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Biomedical subjects

J M Chapman

Publications and source records attributed to J M Chapman.

At least 19 recordsLinked to original sources
PubMed2001

[Role of anomalies of low density lipoproteins (LDL) in atherogenicity].

Qualitative and quantitative anomalies of low-density lipoproteins (LDL) play a key role in the pathophysiology of atherosclerosis. Such anomalies are characteristics of the atherogenic dyslipidemias which occur most frequently, i.e. primary hypercholesterolemia of phenotype IIA (including familial hypercholesterolemia), combined hyperlipidemias (Type IIB) and hypertriglyceridemia (Type IV). An elevated concentration of circulating LDL occurs either as a result of hepatic overproduction of VLDL particles, the major precursors of LDL, or as a result of delayed catabolism, as occurs when there is a deficit of cellular LDL receptors (e.g. familial hypercholesterolemia), or as a combination of both. The major qualitative anomaly of LDL which results in elevated atherogenicity involves a predominance of small dense LDL, as seen in patients with premature coronary heart disease and equally in combined hyperlipidemia and in hypertriglyceridemia. The mechanism of the formation of these particles is complex and involves the concerted intravascular action of cholesteryl ester transfer protein (CETP), lipoprotein lipase (LPL) and hepatic lipase (HL) on triglyceride-rich precursors of dense LDL Lipid-lowering agents, such as fibrates and statins, act to reduce the atherogenicity of dense LDL by distinct mechanisms, which lead to normalisation of circulating LDL levels and/or to targeted reduction in dense particles of elevated atherogenicity. Indeed, such pharmacological probes have facilitated new insight into the molecular and cellular mechanisms which underlie each of the major forms of atherogenic dyslipidemia.

Arteriosclerosis↗
PubMed1999

Usefulness in predicting coronary artery disease by ultrasonic evaluation of the carotid arteries in asymptomatic hypercholesterolemic patients with positive exercise stress tests.

A positive exercise electrocardiogram (ECG) is not infrequent occurrence in asymptomatic hypercholesterolemic patients, but the number of false-positive tests may be relatively high (50%). Therefore, the ability of a positive stress ECG to predict coronary artery lesions is low even in populations with > or =1 cardiovascular risk factors. To increase the diagnostic value of exercise tests for screening asymptomatic individuals, we analyzed whether combined clinical parameters with carotid echography would accurately predict coronary atherosclerotic lesions by coronary angiography in asymptomatic hypercholesterolemic patients with a positive exercise ECG. Seventy-six asymptomatic patients (between 35 and 65 years of age) with hypercholesterolemia (total plasma cholesterol >6.5 mmol/L or 250 mg/dl) and a positive stress ECG were referred for carotid B-mode echography and coronary angiography. Carotid echography data were divided into 2 categories: (1) absence of any atherosclerotic plaque, or (2) presence of > or =1 arterial plaques. Coronary stenosis assessed by coronary angiography was considered to correspond to a > or =50% reduction of coronary lumen diameter. Forty-three patients (57%) displayed coronary lesions; most (38; 88%) had carotid plaque. Multivariate analysis showed that the presence of carotid plaque was significantly associated with coronary stenosis (odds ratio 15.2; confidence interval 5.0 to 54.5). In subgroups characterized by high frequency of false-positive exercise electrocardiographic tests (women and patients with a 10-year predicted risk of coronary artery disease [CAD] <15%), none of the patients without carotid plaque exhibited coronary lesions. Echographic evaluation of carotid plaque (plaque vs no plaque) significantly improved the diagnostic specificity of exercise electrocardiography. We conclude that the combination of clinical, electrical, and echographic data facilitates cost-effective noninvasive detection of CAD in asymptomatic hypercholesterolemic patients.

Carotid Arteries↗
PubMed1997

CaSm: an Sm-like protein that contributes to the transformed state in cancer cells.

A novel gene encoding a protein containing Sm motif-like domains was found to have elevated expression in pancreatic cancer and in several cancer-derived cell lines. CaSm (for Cancer-associated Sm-like) mRNA is up-regulated in 87.5% (seven of eight) of pancreatic tumor/normal pairs. Similarly, cell lines from cancers originating in liver, ovary, lung, and kidney show increased CaSm expression compared to their normal tissue cognates. CaSm encodes a 133-amino acid open reading frame that contains the two Sm motifs found in the common snRNP proteins, with the greatest homology to the Sm G protein (60% similarity). Two hypothetical proteins from Caenorhabditis elegans and Saccharomyces cerevisiae share even greater similarity (72.8 and 67.7%, respectively), suggesting a broad family of proteins containing Sm motifs. Antisense CaSm RNA is able to alter the transformed phenotype of pancreatic cancer cells by reducing their ability to form large colonies in soft agar when compared to untransfected cells. Therefore, CaSm expression appears to be necessary for maintenance of the transformed state.

Amino Acid Sequence↗
PubMed1997

Potent hypocholesterolemic activity of novel ureido phenoxyisobutyrates correlates with their intrinsic fibrate potency and not with their ACAT inhibitory activity.

The hypocholesterolemic activity for novel ureido fibrate analogues was found to be over 100-fold greater than for any "second-generation" fibrate in cholesterol-fed rats. A comparison of 12 related analogues revealed that the optimal configuration for a urea-bridging region located between two aromatic rings consisted of a trisubstituted nitrogen, optimally substituted with a C7 alkyl chain and linked by dimethylene to a phenoxyisobutyrate moiety found in most fibrate analogues. The hypocholesterolemic potency of these compounds was found to correlate with their increased intrinsic fibrate activity as determined by the ability to induce omega-hydroxylase activity either in rat hepatocyte cultures or in vivo, and not with their 10-fold increased ACAT inhibitory potency when compared to other fibrates. The most active compound, 2-(4-(2-(N'-(2,4- difluorophenyl)-N-heptylureido)ethyl)phenoxy)-2-methylpropionic acid, referred to as (2), was found to induce omega-hydroxylase activity in hepatocytes at concentrations between 5 and 100 nM compared to 1-20 microM concentrations for bezafibrate, and lower serum VLDL+LDL cholesterol in rats at doses between 0.1 and 0.5 mg/kg per day compared to doses of 25-100 mg/kg per day for bezafibrate. Single-dose pharmacokinetic studies with 2 indicated that total drug exposure will be much lower at hypocholesterolemic doses due to the enhanced intrinsic activity, and may result in an improved safety profile for these novel trisubstituted ureido fibrate analogues in rats and humans compared to other fibrates.

Animals↗
PubMed1996

Crystallization and preliminary X-ray analysis of a low density lipoprotein from human plasma.

Single crystals of human plasma low density lipoprotein (LDL), the major transport vehicle for cholesterol in blood, have been produced with a view to analysis of the three-dimensional structure by x-ray crystallography. Crystals with dimensions of approximately 200 x 100 x 50 microm have been reproducibly obtained from highly homogeneous LDL particle subspecies, isolated in the density ranges d = 1.0271-1. 0297 g/ml and d = 1.0297-1.0327 g/ml. Electron microscopic imaging of ultrathin-sectioned preparations of the crystals confirmed the existence of a regular, quasihexagonal arrangement of spherical particles of approximately 18 nm in diameter, thereby resembling the dimensions characteristic of LDL after dehydration and fixation. X-ray diffraction with synchrotron radiation under cryogenic conditions revealed the presence of well resolved diffraction spots, to a resolution of about 29 A. The diffraction patterns are indexed in terms of a triclinic lattice with unit cell dimensions of a = 16. 1 nm, b = 39.0 nm, c = 43.9 nm; alpha = 96.2 degrees, beta = 92.1 degrees, gamma = 102 degrees, and with space group P1.

Crystallography, X-Ray↗
PubMed1995

Cytotoxicity of imides-N-alkyl semicarbazones, thiosemicarbazones, acetylhydrazones and related derivatives.

The semicarbazones, thiosemicarbazones and acetyl-hydrazones of phthalimide, o-benzosulfimide, naphthalimide and diphenimide demonstrated potent cytotoxicity against murine and human leukemia cell growth and cultured cell growth from human solid tumors. The major site of inhibition in L1210 leukemia cells was DNA synthesis after 60 min incubated with the agents at 25, 50 and 100 microM. De novo synthesis of purines at the regulatory enzyme sites of PRPP amidotransferase and IMP dehydrogenase were the major targets of the agent. Thymidylate synthetase, dihydrofolate reductase and ribonucleoside reductase activities were inhibited by the agents in a manner which would contribute to the overall reduction of DNA synthesis and cell death. d(NTP) pools were significantly reduced and the evidence suggests that the agents interacted with DNA affording DNA strand scission which would interfere with both template utilization by the polymerases and also ultimately reduce nucleic acid synthesis.

Amidophosphoribosyltransferase↗
PubMed1994

Effects of lipoprotein(a) on the binding of plasminogen to fibrin and its activation by fibrin-bound tissue-type plasminogen activator.

Molecular assembly of plasminogen and tissue-type plasminogen activator (t-PA) at the surface of fibrin results in the generation of fibrin-bound plasmin and thereby in the dissolution of a clot. This mechanism is triggered by specific interactions of intra-chain surface lysine residues in fibrin with the kringle domains of plasminogen, and is further amplified via the interaction of plasminogen kringles with the carboxy-terminal lysine residues of fibrin that are exposed by plasmin cleavage. By virtue of its marked homology with plasminogen, apo(a), the specific apolipoprotein component of Lp(a), may bind to the lysine sites available for plasminogen on the surface of fibrin and thereby interfere with the fibrinolytic process. A sensitive solid-phase fibrin system, which allows the study of plasminogen activation at the plasma fibrin interface and makes feasible the analysis of products bound to fibrin, has been used to investigate the effects of Lp(a) on the binding of plasminogen and its activation by fibrin-bound t-PA. Plasma samples from human subjects with high levels of Lp(a) were studied. We have established that Lp(a) binds to the fibrin surface and thereby competes with plasminogen (Ki = 44 nM) so as to inhibit its activation. We have further shown that Lp(a) blocks specifically carboxy-terminal lysine residues on the surface of fibrin. To further explore the role of apo(a) on the Lp(a) fibrin interactions, we have performed ligand-binding studies using a recombinant form of apo(a) that contains 17 kringle 4-like units. We have shown that recombinant apo(a) binds specifically to fibrin (Kd = 26 +/- 8 nM, Bmax = 26 +/- 2 fmol/well) and that this binding increases upon treatment of the fibrin surface with plasmin (Kd = 8 +/- 4 nM, Bmax = 115 +/- 14 fmol/well). Altogether, our results indicate clearly that binding of native Lp(a) through this mechanism may impair clot lysis and may favor the accumulation of cholesterol in thrombi at sites of vascular injury.

Apolipoproteins↗
PubMed1994

The cytotoxic activity of cyclic imido alkyl ethers, thioethers, sulfoxides, sulfones and related derivatives.

Cyclic imides such as N-substituted alkyl ethers, thioethers, sulfoxides, sulfones and related derivatives were potent agents against human single cell tumors and selected solid tumor growths, eg adenocarcinoma of the colon and glioma. These agents in the L1210 lymphoid leukemia tumor model preferentially inhibited DNA synthesis. The regulatory enzyme sites in the purine pathway were targets of the agents. Other sites of inhibition were DNA polymerase alpha and thymidylate synthetase activities. d(NTP) pool levels were also reduced by the agents over 60 min.

Animals↗
PubMed1993

Facilitated transport of two model steroids by esters and amides of clofibric acid.

A series of novel dermal penetration enhancers, esters and amides of clofibric acid, was synthesized. The permeation parameters and skin retention of two steroids (hydrocortisone-21-acetate and betamethasone-17-valerate) in propylene glycol were studied with athymic nude mouse skin by in vitro diffusion cell techniques in the presence of the novel enhancer compounds. Isopropyl myristate, dimethyl lauramide, and 1-dodecylazacycloheptan-2-one (laurocapram, Azone) were used as control enhancers. The most satisfactory enhancement of both the ester and amide series was observed with clofibric acid octyl amide; coadministration increased skin retention of hydrocortisone acetate after 24 h by 3.5-fold and that of betamethasone valerate by 2.9-fold. Diffusion cell receptor concentrations increased 51.6- and 10.3-fold, respectively, during the same time period. However, the enhancer compound in this case was applied to the skin 1 h prior to each of the steroids. The amide analogues were more effective than the equivalent ester compounds of the same carbon chain length. The best enhancer compounds (2c, 3d, 3e, and 3f) were nonirritating to athymic mouse skin in vivo.

Animals↗
PubMed1992

Synthesis and cholinergic properties of N-aryl-2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamino analogs of ranitidine.

A series of N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamino analogs of the H2-antagonist, ranitidine, was synthesized and the abilities of the compounds to alleviate the cholinergic deficit characteristic of Alzheimer's disease evaluated. The compounds were initially tested for their ability to inhibit human erythrocyte acetylcholinesterase activity in vitro. Selected compounds were further evaluated for butyrylcholinesterase inhibition, M1 and M2 cholinergic receptor binding, potentiation of ileal contractions, and the ability to elevate brain acetylcholine levels in mice. The analogs were compared to tetrahydroaminoacridine and to a recently reported series of bis-[[(dimethylamino)methyl]furans]. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamine derivatives were generally comparable to tetrahydroaminoacridine and the bis[[(dimethylamino)methyl]furans] in acetylcholinesterase inhibition, M1/M2 receptor binding, and the potentiation of ileal contractions, while being more potent inhibitors of acetylcholinesterase than butyrylcholinesterase. The 4-nitro-3-pyridazinyl analog, 26, was notable in demonstrating a potent and selective binding to the M2 receptor, with an M2 IC50/M1 IC50 of 0.060. Compounds in which the substituents on the dinitro-N-aryl moiety were relatively small were the best at inhibiting acetylcholinesterase in vitro. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamines in general, and those with small N-aryl substituents in particular, were superior to the bis[[(dimethylamino)methyl]furans] in elevating brain ACh levels in mice, probably due to enhanced distribution into the CNS. The 1,5-difluoro-2,4-dinitrophenyl analog, 8, resulted in the largest elevation in brain acetylcholine levels, affording a 53% increase at 88 mg/kg.

Acetylcholine↗
PubMed1992

Synthesis and cholinergic properties of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine.

The histaminergic H2 antagonist, ranitidine, has also been found to significantly inhibit acetylcholinesterase (AChE) in vitro. In an effort to develop novel, nonquaternary AChE inhibitors capable of penetrating into the CNS and alleviating the cholinergic deficit characteristic of Alzheimer's disease, a series of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine has been synthesized. All compounds were evaluated for human erythrocyte AChE inhibitory activity and compared to ranitidine, physostigmine, and tetrahydro-9-aminoacridine (THA). The most active AChE inhibitors were N,N'-disubstituted derivatives of 2-nitro-1,1-ethenediamine and 4,6-dinitro-1,3-benzenediamine, with compound 8 demonstrating activity greater than physostigmine. Deletion of the diaminonitroethene group in a series of alkyl and aryl bis-thioethers, yielded a number of slightly less active compounds, comparable in potency to THA. The 13 most active AChE inhibitors all demonstrated a more selective inhibition of AChE, as opposed to butyrylcholinesterase inhibition, than did THA. Compounds 3 and 22 were equally active to THA in potentiating rat ileal contractions. Binding studies demonstrated M1 and M2 cholinergic receptor affinities slightly greater than or equal to THA. Differential receptor binding studies showed compound 12 resembled THA in agonist/antagonist activity. Compounds 11-13 significantly elevated mouse brain acetylcholine levels, when administered at 80% of their approximate lethal doses, but were less active than THA or physostigmine.

Animals↗
PubMed1992

Drug interaction with intraocular lenses of different materials.

The uptake and washout kinetics of four drugs representing different classes of ophthalmic medications were measured in intraocular lenses of different materials. The materials ranged from hydrogel lenses to poly(methyl methacrylate) (PMMA), Acrysof (acrylic/methacrylic), and two types of silicone lenses (Chiroflex and AMO SI-18NB). Uptake was determined after seven days of immersion in a large volume of Ringer's solution containing drug concentrations that equaled those found in aqueous humor 30 minutes to one hour after topical administration. Washout was determined after placing lenses in 1 ml of 0.9% saline for 24 hours. Only hydrogel lenses could be digested in acid to measure lens uptake directly. The PMMA, Acrysof, and silicone lenses behaved similarly toward gentamicin and dexamethasone--low uptake (less than 3.5 ng/mg lens) and low washout (less than 4.0%). Their uptake of norepinephrine was lower (less than 0.7 ng/mg lens) but the washout varied from 29% (AMO silicone) to 100% (PMMA and Acrysof). The pilocarpine uptake was the lowest of drugs tested (less than 0.03 ng/mg lens) and the washout varied from 1.5% (acrylic) to 100% (PMMA and Chiroflex silicone). Hydrogel lenses took up the most drug in the following order: dexamethasone greater than pilocarpine greater than gentamicin greater than norepinephrine. Washout was high, ranging from 83% to 98%. Despite the greater uptake and washout, the maximum drug uptake would only provide one-tenth of the greatest aqueous humor concentration that occurs after topical drug administration. Intraocular lenses of the materials tested did not interfere with the intraocular drug pharmacokinetics, nor did the data indicate that presoaking intraocular lenses of these materials in drugs would enhance post-surgical intraocular drug concentrations.

Absorption↗
PubMed1992

Subconjunctival gentamicin induction of extraocular toxic muscle myopathy.

Subconjunctival injection of commercially available gentamicin, delivered in one of several protocols, caused an acute toxic reaction myopathy of the extraocular muscles. The response began as a small focal infiltrate of polymorphonuclear leukocytes, and as the lesion progressed it assumed a mononuclear cell predominance accompanied by muscle fiber degeneration. The injection of individual components of the commercial preparation (gentamicin, methylparaben, ethylenediaminetetraacetic acid (EDTA) and sodium bisulfite), each at the same concentration as in the parent solution, gave no response except for gentamicin alone. Gentamicin caused acute toxic myopathy when injected away from the muscles and when given as an isotonic solution in saline compared to the hypotonic commercial solution. Solutions at acidic pH not containing gentamicin did not initiate myopathy. Several factors that have been inferred as participating in the toxic response to gentamicin have been eliminated. Gentamicin alone is responsible for the induction of the extraocular muscle myopathy.

Animals↗