forms of both antagonists were equipotent towards inhibition of hemoconcentration and bronchoconstriction, suggesting a lack of enantiomeric selectively. SRI 63-072 was further evaluated for its ability to inhibit dermal extravasation in the reverse passive Arthus reaction. Guinea pigs given 125I-BSA i.v as antigen and anti-BSA antibodies by intradermal injection exhibited plasma leakage that was dose- and time-dependent relative to the antibody amount. SRI 63-072 exhibited 46% maximal inhibition of dermal plasma leakage when injected in the skin (100 micrograms site-1 i.d.) with the antibody but less than 10% inhibition when administered intra-arterially (3.0 mg kg-1 i.a.) with the antigen. Therefore, these antagonists effectively inhibit systemic effects of PAF-acether and are partially effective towards inhibition of the dermal extravasation induced by immune complexes. Furthermore, unlike the enantiomeric differences between R and S PAF-acether, the chiral molecules of 63-119 and 63-072 effectively antagonized hemoconcentration and bronchoconstriction induced by PAF-acether.

Administration, Oral↗
PubMed1987

In vitro and in vivo pharmacological profiles of the PAF receptor antagonist SRI 63-675.

We have examined a recently developed PAF antagonist SRI 63-675 (dimethyl-tetrahydrofuran-methoxyphosphinyloxy-ethylquinolinium ) for its ability to inhibit several major PAF-induced physiological responses. The compound was a potent inhibitor of PAF-induced platelet aggregation in platelet rich plasma obtained from humans, guinea pigs, and rabbits, with IC50 values of 3.43, 0.25, and 0.97 microM, respectively. SRI 63-675 did not inhibit ADP, collagen nor epinephrine-induced human platelet aggregation. The IC50 for inhibition of PAF receptor binding to human platelets was 0.37 microM. In the rat SRI 63-675 inhibited 0.1 microgram kg-1 i.v. PAF-induced hypotension, with an ED50 of 32 micrograms kg-1 i.v. Using the same PAF challenge in the guinea pig, SRI 63-675 inhibited the hemoconcentration (ED50 = 17 micrograms kg-1 i.v.) and bronchoconstriction (ED50 = 24 micrograms kg-1 i.v.) responses. In the primate, the ED50 was 28 micrograms kg-1 i.v. against 3.5 micrograms kg-1 PAF-induced hemoconcentration. The ratio (1:6) in the primate of PAF used (6.3 nmol kg-1) to antagonist at the ED50 (40.7 nmol kg-1) indicates exceptional potency of SRI 63-675 in this species. The inhibition by SRI 63-675 of the major PAF-induced effects in the rat, guinea pig and primate suggests a common receptor may be involved in the expression of these PAF responses.

Animals↗
PubMed1987

Antitumor activity of SRI 62-834, a cyclic ether analog of ET-18-OCH3.

SRI 62-834, an analog of the antitumor agent ET-18-OCH3 in which the oxygen atom at carbon atom 2 has been incorporated into a five-membered heterocycle, has been prepared and evaluated as an antitumor agent. The compound exhibited good cytotoxicity in vitro against a variety of tumor cell lines and was as effective as ET-18-OCH3 given orally in the mouse Meth A sarcoma model. SRI 62-834 was shown to be an inhibitor of platelet-derived growth factor (PDGF), possibly at the receptor level, and platelet-activating factor (PAF) at the receptor level.

Animals↗
PubMed1987

Determinants of the uptake of very low density lipoprotein remnants by the perfused rat liver.

The receptor-mediated uptake of very low density lipoprotein (VLDL) remnants by the rat liver was studied. Livers were perfused with native 125I-VLDL remnants, radiolabeled apo E-deficient remnants, and radiolabeled remnants that contained reductively methylated apo B and unmodified apo E. The specific uptake of the apo E-deficient remnants was 20% of that for the native remnants, whereas the specific uptake of the remnants containing unreactive apo B was 78% of the control value. This suggests that the apo E of VLDL remnants is the principal ligand for binding to the receptor, and in the absence of apo E, apo B may participate in binding. This conclusion is supported by the finding that dimyristoyl phosphatidylcholine (DMPC)- apo E complexes were effective in competing for the hepatic uptake of 125I-VLDL remnants. The intracellular distribution of radioactivity was analyzed by Percoll density gradient centrifugation. At five minutes after perfusion, radioactivity was associated with the plasma membrane and lysosomal fractions, and at 30 minutes most of the radioactivity was associated with the lysosomal fraction. Binding and internalization of VLDL remnants was also directly visualized by electron microscopy. Internalization proceeded by coated pit-coated vesicle formation with subsequent delivery to lysosomes. Our findings demonstrate that the apo E of VLDL remnants mediates binding to the hepatic receptor and that the internalization and degradation of VLDL remnants is by a similar pathway to that previously described for LDL.

Animals↗
PubMed1987

Biological properties of the antagonist SRI 63-441 in the PAF and endotoxin models of hypotension in the rat and dog.

Intravenous administration of platelet-activating factor (PAF) produces dose-dependent hypotension in several species. We have evaluated a recently developed PAF antagonist, SRI 63-441, for its ability to inhibit the hypotensive effect of PAF in the rat and dog. In the rat, 100 ng/kg PAF produced a 38.6 +/- 5.1% decrease in carotid mean arterial pressure (MAP), followed by a 3.2 +/- 0.7 min recovery period for MAP to return to baseline values. SRI 63-441 reduced the hypotension response in the rat, where the ED50 values for inhibition of MAP were 0.16 mg/kg i.v. and 0.19 mg/kg i.v. for the recovery period. Dogs challenged with 1.5 micrograms/kg PAF i.v. demonstrated a 52 +/- 8% decrease in MAP that persisted for at least 15 min. The ED50 for inhibition of MAP by SRI 63-441 was 0.20 mg/kg i.v. Following injection of tritium-labeled SRI 63-441, 56.8 +/- 2.4% of the dose was recovered in the urine and 43.2 +/- 8.9% in the feces in the rats while in dogs 38.7 +/- 5.6% and 60.9 +/- 23.5% of the dose was excreted in the urine and feces, respectively. In the rat model of endotoxin-induced hypotension, SRI 63-441 given 1 min after a 5 mg/kg endotoxin challenge (which produced a 52 +/- 7% decrease in MAP), reversed the systemic effects, with an ED50 of 0.18 mg/kg i.v. The ED50 for reversal 6 min after endotoxin injection was 0.01 mg/kg. These results of inhibition and reversal by SRI 63-441 strongly implicate PAF as a pivotal mediator of hypotension and shock.

Animals↗
PubMed1987

Platelet-activating factor antagonists.

Over the past decade platelet-activating factor has achieved the status of an important inflammatory mediator. The scientific enthusiasm and number of research investigators, publications, and meetings recently devoted to PAF suggest that this mediator will be the subject of continued study in the foreseeable future. The potential for the presence and involvement of PAF in human disease is easily concluded from the reports described in this review. Both the need for low concentrations for cellular response and the rapid biological clearance mechanisms have made the proof of the involvement of PAF in human disease difficult. The discovery of PAF receptor antagonists and structure-activity relationships of such antagonists (159) will make this determination possible in the near future. The current PAF antagonists may be considered as first generation agents, since the most potent antagonist is still less than 1/100th as potent as PAF is as an agonist. The wide diversity of clinical applications from asthma to septic shock may also require antagonists with selective attributes such as delivery route (oral vs intravenous vs topical) or biological half-life (prolonged vs short). PAF may prove to be the key mediator of several poorly understood disease syndromes such as hyperacute organ transplant rejection, ischemic bowel necrosis (160), and adult respiratory distress syndrome. We must wait for clinical results to draw further conclusions.

Animals↗
PubMed1987

Receptor-mediated binding, endocytosis and cellular processing of macromolecules conjugated with colloidal gold.

Receptor-mediated expression of cellular functions assures biological specificity, regulation, and control of nutritive and metabolic requirements. The study of receptor-ligand interactions is a central theme in many published reports employing colloidal gold labeling. With the ligand directly conjugated with colloidal gold, the investigator is afforded the opportunity to observe all phases of cellular binding, endocytosis, lysosomal delivery and catabolism. Reviewed are published studies employing direct ligand conjugation with colloidal gold, the relative merits and disadvantages of this type of procedure and data from recent studies investigating endothelial receptor binding of proteins in the coagulation and fibrinolysis cascades.

Animals↗