The Predictive Value of the Syntax Score in Patients With Chronic Coronary Artery Disease Undergoing Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting: A Pilot Study.

OBJECTIVES: To evaluate the usefulness of the SYNTAX score (SS) in predicting 1-year clinical outcomes in a population of patients with chronic coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). BACKGROUND: Despite the proven prognostic value of the SS in patients with multivessel and/or left main (LM) CAD, its usefulness in other patient subsets remains uncertain. METHODS: This was a prospective single centre cohort study conducted from September 2012 to November 2014 at the Nicosia General Hospital, Cyprus. Patients (n=140; 94% men and 6% women) with chronic CAD undergoing revascularization with either PCI or CABG were evaluated. RESULTS: At 1-year, angina occurred in 20 patients (14.3%), myocardial infarction (MI) in 3 patients (2.1%), repeat revascularization procedures in 9 patients (6.4%) and death in 12 patients (8.6%). The SS independently predicted angina (p=0.024) but was not predictive of MI (p=0.964), death (p=0.292) or repeat revascularization (p=0.069). CONCLUSION: In this patient population, the SS predicted angina in the year following revascularization but was not predictive of MI, death or repeat revascularization.

Diastolic gradient in hypertrophic cardiomyopathy of the apical type.

Diastolic intracavitary gradient in the left ventricle is a common finding in patients with apical hypertrophy. We report the case of a patient with hypertrophic cardiomyopathy and midventricular obstruction. The paradoxical jet flow in this patient, during diastole, was directed towards the base away from the apex.

Biorelevant dissolution testing to predict the plasma profile of lipophilic drugs after oral administration.

PURPOSE: To quantitatively compare in vitro dissolution data in biorelevant and compendial media, to investigate whether in vitro differences are reflected in the simulated plasma profile and to specify under which circumstances prediction of the plasma profile of orally administered lipophilic drugs can be achieved. METHODS: Previously published dissolution data from seven products of four lipophilic drugs were compared using the first order model, the RRSBW distribution, and a model based on the Noyes-Whitney theory. Simulated plasma profiles were then obtained using a model-dependent approach. Simulated and observed plasma profiles were compared with the difference factor, f1. RESULTS: No model consistently provided the best fit to the in vitro data, which varied significantly with medium composition. Prediction of the plasma profile was possible (9.6 < or = f1 < or = 34.2) in seven out of eleven cases. CONCLUSIONS: Although prediction of the plasma profile of lipophilic drugs solely on the basis of in vitro data remains an ambitious target, this study shows that the plasma profile of a lipophilic drug can be predicted with appropriate in vitro dissolution data, provided that the absolute bioavailability of the drug is known and the drug has dissolution limited absorption.

Forecasting the in vivo performance of four low solubility drugs from their in vitro dissolution data.

PURPOSE: To assess the usefulness of biorelevant dissolution tests in predicting food and formulation effects on the absorption of four poorly soluble, lipophilic drugs. METHODS. Dissolution was studied with USP Apparatus II in water, milk, SIFsp, FaSSIF, and FeSSIF. The in vitro dissolution data were compared on a rank order basis with existing in vivo data for the tested products under fasted and fed state conditions. RESULTS: All drugs/formulations showed more complete dissolution in bile salt/lecithin containing media and in milk than in water and SIFsp (USP 23). Comparisons of the in vitro dissolution data in biorelevant media with in vivo data showed that in all cases it was possible to forecast food effects and differences in absorption between products of the same drug with the physiologically relevant media (FaSSIF, FeSSIF and milk). Differences between products (both in vitro or in vivo) were less pronounced than differences due to media composition (in vitro) or dosing conditions (in vivo). CONCLUSIONS: Although biorelevant dissolution tests still have issues which will require further refinement, they offer a promising in vitro tool for forecasting the in vivo performance of poorly soluble drugs.

False positive ST-segment depression during exercise in subjects with short PR segment and angiographically normal coronaries: correlation with exercise-induced ST depression in subjects with normal PR and normal coronaries.

The aim of this study was to investigate exercise-induced ST-segment depression in subjects with a 120-ms or shorter PR segment and normal coronary arteries. A population of 86 individuals who demonstrated ST-segment depression of 1.5 mm or more on treadmill testing and had a subsequent normal coronary arteriography was classified into two groups. Group A (n = 71) comprised those with a normal PR interval on baseline electrocardiogram 160.9 +/- 14.8 ms (mean +/- 1 SD), and group B (n = 15) comprised those with a 120-ms or shorter PR interval 113 +/- 8.8 ms (mean +/- 1 SD). All subjects had undergone a symptom-limited treadmill test by the standard Bruce protocol (mainly for evaluation of chest pain or angina-like pain), during which they demonstrated ST depression of 1.5 mm or more in either lead II, lead V2, or lead V5. All had normal or near normal coronary arteries on angiography. In the subjects with short PR segments and angiographically normal coronaries, a trend of greater ST-segment depression during treadmill testing as compared with control subjects was observed in lead V5. In the same group, ST-segment depression at the 9th minute of exercise was more prevalent in lead V5 than in lead II or V2.

Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs.

PURPOSE: In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. METHODS: Dissolution behavior of two class I drugs, i.e. acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. RESULTS: Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions. CONCLUSIONS: As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.

Noninvasive detection of coronary artery disease in patients presenting with claudication.

ECG chest wall mapping with bicycle ergometry which can detect not only myocardial ischaemia but also individual coronary artery territories involved has been used to screen 100 consecutive patients presenting with claudication. Fifty-three had a positive history and/or evidence of ischaemic heart disease on a resting ECG. The test was positive in 38, negative in 38 and inconclusive in 24, the latter because of inadequate heart rate response. In 11 out of 38 (29%) with a positive test there was no history or evidence of myocardial ischaemia on a conventional resting ECG. ECG changes suggestive of three vessel coronary disease were found in three, single vessel coronary disease in 16 and two vessel disease in 19. Of the latter, eight had changes in the LAD/circumflex distribution, indicating left main stem or equivalent disease. These together with the three with triple vessel coronary disease constituted a subset of 11 (11%) high risk patients who merited coronary angiography with a view to confirming the presence of severe coronary disease.

Renin inhibitors containing isosteric replacements of the amide bond connecting the P3 and P2 sites.

Renin inhibitors having 13 different isosteres connecting the P3 and P2 positions have been prepared. Synthetic routes and in vitro activity exhibited by these compounds are discussed. The two most potent compounds, 47 and 48, contained the hydroxyethylene isostere, psi [CHOHCH2], and had IC50 values of 61 and 22 nM, respectively.

Comparison of intravenous nicardipine and nitroglycerin to control systemic hypertension after coronary artery bypass grafting.

The efficacy of intravenous (i.v.) nicardipine hydrochloride (a calcium antagonist) compared with nitroglycerin, the drug generally used for treatment of hypertension after coronary artery bypass grafting, was tested in 20 postoperative patients. The patients were randomly divided in a nonblinded manner into 2 groups. Baseline characteristics were similar in the 2 groups. Patients in both groups received various oral calcium antagonists. In addition, 1 group was treated with i.v. nitroglycerin. Both drugs were infused at a maximal rate of 30 mg/hour, as needed to maintain systolic blood pressure below 110 mm Hg. If blood pressure increased to more than 120 mm Hg, nitroprusside was administered. Intravenous nicardipine was superior to nitroglycerin in control of hypertension after coronary artery bypass grafting. In patients treated with nicardipine, blood pressure was decreased sooner (mean infusion time 7.7 hours vs 11.9 hours for nitroglycerin), mean systolic blood pressure was reduced (94 vs 108 mm Hg for the nitroglycerin group; p less than 0.05), and no patient required nitroprusside treatment (compared with 3 patients who required this treatment in the nitroglycerin group). There were no differences in heart rate, diastolic pressure, cardiac index and urine flow between the 2 treatment groups. No adverse effects were observed in patients treated with nicardipine.

Accelerated progression of coronary artery disease.

Atheromatous disease of the arteries is progressive and often results in untimely morbidity and premature death. The pathogenesis of the arterial lesion is as complex as its rate of progression is variable and ill understood. In six patients undergoing coronary arteriography, who were being restudied before percutaneous transluminal coronary angioplasty, the angiographic appearance deteriorated considerably over a fairly short period (mean 3.6 months). Although early detection and preventive measures have lowered the incidence of atheromatous disease and improved survival in some patients, rapid progression of the disease remains a serious hazard in others, who, as a group, remain at present unidentifiable.

Incidence and prevention of supraventricular tachyarrhythmias after coronary bypass surgery.

Supraventricular tachyarrhythmias are a frequent complication encountered after coronary artery bypass grafting. A retrospective survey of 102 consecutive patients undergoing exclusive bypass grafting at St. Mary's Hospital supplemented by a review of 16 published reports over a period of 10 years revealed a mean incidence of post-operative tachyarrhythmia of 33.4% in 1344 patients (range 11.4-100%). One hundred and thirty two patients undergoing exclusive bypass surgery, were randomised prospectively in double blind fashion to receive either oral timolol or matched placebo approximately 24 hours after surgery. In the 66 patients receiving timolol, there was a significant reduction of post-operative arrhythmias compared to the 66 patients receiving placebo: from 19.7 to 7.5% (P less than 0.05). Of all arrhythmias, two thirds appeared under 48 hours after surgery. In the timolol group, 4 patients developed systemic hypotension. This was readily reversed by withdrawing the drug. No other side effects were noted. The use of oral timolol after coronary artery surgery significantly lowers the incidence of post-operative supraventricular arrhythmias.

Modified di- and tripeptides of the C-terminal portion of oxytocin and vasopressin as possible cognition activation agents.

A number of peptides and modified peptides were synthesized and studied for their ability to reverse electroconvulsive shock-induced amnesia in rodents. A few of these peptides were selected for secondary evaluation in tests of short-term memory in rats and aged rhesus monkeys. A number of the peptides and modified peptides were active in the amnesia reversal test. In selected secondary tests, however, the chosen compounds failed to show significant activity in enhancing memory. New methods for preparing methyleneamino and methyleneoxy isosteres of peptides are reported. Other modified peptides also included methylenethio, methylenesulfonyl, and ethylene isosteres in place of the normal peptide amide bond.

Anti-writhing activity of some peptides related to neurotensin and tuftsin.

Several small peptides related to neurotensin (NT) and tuftsin were synthesized and tested for analgesic activity against acetic acid induced writhing in mice. None of the peptides approached the activity shown by NT or NT hexapeptide. Tuftsin itself was found to be weakly active. An isosteric dipeptide related to a cobra venom peptide was found to have considerable anti-writhing activity at a high intracerebroventricular dose.

Electrocardiographic chest wall mapping in the diagnosis of coronary artery disease.

Chest wall mapping of ST segment changes, inverted U waves, and Q waves using 16 electrocardiographic electrodes was performed at rest and during and after bicycle ergometry in 150 patients presenting with chest pain suggestive of angina. All patients underwent coronary angiography. The presence or absence of appreciable coronary artery disease (greater than or equal to 50% stenosis) was detected with a sensitivity of 98% and a specificity of 88%. The identification of lesions in individual coronary arteries was also possible with a sensitivity and specificity of 87% and 85% respectively for the territory of the left anterior descending and diagonal artery, 71% and 85% respectively for the right coronary artery, and 85% and 80% respectively for the circumflex artery. This test appears to be a reliable non-invasive screening method for selecting patients for angiography.

Novel synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline and analogues: potent angiotensin converting enzyme inhibitors.

A new approach was developed for the synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline (1) and 23 analogues. The delta-(acylamino)-gamma-keto acid intermediates were obtained by a modified Dakin--West reaction using 3-carbomethoxypropionyl chloride. Acylation of L-proline and recrystallization of the mixture of diastereomers gave the optically pure title compound in three reaction steps. The in vitro angiotensin converting enzyme (ACE) inhibitory activity of 1 was confirmed. Some of the novel analogues (6, 11, 13, and 17) were also found to be potent inhibitors of ACE in vitro with an IC50 of 1.4-8.8 x 10(-9) M (IC50 for captopril = 0.9 x 10(-8) M). In vivo these compounds (6, 11, 17, and 18) were much less active than captopril, especially by the oral route. Against angiotensin I (AI) challenge in normotensive conscious rats, 1 and 6 produced less than 50% inhibition at 30 mg/kg po but 57 to 82% inhibition at 3 mg/kg iv. Inhibition by both routes lasted less than 1 h. In renal hypertensive rats, 1 and 15 of its analogues failed to produce significant blood pressure lowering effects, in contrast to the marked effects of captopril. Near maximum inhibition of AI was achieved by continuous intravenous infusions of 1 and 20, suggesting that limited oral activity may by due to degradation and/or clearance.

Semisynthetic penicillins. A structure - activity study of a new series of acyl amino acid - pyridone and pyrimidone amoxicillin analogs.

The synthesis and biological activities of a series of 12 new semisynthetic penicillins is described. These compounds consisted of acylated amino acid analogs of 6-substituted-1,2-dihydro-2-oxonicotinic acid and 2-substituted-3,4-dihydro-4-oxo-5-pyrimidinecarboxylic acid attached to amoxicillin. The effect of the amino acid substituent, chirality of amino acid and acyl function on biological properties is discussed.

Synthesis and biological activity of peptide antagonists of luliberin (luteinizing hormone-releasing hormone).

A series of des-His2 octa- and nonapeptide analogues of luliberin (luteinizing hormone-releasing hormone) with modifications in the 1 and 6 positions, and in some instances the 10 position, has been prepared. Some of these analogues are potent inhibitors of luliberin in vitro and in vivo. The use of ultraviolet absorption measurements for evaluating peptides containing tyrosine and tryptophan is described. An efficient synthesis of O-methyl-d-tyrosine is reported.