Relationship between severity of coronary artery disease and apolipoprotein E gene polymorphism.

OBJECTIVE: To explore the possible contribution of the apolipoprotein (apo) E polymorphisms to the extent and severity of coronary artery disease (CAD) related to lipid metabolism. METHODS: Overall, 53 Turkish patients, aged 54+/-11 years defined by coronary angiography were included in this cross-sectional study. Reardon's coronary artery scoring was used. Serum lipids were measured with enzymatic colorimetric methods. Apolipoproteins were measured with nephelometry. Apolipoprotein E gene polymorphisms were determined by the reverse hybridization method. Statistical analyses were performed using one-way ANOVA, Kruskal-Wallis and Chi- square tests. RESULTS: The genotype frequencies were 7.5% for E2/E3, 77.4% for E3/E3 and 15.1% for E3/E4. The E2 allele frequency was slightly lower than E4 allele. There were no significant differences between apo E2/E3, E3/E3 and E3/E4 genotypes for severity scorings (26, 41 and 32 respectively, p=0.30) and extent scorings (3.2, 5.5, 4.5, p=0.17). It was found that the most of patients who had E2/3 and E3/4 alleles had low severity scores. On the other hand, there were no significant score difference for patients who had E3/3 alleles. Lipids were not significantly different among the different genotypes. The E3 allele was associated with high apo B levels compared with E2 and E4 genotypes. It was found that severity and extent of disease were not related with lipid metabolism. CONCLUSION: We concluded that there were no statistically significant differences between genotypes for extent and severity scorings, but the apo E3 allele is associated with more severe disease than E2 allele. These associations with severity were mediated not only by changes in lipid metabolism but may be also by other mechanisms in CAD patients.

Dual dopamine D2 receptor and beta2-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease: the pre-clinical rationale.

This paper describes the rationale for the development of dual dopamine D2-receptor and beta2-adrenoceptor agonists as potential treatments for the symptoms of chronic obstructive pulmonary disease (COPD). The putative involvement of pulmonary sensory afferent nerves in mediating the key COPD symptoms of breathlessness, cough and excess sputum production is outlined and the hypothesis that activation of D2-receptors on such nerves would modulate their activity is developed. This premise was tested, in a range of animal models, using the first of a novel class of dual dopamine D2-receptor and beta2-adrenoceptor agonists, sibenadet HCl (Viozan, AR-C68397AA). In the course of these studies it was demonstrated that sibenadet, through activation of D2-receptors, inhibited discharge of rapidly adapting receptors and was effective in reducing reflex-induced tachypnoea, mucus production and cough in the dog. Sibenadet, through its activation of beta2-adrenoceptors, was also shown to be an effective bronchodilator with a prolonged duration of action following topical administration to the lungs. These studies also indicated that sibenadet had a wide therapeutic ratio with respect to expected undesirable side-effects such as emesis and cardiovascular disturbances. These results provided a compelling rationale for the initiation of a clinical development programme with sibenadet for the treatment of COPD.

Novel cobalt complex inhibitors of mitochondrial calcium uptake.

Reperfusion of the ischaemic myocardium leads to intracellular calcium overload followed by mitochondrial dysfunction, resulting in insufficient energy supply and ultimately myocardial necrosis. Ruthenium red (RR), a potent mitochondrial calcium uptake inhibitor, prevents this disruption to mitochondrial metabolism and improves post reperfusion recovery. This therefore suggested that mitochondrial calcium influx is an attractive target for the treatment of reperfusion injury. However, RR is unsuitable for therapeutic use, so we undertook a search for novel compounds which inhibit mitochondrial calcium uptake. The most potent compounds discovered were simple tris(ethylenediamine) transition metal complexes and dinuclear Co complexes. The structure-activity relationship (SAR) of these small molecules has helped to define the structural requirements for inhibition of calcium transport by outlining the size and charge dependency of the interactive site on the mitochondrial calcium uniporter.

Discovery and synthesis of methyl 2,5-dimethyl-4-[2- (phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate (FPL 64176) and analogues: the first examples of a new class of calcium channel activator.

Methyl 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate, FPL 64176 (1), is the first example of a new class of calcium channel activator (CCA) that does not act on any of the well-defined calcium channel modulator receptor sites, as typified by verapamil, diltiazem, and the dihydropyridines. The potent activity of 1, having the 2-(phenylmethyl)benzoyl substituent, was predicted using QSAR on an initial set of less potent benzoylpyrroles. When compared to the CCA Bay K 8644, 1 has similar potency on calcium uptake into GH3 cells (both have EC50 approximately 0.015 microM) but is appreciably more potent functionally at increasing contractility in a guinea pig atria preparation (1 has EC50 = 0.049 microM vs Bay K 8644 EC50 = 1.95 microM). 1 is an achiral, pharmacologically clean agonist with no demonstrable partial agonist properties and possesses appreciably higher efficacy than Bay K 8644. It should therefore become a useful biochemical and pharmacological tool for the study of calcium channels in many cell types.

FPL 63012AR: a potent D1-receptor agonist.

1. FPL 63012AR is a D1-receptor agonist in the dog kidney, 10 times as potent as dopamine, reducing renal vascular resistance by 20% with an intra-arterial dose of 0.42 nmol kg-1. 2. No prejunctional inhibitory D2-receptor agonist activity was detected in either the isolated ear artery of the rabbit or in the conscious dog as D2-receptor-mediated emesis. 3. Unlike dopamine, FPL 63012AR had no significant agonist activity at alpha 1-, alpha 2-, beta 1- or beta 2-adrenoceptors. 4. FPL 63012AR is a potent inhibitor of [3H]-noradrenaline uptake (Uptake1) into brain synaptosomes, with an IC50 of 29.5 nM, i.e. 9.2 times more potent than dopamine. 5. The ability to block Uptake1, in the anaesthetised dog was confirmed by inhibition of the tyramine-induced pressor and inotropic responses. 6. Intravenous infusion of FPL 63012AR in anaesthetized and conscious dogs (0.3 to 3 nmol kg-1 min-1) reduced vascular resistance and increased blood flow to the kidney which was accompanied by hypotension and tachycardia. 7. It is concluded that FPL 63012AR is an example of a novel class of potent agonists at the D-receptor. Such compounds may have the potential for use clinically in improving renal perfusion and reducing afterload.

Dopexamine: a novel agonist at peripheral dopamine receptors and beta 2-adrenoceptors.

Dopexamine is an agonist at peripheral dopamine receptors and at beta 2-adrenoceptors. Dopexamine has approximately one-third the potency of dopamine in stimulating the vascular DA1-receptor in the dog, resulting in a fall in renal vascular resistance of 20% at 2.3 X 10(-8) mol kg-1 (i.a.). Prejunctional DA2-receptors are also stimulated by dopexamine, resulting in a reduction of neurogenic vasoconstriction in the rabbit isolated ear artery (IC50 of 1.15 X 10(-6)M) and of neurogenic tachycardia in the cat (ID50 of 5.4 X 10(-8) mol kg-1, i.v.), with a potency six and four times less respectively than that of dopamine. By contrast, dopexamine is approximately 60 times more potent than dopamine as an agonist at the beta 2-adrenoceptor of the guinea-pig isolated tracheal chain, with an EC50 of 1.5 X 10(-6)M. Both dopexamine and dopamine are weak agonists at the guinea-pig atrial beta 1-adrenoceptor over the concentration range 10(-7) to 10(-4) M, but dopexamine has an intrinsic activity of only 0.16 relative to dopamine. Dopexamine does not stimulate postjunctional alpha 1- or alpha 2-adrenoceptors in the canine isolated saphenous vein, whereas dopamine is an agonist, approximately 120 times less potent than noradrenaline. Unlike dopamine and salbutamol, dopexamine does not cause arrhythmias in the guinea-pig isolated perfused heart at doses of up to 10(-5) mol, which is a thousand times the minimum cardiostimulant dose. The combination of agonist properties at peripheral dopamine receptors and at beta 2-adrenoceptors, with little or no activity at alpha- and beta 1-adrenoceptors gives dopexamine a novel pharmacological profile. This may confer advantages over dopamine in the treatment of acute heart failure.