Bio

Clinical Focus


  • Cardiology (Heart)
  • Cardiovascular Disease

Academic Appointments


Administrative Appointments


  • Associate Chief (Veterans Affairs), Division of Cardiovascular Medicine (1995 - Present)
  • Chief, Cardiology Section, VA Palo Alto Health Care System (1983 - Present)

Professional Education


  • Fellowship:SUNY Medical School - Buffalo (1978) NY
  • Residency:SUNY Medical School - Buffalo (1977) NY
  • Board Certification: Cardiovascular Disease, American Board of Internal Medicine (1989)
  • Board Certification: Cardiology, American Board of Internal Medicine (1978)
  • Fellowship:Stanford University Medical Center (1978) CA
  • Internship:SUNY Medical School - Buffalo (1975) NY
  • Medical Education:Baylor College of Medicine (1973) TX

Research & Scholarship

Current Research and Scholarly Interests


Calcium channel blockers; membrane pharmacology;, coronary physiology; antiarrhythmic drugs; cardiac hemodynamics;, cellular mechanisms of myocyte hypertrophy.

Teaching

2016-17 Courses


Publications

All Publications


  • Transcatheter CoreValve valve-in-valve implantation in a stentless porcine aortic valve for severe aortic regurgitation. Clinical case reports Yong, C. M., Buchbinder, M., Giacomini, J. C. 2014; 2 (6): 281-285

    Abstract

    We describe the first valve-in-valve Corevalve transcatheter aortic valve replacement in the St. Jude Toronto stentless porcine aortic valve in the United States, which enabled this 59-year-old patient with a history of bacterial endocarditis and aortic regurgitation to avoid heart transplant with complete resolution of his severe left ventricular dysfunction.

    View details for DOI 10.1002/ccr3.113

    View details for PubMedID 25548631

  • Efficacy of optimal long-term management of multiple cardiovascular risk factors (CVD) on walking and quality of life in patients with peripheral artery disease (PAD): Protocol for randomized controlled trial VASCULAR MEDICINE Oka, R. K., Conte, M. S., Owens, C. D., Rapp, J., Fung, G., Alley, H. F., Giacomini, J. C., Myers, J., Mohler, E. R. 2012; 17 (1): 17-28

    Abstract

    Peripheral artery disease (PAD) is an understudied chronic illness most prevalent in elderly individuals. PAD patients experience substantial walking impairment due to symptoms of limb ischemia that significantly diminishes quality of life (QOL). Cardiovascular disease (CVD) morbidity and mortality is increased in this population because of aggressive atherosclerosis resulting from untreated CVD risk factors. Despite current national guidelines recommending intensive CVD risk factor management for PAD patients, untreated CVD risk factors are common. Interventions that bridge this gap are imperative. The Vascular Insufficiency - Goals for Optimal Risk Reduction (VIGOR(2)) study is a randomized controlled trial (RCT) that examines the effectiveness of a long-term multifactor CVD risk reduction program on walking and quality of life in patients with PAD. The purpose of this article is to provide a detailed description of the design and methods of VIGOR(2). Clinical Trial Registration - URL: http://clinicaltrials.gov/ct2/show/NCT00537225.

    View details for DOI 10.1177/1358863X11430886

    View details for Web of Science ID 000300557500003

    View details for PubMedID 22363015

  • Successful lysis of an aortic prosthetic valve thrombosis with a dosing regimen for peripheral artery and bypass graft occlusions JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Nguyen, P. K., Wasserman, S. M., Fann, J. I., Giacomini, J. 2008; 135 (3): 691-693

    View details for DOI 10.1016/j.jtcvs.2007.11.012

    View details for Web of Science ID 000253860300043

    View details for PubMedID 18329497

  • Same-day discharge after elective percutaneous coronary intervention was noninferior for safety to staying overnight in hospital. ACP journal club Hlatky, M., Giacomini, J. 2007; 147 (2): 35-?

    View details for PubMedID 17764126

  • Statin therapy in heart failure CURRENT OPINION IN LIPIDOLOGY Pham, M., Oka, R. K., Giacomini, J. C. 2005; 16 (6): 630-634

    Abstract

    The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors, or statins, have been shown to reduce cardiovascular morbidity and mortality among a wide spectrum of patients with established atherosclerotic vascular disease. Mounting experimental and clinical evidence also suggest a potential benefit as well as theoretical harm of statin therapy in patients with heart failure.This article briefly summarizes the therapeutic properties of statins that may be of benefit to patients with heart failure and the theoretical adverse effects of cholesterol reduction in this group of patients. A number of nonrandomized clinical studies over the past several years have shown an association between statin use and reduced overall mortality. Several large-scale randomized studies designed to confirm these findings are currently under way.Statin therapy appears to improve clinical outcomes in patients with both ischemic and nonischemic cardiomyopathy independently of their cholesterol-lowering properties. The theoretical adverse properties of statins in heart failure patients have not been substantiated in small to medium-sized clinical trials. Although the encouraging results of these preliminary studies suggest a role for statin therapy in heart failure, larger studies are needed to validate these findings. Several ongoing randomized trials are currently under way to evaluate the effect of statin therapy on cardiovascular outcomes in heart failure patients. The results of these studies, expected in the next several years, should provide scientific evidence for the role of statins in the treatment of failure.

    View details for Web of Science ID 000233795300006

    View details for PubMedID 16276240

  • A pilot study of L-arginine supplementation on functional capacity in peripheral arterial disease VASCULAR MEDICINE Oka, R. K., Szuba, A., Giacomini, J. C., Cooke, J. P. 2005; 10 (4): 265-274

    Abstract

    Peripheral arterial disease (PAD) impairs walking capacity and is often associated with a profound endothelial vasodilator dysfunction, characterized by reduced bioactivity and/or synthesis of endothelium-derived nitric oxide (NO). Previous studies have suggested that dietary supplementation of L-arginine, the precursor of NO, improves endothelium-dependent vasodilation, limb blood flow and walking distance. However, these studies have been small, and have used large intravenous doses of L-arginine. The optimal dose of L-arginine has not been determined. Accordingly, this pilot study was conducted to establish the lowest effective oral dose of L-arginine to improve walking distance in preparation for the definitive study. Patients with PAD and intermittent claudication (n = 80) participated in this study. Eligibility criteria included: (1) ankle-brachial index (ABI) at rest < or = 0.90; (2) post-exercise reduction in ABI > or = 25%; and (3) difference in absolute claudication distance of < or = 25% between two consecutive treadmill tests. Treadmill testing was performed using the Skinner-Gardner protocol and community-based walking was assessed using the walking impairment questionnaire. Patients were randomly assigned to oral doses of 0, 3, 6 or 9 g of L-arginine daily in three divided doses for 12 weeks. Treadmill testing was performed prior to administration of the study drug and again after 12 weeks of treatment. The study drug was well tolerated, with no significant adverse effects of L-arginine therapy. The safety laboratory studies were unremarkable, except for a statistically significant reduction in hematocrit in the L-arginine-treated groups. There was no significant difference observed in absolute claudication distance between the groups. However, a trend was observed for a greater increase in walking distance in the group treated with 3 g L-arginine daily, and there was a trend for an improvement in walking speed in patients treated with L-arginine. This pilot study provided data for safety, for power calculation and for dosing for the larger definitive trial that is now underway.

    View details for DOI 10.1191/1358863x05vm637oa

    View details for Web of Science ID 000234803000003

    View details for PubMedID 16444855

  • Suboptimal intensity of risk factor modification in PAD VASCULAR MEDICINE Oka, R. K., Umoh, E., Szuba, A., Giacomini, J. C., Cooke, J. P. 2005; 10 (2): 91-96

    Abstract

    This study extends earlier trials indicating that atherosclerosis risk factors are underdetected and undertreated in peripheral arterial disease (PAD) patients. Recognition and treatment of hyperlipidemia and hypertension in PAD patients is suboptimal. Diabetes appears to be detected more frequently although glycemic control is still suboptimal. The use of antiplatelet therapy is particularly underutilized. Additionally, despite the demonstrated efficacy of regular exercise in PAD patients, almost half of the study sample was sedentary. Approximately one third of the current study sample was overweight and nearly one third was obese by ATP-III guidelines. Only 31% of subjects were taking dietary measures to improve their cardiovascular health, and even fewer were physically active. To rectify suboptimal management of risk factors, there is a need for increased public awareness of PAD, reimbursement and implementation of screening programs and more aggressive treatment. Future studies are needed to examine innovative interventions for identification and management of cardiovascular risk factors in patients with PAD.

    View details for DOI 10.1191/1358863x05vm611oa

    View details for Web of Science ID 000229902800002

    View details for PubMedID 16013192

  • Gender differences in perception of PAD: a pilot study VASCULAR MEDICINE Oka, R. K., Szuba, A., Giacomini, J. C., Cooke, J. P. 2003; 8 (2): 89-94

    Abstract

    Patients with peripheral arterial disease (PAD) report profound limitations in all domains of quality of life that are worse than those for patients with chronic pulmonary disease and moderate to severe heart failure. While claudication has detrimental effects on quality of life, little is understood about the factors that influence quality of life and whether these determinants are similar for men and women with PAD and claudication. The purpose of the present investigation was to evaluate the effect of claudication on quality of life in 71 men and 26 women (mean age 72 and 73 years respectively) with PAD. Disease severity as assessed by ankle brachial index (ABI) and community-based walking was similar for men and women, although men reported greater comorbid conditions than women. Despite the similarity in disease severity, women reported decreased physical functioning (p = 0.01), more bodily pain (p = 0.04) and greater mood disturbance (p = 0.012) than men. Claudication and PAD had a greater impact on women than on men and may result from the higher prevalence of mood disturbance and bodily pain reported by women.

    View details for DOI 10.1191/1358863x03vm479oa

    View details for Web of Science ID 000185487900003

    View details for PubMedID 14518610

  • Two- to three-year follow-up of patients with single-vessel coronary artery disease randomized to PTCA or medical therapy (results of a VA cooperative study) AMERICAN JOURNAL OF CARDIOLOGY Hartigan, P. M., Giacomini, J. C., Folland, E. D., Parisi, A. F. 1998; 82 (12): 1445-1450

    Abstract

    Despite increasing use of percutaneous transluminal coronary angioplasty (PTCA) to treat stenotic coronary artery disease, there are relatively few prospective studies evaluating its long-term effectiveness. We prospectively randomized 212 stable patients with provocable myocardial ischemia and single-vessel subocclusive coronary disease to receive primary therapy with either PTCA or medical therapy. This report presents the clinical follow-up of these patients at a mean, after randomization, of 2.4 years for interview and 3.0 years for exercise testing. Of the 212 patients originally randomized, 175 received an extended follow-up interview, and 132 underwent exercise testing; 62% of patients in the PTCA group were angina free compared with 47% of patients in the medical group (p <0.05). Furthermore, exercise duration as measured by treadmill testing was prolonged by 1.33 minutes over baseline in the PTCA group, whereas it decreased by 0.28 minutes in the medical group (p <0.04). Although the angina-free time on the treadmill was not different (p=0.50), fewer patients in the medical group developed angina on the treadmill at 3 years than those in the PTCA group (p=0.04). By 36 months, excluding the initial randomized PTCA, use of PTCA and use of coronary artery bypass surgery were not different in the 2 treatment groups. These data indicate that some of the early benefits derived from PTCA in patients with single-vessel coronary artery disease are sustained, making it an attractive therapeutic option for these patients.

    View details for Web of Science ID 000077614000003

    View details for PubMedID 9874045

  • Bronchial imaging in humans using xenon K-edge dichromography NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION A-ACCELERATORS SPECTROMETERS DETECTORS AND ASSOCIATED EQUIPMENT Giacomini, J. C., Gordon, H., O'Neil, R., Van Kessel, A., Cason, B., Chapman, D., Lavendar, W., Gmur, N., Menk, R., Thomlinson, W., Zhong, Z., Rubenstein, E. 1998; 406 (3): 473-478
  • The concept of spatial frequency depending DQE and its application to a comparison of two detectors used in transvenous coronary angiography NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION A-ACCELERATORS SPECTROMETERS DETECTORS AND ASSOCIATED EQUIPMENT Menk, R. H., Thomlinson, W., Gmur, N., Zhong, Z., Chapman, D., Arfelli, F., Dix, W. R., Graeff, W., Lohmann, M., Illing, G., Schildwachter, L., Reime, B., Kupper, W., Hamm, C., Giacomini, J. C., GORDON, H. J., Rubenstein, E., Dervan, J., Besch, H. J., Walenta, A. H. 1997; 398 (2-3): 351-367
  • XENON K-EDGE DICHROMOGRAPHIC BRONCHOGRAPHY - SYNCHROTRON-RADIATION BASED MEDICAL IMAGING NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION A-ACCELERATORS SPECTROMETERS DETECTORS AND ASSOCIATED EQUIPMENT Rubenstein, E., Giacomini, J. C., GORDON, H. J., RUBENSTEIN, J. A., Brown, G. 1995; 364 (2): 360-361
  • THE EFFECTS OF MODULATION OF CALCIUM INFLUX THROUGH THE VOLTAGE-SENSITIVE CALCIUM-CHANNEL ON CARDIOMYOCYTE HYPERTROPHY JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Lubic, S. P., Giacomini, K. M., Giacomini, J. C. 1995; 27 (3): 917-925

    Abstract

    In human hypertrophic cardiomyopathy and hypertension associated ventricular hypertrophy, chronic use of calcium channel blockers results in a significant regression of hypertrophy. The main objective of this study was to test the hypothesis that modulation of calcium influx through the voltage-sensitive L-type Ca2+ channel directly affects myocardial hypertrophy. Agents that modified calcium influx through the L channel, reduced or enhanced mechanical activity, or uncoupled excitation-contraction coupling were evaluated in cell culture models of myocardial hypertrophy. The calcium channel blocker, verapamil, significantly reduced serum-stimulated cardiomyocyte hypertrophy in a stereoselective manner. The 1,4-dihydropyridine (DHP) calcium channel blocker, nifedipine, also significantly inhibited cardiomyocyte hypertrophy while the DHP calcium channel activator, Bay K 8644, promoted a significant increase in serum-stimulated hypertrophy. Norepinephrine (NE) and, to a lesser degree, isoproterenol (ISO) modulated serum-stimulated hypertrophy. KCl, verapamil, and nifedipine at concentrations that completely arrested beating produced comparable reductions in serum-stimulated hypertrophy. The excitation-contraction uncoupler, 2,3-butanedione monoxime (BDM), KCl and verapamil reduced hypertrophy in high density spontaneously contracting serum-free cardiomyocytes. Addition of NE or serum to BDM treated cells partially offset this reduced hypertrophy. In conclusion, agents that altered calcium influx through the L-type Ca2+ channel or inhibited mechanical activity affected cardiomyocyte hypertrophy. The negative inotropic or chronotropic effects of calcium channel blockers on the heart may contribute to their efficacy in the treatment of myocardial hypertrophy.

    View details for Web of Science ID A1995QR78900010

    View details for PubMedID 7602609

  • EFFECTS OF SPATIAL-RESOLUTION AND SPECTRAL PURITY ON TRANSVENOUS CORONARY ANGIOGRAPHY IMAGES Chapman, D., Thomlinson, W. C., GMUR, N. F., Dervan, J. P., STAVOLA, T., Giacomini, J., Gordon, H., Rubenstein, E., LAVENDER, W., Schulze, C., Thompson, A. C. AMER INST PHYSICS. 1995: 1329-1331
  • ANTIARRHYTHMIC AGENT AMIODARONE POSSESSES CALCIUM-CHANNEL BLOCKER PROPERTIES JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Lubic, S. P., NGUYEN, K. P., Dave, B., Giacomini, J. C. 1994; 24 (5): 707-714

    Abstract

    Amiodarone possesses multiple pharmacologic properties, including peripheral and coronary vasodilatation, negative inotropy, and negative chronotropic and dromotropic effects. These properties are shared by the group of drugs termed calcium channel blockers. We examined the interaction of amiodarone with receptors for the 1,4-dihydropyridine (DHP) calcium blockers in rat and rabbit myocardial membrane particulates. Amiodarone displaced specifically bound [3H]nitrendipine in both rat and rabbit preparations in a competitive, concentration-dependent manner at a single class of binding sites (Ki approximately 0.27 micxroM). Calcium channel activity was determined pharmacologically in a tissue bath with electrically stimulated rabbit right ventricular strips, KCl-induced aortic ring contraction, and 45Ca2+ uptake in K(+)-depolarized cultured rat cardiomyocytes. Amiodarone completely inhibited myocardial contraction (EC50 = 1.7 microM), completely antagonized depolarization-induced aortic ring contraction (EC50 = 24 nM), and significantly reduced (29% vs. control) 45Ca2+ uptake into cultured cells. The calcium channel blocking effects of amiodarone may contribute significantly to its pharmacologic profile.

    View details for Web of Science ID A1994PP29500004

    View details for PubMedID 7532747

  • A 1200 ELEMENT DETECTOR SYSTEM FOR SYNCHROTRON-BASED CORONARY ANGIOGRAPHY Thompson, A. C., LAVENDER, W. M., Chapman, D., Gmur, N., Thomlinson, W., Rosso, V., Schulze, C., Rubenstein, E., Giacomini, J. C., GORDON, H. J., Dervan, J. P. ELSEVIER SCIENCE BV. 1994: 545-552
  • INCREASED 1,4-DIHYDROPYRIDINE BINDING-SITES IN SERUM-STIMULATED CARDIOMYOCYTE HYPERTROPHY JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Lubic, S. P., Giacomini, K. M., Giacomini, J. C. 1994; 270 (2): 697-701

    Abstract

    Altered calcium channel number or function may be associated with myocardial hypertrophy. Treatment of cultured neonatal rat cardiomyocytes with norepinephrine or serum results in cellular hypertrophy without an increase in cell number. Cell culture is a convenient system for examining possible changes in channels and receptors associated with hypertrophy. The specific objective of this study was to measure the density of calcium channels in serum-free (as control), norepinephrine and serum-treated cardiomyocyte cultures. Measurements of high affinity [3H]nitrendipine binding and 45Ca++ uptake were made in K(+)-depolarized cardiomyocyte cultures. We report that there is an increased density of functional voltage-sensitive calcium channels in the serum-stimulated model of cardiomyocyte hypertrophy. This increased density of calcium channels in the serum-treated cells may represent a mechanism responsible for initiating and promoting cardiomyocyte hypertrophy.

    View details for Web of Science ID A1994PD45500038

    View details for PubMedID 8071861

  • SYNCHROTRON-RADIATION CORONARY ANGIOGRAPHY IN HUMANS Rubenstein, E., Brown, G. S., Chapman, D., GARRETT, R. F., Giacomini, J. C., Gmur, N., GORDON, H. J., LAVENDER, W. M., Morrison, J., Thomlinson, W., Thompson, A. C., Zeman, H. OXFORD UNIVERSITY PRESS. 1994: 639-645
  • ANGER REPORT PREDICTS CORONARY-ARTERY VASOMOTOR RESPONSE TO MENTAL STRESS IN ATHEROSCLEROTIC SEGMENTS AMERICAN JOURNAL OF CARDIOLOGY BOLTWOOD, M. D., Taylor, C. B., Burke, M. B., GROGIN, H., Giacomini, J. 1993; 72 (18): 1361-1365

    Abstract

    To determine the effects of anger on coronary artery vasoconstriction, 12 patients with symptomatic myocardial ischemia were studied during cardiac catheterization. During catheterization, the patients were asked to recall a recent event that had produced anger. One narrowed and 2 non-narrowed arterial segments were selected using predetermined criteria. Patients also completed various self-report measurements upon entering the catheterization laboratory before any procedures, after completion of the clinical angiogram and after the anger recall stressor. There was a significant increase in subject reports of anger (F[1,6] = 21.94, p < 0.01) and arousal (F [2,6] = 5.49, p < 0.05) during the anger stressor. There were no significant changes in heart rate, systolic or diastolic blood pressure, or heart rate x systolic blood pressure product during the anger stressor. A total of 27 arterial segments (9 narrowed and 18 non-narrowed) were selected and analyzed using quantitative angiographic techniques. Repeated-measures analysis of variance (baseline vs anger stressor) found no significant group differences with regard to changes in arterial diameter between conditions or among segments. Reported anger was significantly correlated with a decrease in both mean (r = -0.76, p < 0.05) and minimal (r = -0.82, p < 0.05) diameter changes in narrowed arteries. Vasoconstriction only occurred with high levels of anger. There were no significant correlations between anger report and diameter change in non-narrowed arteries. Thus, anger may produce coronary vasoconstriction in previously narrowed coronary arteries.

    View details for Web of Science ID A1993ML96800005

    View details for PubMedID 8256727

  • 1ST OPERATION OF THE MEDICAL-RESEARCH FACILITY AT THE NSLS FOR CORONARY ANGIOGRAPHY Thomlinson, W., Gmur, N., Chapman, D., Garrett, R., LAZARZ, N., Moulin, H., Thompson, A. C., Zeman, H. D., Brown, G. S., Morrison, J., Reiser, P., PADMANABAHN, V., Ong, L., Green, S., Giacomini, J., Gordon, H., Rubenstein, E. AMER INST PHYSICS. 1992: 625-628
  • CORONARY-OCCLUSION FOLLOWING DIAGNOSTIC ANGIOGRAPHY - SALVAGE BY INTRACORONARY STENTING CATHETERIZATION AND CARDIOVASCULAR DIAGNOSIS STGOAR, F. G., Giacomini, J. C., Fischell, T. A. 1991; 23 (4): 294-296

    Abstract

    Catheter-induced coronary artery dissection and occlusion is a rare but serious complication of diagnostic cardiac angiography. This report describes the successful management of this complication with an intracoronary stent after prolonged balloon inflations and intracoronary thrombolytic therapy were unsuccessful.

    View details for Web of Science ID A1991FX14300012

    View details for PubMedID 1909604

  • SYNCHROTRON RADIATION CORONARY ANGIOGRAPHY WITH A DUAL-BEAM, DUAL-DETECTOR IMAGING-SYSTEM Rubenstein, E., Giacomini, J. C., GORDON, H. J., Thompson, A. C., Brown, G., Hofstadter, R., Thomlinson, W., Zeman, H. D. ELSEVIER SCIENCE BV. 1990: 80-85
  • DETERMINANTS OF SURVIVAL AND LEFT-VENTRICULAR PERFORMANCE AFTER MITRAL-VALVE REPLACEMENT CIRCULATION Crawford, M. H., Souchek, J., Oprian, C. A., Miller, D. C., Rahimtoola, S., Giacomini, J. C., Sethi, G., Hammermeister, K. E. 1990; 81 (4): 1173-1181

    Abstract

    To determine how survival and clinical status were related to left ventricular (LV) size and systolic function after mitral valve replacement, 104 patients (48 mitral regurgitation [MR], 33 mitral stenosis [MS], and 23 MS/MR) with isolated mitral valve replacement were evaluated before and after surgery. Preoperative hemodynamic abnormalities by cardiac catheterization were improved 6 months after surgery in all three patient groups. The patients with MR exhibited reductions in LV end-diastolic volume index (EDVI) (117 +/- 51 to 89 +/- 27 ml/m2, p less than 0.001) and ejection fraction (EF) (0.56 +/- 0.15 to 0.45 +/- 0.13, p less than 0.001); however, the ratio of forward stroke volume to end-diastolic volume increased (0.32 +/- 0.21 to 0.45 +/- 0.17, p less than 0.001) because of the elimination of regurgitant volume. Survival analysis revealed that mortality was significantly higher in MS or MS/MR patients with postoperative EDVI more than 101 ml/m2 (p less than 0.001 and p less than 0.042, respectively) and in MR patients with postoperative EF less than or equal to 0.50 (p less than 0.031). Also, the majority of patients with MR or MS/MR and postoperative EDVI more than 101 ml/m2 and EF less than or equal to 0.50 were in New York Heart Association class III or IV. Multivariate logistic regression analysis in the patients with MR revealed that the strongest predictor of postoperative EF was preoperative EF (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1990CX49900002

    View details for PubMedID 2317900

  • STUDIES ON CA-2+ CHANNEL ANTAGONISTS - A 2-DIAZO-3,3,3-TRIFLUOROPROPIONAMIDE DERIVATIVE RELATED TO VERAPAMIL AS A POTENTIAL PHOTOAFFINITY PROBE JOURNAL OF MEDICINAL CHEMISTRY Theodore, L. J., Nelson, W. L., Dave, B., Giacomini, J. C. 1990; 33 (2): 873-877

    Abstract

    2-(3,4-Dimethoxyphenyl)-2-isopropyl-5-[N-[4-(N-methyl-2-diazo- 3,3,3-trifluoropropionamido)phenethyl]methyl-amino]valeronitril e (3), a potential photoaffinity probe for Ca2+ channels related to verapamil (1), was prepared from N-methyl-4-nitrophenethylamine (7) and 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methanesulfonoxy)valeron itrile (12). Compound 3 showed concentration-dependent negative inotropic effects in rat right myocardial ventricular strips, EC50 = (1.05 +/- 0.33) X 10(-7) M (mean +/- SD), being slightly less potent than gallopamil (2), EC50 = (2.18 +/- 0.66) X 10(-8) M. It displaced [3H]gallopamil in myocardial membranes, Ki = (3.76 +/- 1.55) X 10(-8) M, compared to 2, Ki = (1.55 +/- 0.16) X 10(-8) M. Photoactivation at 265 nm reduced the recoverable binding of [3H]gallopamil to 26% compared to no effect on 2. This agent may be a useful photoaffinity probe to aid in further characterization of Ca2+ channels.

    View details for Web of Science ID A1990CK74400064

    View details for PubMedID 2153831

  • CORONARY ANGIOGRAPHY USING SYNCHROTRON RADIATION REVIEW OF SCIENTIFIC INSTRUMENTS Thompson, A. C., Rubenstein, E., Zeman, H. D., Hofstadter, R., Otis, J. N., Giacomini, J. C., GORDON, H. J., Brown, G. S., Thomlinson, W., Kernoff, R. S. 1989; 60 (7): 1674-1679
  • IMAGING OF CORONARY-ARTERIES USING SYNCHROTRON RADIATION NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION B-BEAM INTERACTIONS WITH MATERIALS AND ATOMS Thompson, A. C., Zeman, H., Thomlinson, W., Rubenstein, E., Kernoff, R. S., Hofstadter, R., Giacomini, J. C., GORDON, H. J., Brown, G. S. 1989; 40-1: 407-412
  • SPECIES-DIFFERENCES IN THE NEGATIVE INOTROPIC RESPONSE OF 1,4-DIHYDROPYRIDINE CALCIUM-CHANNEL BLOCKERS IN MYOCARDIUM JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Boyd, R. A., Giacomini, J. C., Giacomini, K. M. 1988; 12 (6): 650-657

    Abstract

    To determine if species differences exist in myocardial response to 1,4-dihydropyridine (DHP) calcium channel blockers, the binding and pharmacologic responses of a series of DHP compounds were examined in both rat and rabbit myocardium. [3H]Nitrendipine was used to label specific binding sites in myocardial membrane particulates. The results of saturation binding experiments (n = 3) indicated no statistically significant difference in either Kd or Bmax between rat and rabbit myocardial membranes (0.19 +/- 0.02 nM and 157 +/- 29 fmol/mg protein in rat and 0.14 +/- 0.06 nM and 227 +/- 125 fmol/mg protein in rabbit). Furthermore, [3H]nitrendipine binding inhibition experiments using 12 unlabeled DHP analogues yielded Ki values for each compound that were almost identical in myocardium from rat and rabbit, resulting in an excellent 1:1 correlation when data for all of the compounds were compared (r = 0.997, p less than 0.001). The negative inotropic effect of five of these DHP compounds was studied in vitro in isolated right papillary muscles from rabbit and right ventricular strips from rat, and concentration required to displace 50% of ligand binding (IC50) values for inhibition of contraction were determined. The IC50 values were significantly greater in rat myocardium than in rabbit myocardium (p less than 0.003). Therefore, a significantly lower potency of DHP calcium channel blockers has been demonstrated in rat compared with rabbit myocardium, and this species difference cannot be explained by a difference in the DHP binding site. Rat myocardium differs from rabbit myocardium in a number of ways that may explain this lower potency.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1988R055200005

    View details for PubMedID 2467082

  • TRANSVENOUS CORONARY ANGIOGRAPHY USING SYNCHROTRON RADIATION NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION A-ACCELERATORS SPECTROMETERS DETECTORS AND ASSOCIATED EQUIPMENT Thompson, A. C., Hofstadter, R., Otis, J. N., Zeman, H. D., Kernoff, R. S., Rubenstein, E., Giacomini, J. C., GORDON, H. J., Brown, G. S., Thomlinson, W. 1988; 266 (1-3): 252-259
  • PROGRESS REPORT ON SYNCHROTRON RADIATION ANGIOGRAPHY ON HUMAN-SUBJECTS JOURNAL DE PHYSIQUE Rubenstein, E., Brown, G. S., Giacomini, J. C., GORDON, H. J., Hofstadter, R., Kernoff, R. S., Otis, J. N., Thomlinson, W., Thompson, A. C., Zeman, H. D. 1987; 48 (C-9): 5-8
  • COMPARISON OF BINDING AFFINITIES AND NEGATIVE INOTROPIC POTENCIES OF THE 1,4-DIHYDROPYRIDINE CALCIUM-CHANNEL BLOCKERS IN RABBIT MYOCARDIUM JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Boyd, R. A., Giacomini, J. C., Wong, F. M., Nelson, W. L., Giacomini, K. M. 1987; 243 (1): 118-125

    Abstract

    The binding and pharmacologic response of a series of 1,4-dihydropyridine analogs were examined in rabbit myocardium. [3H]Nitrendipine was used to label specific binding sites in myocardial membrane particulates and displacement experiments were carried out with the unlabeled analogs to determine their IC50 values. Binding of [3H]nitrendipine could be characterized by a Kd of 0.15 +/- 0.06 nM and a maximum number of binding sites of 247 +/- 150 fmol/mg of protein. Saturation binding experiments performed with higher concentrations of [3H]nitrendipine did not reveal the presence of a lower affinity site. Binding IC50 values of 12 unlabeled 1,4-dihydropyridine analogs ranged from 4.3 X 10(-10) M to 1.32 X 10(-6) M. The negative inotropic effect of the same compounds was studied in vitro in isolated papillary muscles and the IC50 values for inhibition of contraction determined. There was a statistically significant correlation between the IC50 values for binding and response (r = 0.79, P less than .005; rs = 0.78, P less than .005). Consistent with previous studies with several of these compounds, the response IC50 value for each compound was greater than the binding IC50 value. For most of the compounds, this difference was from one to two orders of magnitude. For three compounds, nitrendipine, nimodipine and nicardipine, this difference reached three orders of magnitude. These three dihydropyridine analogs share structural features that may determine their low myocardial potency and, at the same time, their high vascular smooth muscle potency. Elucidation of these structural features may be useful in determining which analogs will have the highest vascular smooth muscle selectivity.

    View details for Web of Science ID A1987K584400016

    View details for PubMedID 2822893

  • ANGIOGRAPHY BY SYNCHROTRON RADIATION PHYSICA SCRIPTA Rubenstein, E., Brown, G. S., Giacomini, J. C., GORDON, H. J., Hofstadter, R., Kernoff, R. S., Otis, J. N., Thomlinson, W., Thompson, A. C., Zeman, H. D. 1987; T19B: 487-490
  • TRANSVENOUS CORONARY ANGIOGRAPHY IN HUMANS USING SYNCHROTRON RADIATION PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Rubenstein, E., Hofstadter, R., Zeman, H. D., Thompson, A. C., Otis, J. N., Brown, G. S., Giacomini, J. C., GORDON, H. J., Kernoff, R. S., HARRISON, D. C., Thomlinson, W. 1986; 83 (24): 9724-9728

    Abstract

    The risks and costs of the present method of visualizing the coronary arteries have limited the use of coronary angiography in long-term serial studies needed to establish the natural history of coronary atherosclerosis and its response to interventions. A less invasive method, in which the contrast agent is administered intravenously, has been developed using synchrotron radiation as the illuminating source. The present report describes the initial results in human subjects. The findings indicate that transvenous coronary angiograms can be acquired in this manner. Further refinements in the x-ray imaging system are expected to result in increased x-ray fluence and improved image quality.

    View details for Web of Science ID A1986F500600094

    View details for PubMedID 3467334

  • THE INTERACTION OF PHENYLALKYLAMINE CALCIUM-CHANNEL BLOCKERS WITH THE 1,4-DIHYDROPYRIDINE BINDING-SITE JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Zobrist, R. H., Giacomini, K. M., Nelson, W. L., Giacomini, J. C. 1986; 18 (9): 963-974

    Abstract

    The interaction of verapamil and other phenylalkylamine calcium channel blockers with the 1,4-dihydropyridine receptor was examined. Studies characterizing the interaction and relationship between calcium channel blocking potency and binding affinity were performed in rat myocardium. The 1,4-dihydropyridines, nifedipine and nitrendipine, interacted competitively. The apparent Kd and Bmax of nitrendipine were 270 +/- 140 pM and 390 +/- 76 fmol/mg protein, respectively. In contrast, the interaction of the phenylalkylamines with the 1,4-dihydropyridine receptor was not competitive. At a 3H-nitrendipine concentration of 0.12 nM, verapamil displaced only 60% of specifically bound radioactivity and progressively less as the concentration of 3H-nitrendipine increased. Kinetic data indicated that the interaction of both D600 and verapamil with the 1,4-dihydropyridine receptor was not cooperative. At infinite dilution the dissociation rate constant (k-1) was not altered in the presence of 10(-5) M D600. We examined the hypothesis that 3H-nitrendipine interacts at several sites with similar affinities and that the phenylalkylamines interact at one of these sites. Although D600 could not further displace 3H-nitrendipine in the presence of a maximally displacing concentration of nifedipine (10(-6) M), nifedipine could further displace 3H-nitrendipine in the presence of a maximally displacing concentration of D600 (10(-5) M). These results are consistent with competitive interactions at multiple sites but do not explain the diminished ability of the phenylalkylamines to displace progressively less radioactivity at increasing 3H-nitrendipine concentrations. No relationship between binding affinity and pharmacologic potency of the phenylalkylamines was found suggesting that the interaction of the phenylalkylamines with the 1,4-dihydropyridine receptor is not responsible for their calcium channel blocking effects.

    View details for Web of Science ID A1986E128600010

    View details for PubMedID 3783730

  • ANCILLARY PHARMACOLOGIC PROPERTIES OF ACEBUTOLOL - CARDIOSELECTIVITY, PARTIAL AGONIST ACTIVITY, AND MEMBRANE-STABILIZING ACTIVITY AMERICAN HEART JOURNAL Giacomini, J. C., THODEN, W. R. 1985; 109 (5): 1137-1144

    Abstract

    Acebutolol, a new beta-blocking agent, possesses the ancillary pharmacologic properties of cardioselectivity and partial agonist and membrane-stabilizing activities. Compared to propranolol at equipotent doses, acebutolol produces less bronchoconstriction and preserves the bronchodilator response to isoprenaline. Similarly, acebutolol has less of an effect on peripheral vascular hemodynamics than does propranolol. Because of partial agonist activity, acebutolol produces a lesser reduction in heart rate and cardiac output than do propranolol and atenolol and has been found to have minimal effects on lipoprotein metabolism. Acebutolol may be the only beta-blocking agent that demonstrates some membrane-stabilizing activity at clinically achievable plasma concentrations. The ancillary pharmacologic properties of cardioselectivity and partial agonist activity are distinct and offer definite advantages to selected patients, particularly patients with respiratory disease, in whom cardioselective acebutolol, particularly at low doses, can minimize patient risk. The ancillary property of membrane-stabilizing activity may also guide therapy in selected patients.

    View details for Web of Science ID A1985AGY2000005

    View details for PubMedID 2859777

  • ELECTROPHYSIOLOGY OF THE ENANTIOMERS OF DISOPYRAMIDE IN DOGS JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Giacomini, J. C., Giacomini, K. M., Nelson, W. L., HARRISON, D. C., Blaschke, T. F. 1985; 7 (5): 884-890

    Abstract

    The antiarrhythmic agent disopyramide comprises two enantiomers. In the present study, we examined the effects of the individual enantiomers on in vivo electrophysiology in anesthetized, closed-chest dogs. Six dogs received d-disopyramide, seven received l-disopyramide, and three dogs served as controls. Electrophysiologic measurements were performed at a series of geometrically increasing steady-state plasma concentrations of d- or l-disopyramide. Concentration-response curves were constructed for each electrophysiologic parameter, and the slopes of the regression lines of response versus plasma concentration were compared between enantiomers. Electrophysiologic parameters in the control dogs did not significantly change with time. However, stereoselective electrophysiologic effects were observed, with l-disopyramide being more potent than d-dispopyramide in prolonging sinus cycle length, Wenckebach cycle length, and atrioventricular nodal refractoriness (p less than 0.05). These findings are consistent with the established increased anticholinergic activity of the d-enantiomer which appeared to offset its local anesthetic or sodium channel inhibiting properties. Interrelationships between the autonomic nervous system and the cardiac electrophysiologic effects of disopyramide may be important in its antiarrhythmic effects.

    View details for Web of Science ID A1985ARF5000011

    View details for PubMedID 2413296

  • THE PHARMACOKINETICS AND PHARMACODYNAMICS OF D-VERAPAMIL AND DL-VERAPAMIL IN RABBITS JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Giacomini, J. C., Nelson, W. L., Theodore, L., Wong, F. M., Rood, D., Giacomini, K. M. 1985; 7 (3): 469-475

    Abstract

    The pharmacokinetics and pharmacodynamics of d- and dl-verapamil were studied in conscious rabbits in randomized cross-over fashion. Following a single intravenous dose, there was a biexponential decline in plasma concentration with time. No differences were observed in the pharmacokinetic properties of the compounds. The mean (+/- SD) clearances of d- and dl-verapamil were 0.13 +/- 0.03 and 0.12 +/- 0.05 L/min/kg, respectively. The mean (+/- SD) steady-state volume of distribution was 9.7 +/- 5.2 L/kg for d-verapamil and 8.1 +/- 4.1 L/kg for dl-verapamil. No difference was observed between the compounds in their binding to plasma proteins. The mean (+/- SD) half-life in plasma was 98.7 +/- 63.8 min for d-verapamil and 96.3 +/- 38.0 min for dl-verapamil. In contrast to the lack of stereoselective differences in the pharmacokinetic properties of verapamil, there were marked differences in the pharmacodynamics of d- and dl-verapamil. dl-Verapamil appeared to prolong the PR interval to a greater degree than did d-verapamil, consistent with the more potent calcium channel effects of the l-enantiomer. Similarly, dl-verapamil had more potent hypotensive effects compared with the d-enantiomer, which produced no effects on systemic arterial pressure. Chronotropic effects, judged to be caused by autonomic reflexes in response to the hypotensive effects of the compound, were also statistically greater for dl-verapamil than for d-verapamil. These results demonstrate stereo-selective pharmacodynamic effects in vivo of verapamil.

    View details for Web of Science ID A1985AJZ0500009

    View details for PubMedID 2410676

  • REDUCTION OF ISCHEMIC DEPOLARIZATION BY THE CALCIUM-CHANNEL BLOCKER DILTIAZEM - CORRELATION WITH IMPROVEMENT OF VENTRICULAR CONDUCTION AND EARLY ARRHYTHMIAS IN THE DOG CIRCULATION RESEARCH Clusin, W. T., Buchbinder, M., Ellis, A. K., Kernoff, R. S., Giacomini, J. C., HARRISON, D. C. 1984; 54 (1): 10-20

    Abstract

    Calcium channel blockers suppress early ischemic arrhythmias, possibly by diminishing intracellular calcium overload and its effect on the ventricular action potential. To explore this, we compared the effects of diltiazem on ischemic "injury" potentials and ventricular fibrillation during serial coronary artery occlusions in dogs. Injury potentials and ventricular fibrillation were elicited every 15-25 minutes by simultaneous occlusion of the left anterior descending and circumflex arteries during rapid atrial pacing. DC epicardial electrograms were recorded differentially between the ischemic region and a small nonischemic region supplied by a proximal branch of the left anterior descending artery. Injury potentials developed with a uniform time course during five control occlusions, but were reduced by diltiazem infusion (0.5 mg/kg over 25 minutes) in each of eight dogs. The mean diastolic injury potential (T-Q depression) at 150 seconds of ischemia was 9.1 +/- 2.7 mV before diltiazem and 6.1 +/- 1.6 mV afterward (P less than 0.001). Diltiazem increased the mean time between coronary occlusion and ventricular fibrillation from 186 to 366 seconds (P less than 10(-5), but did not change the magnitude of the diastolic injury potential at onset of ventricular fibrillation. Diltiazem also delayed ischemia-induced conduction impairment to the same extent that it delayed injury potential development. In five dogs, the effect of diltiazem on regional blood flow near the epicardial electrodes was measured by infusion of radionuclide-labeled microspheres. Coronary occlusion reduced flow to the ischemic zone from 0.86 to 0.05 ml/min per g (P = 0.001). Diltiazem increased preocclusion flow by 11% (P = 0.03), but did not significantly alter flow during occlusion. Hemodynamic measurements show that diltiazem did not diminish cardiac work. Diltiazem therefore produced a flow-independent reduction of cellular depolarization during ischemia, which may be due to relief of calcium overload, and which may explain the antifibrillatory effect.

    View details for Web of Science ID A1984SB78500002

    View details for PubMedID 6692497

  • DECREASED BINDING OF VERAPAMIL TO PLASMA-PROTEINS IN PATIENTS WITH LIVER-DISEASE JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Giacomini, K. M., Massoud, N., Wong, F. M., Giacomini, J. C. 1984; 6 (5): 924-928

    Abstract

    The binding of verapamil to proteins in plasma of patients with liver disease was studied using equilibrium dialysis. Compared with an age- and sex-matched control group, the fraction unbound of verapamil was significantly greater in patients with liver disease (p less than 0.01). The mean +/- SD fraction unbound in the patients was 0.16 +/- 0.05 compared with 0.099 +/- 0.015 in the control group (p less than 0.01). The higher fraction unbound in the liver disease patients appeared to be largely due to lower concentrations of binding proteins in plasma. A substantial effect of pH on the binding of verapamil to plasma proteins was observed. The increase in fraction unbound is consistent with previous findings of an increased apparent volume of distribution in patients with liver disease. Because of the pharmacokinetic characteristics of verapamil, the observed altered binding to plasma proteins would be expected to result in higher steady-state plasma concentrations of unbound drug after intravenous but not oral administration. For clinical monitoring, at any given total concentration, the unbound concentration would be approximately 60% higher in patients with liver disease. This study, together with previous studies in the literature, suggests that caution should be exercised in the administration of verapamil to patients with liver disease.

    View details for Web of Science ID A1984TM25000028

    View details for PubMedID 6209501

  • SYNTHESIS AND ANTICHOLINERGIC PROPERTIES OF THE ENANTIOMERS OF 4-(ISOPROPYLAMINO)-2-(2-PYRIDYL)-2-PHENYLBUTYRAMIDE, THE MONO-N-DEALKYLATED METABOLITE OF DISOPYRAMIDE JOURNAL OF MEDICINAL CHEMISTRY Nelson, W. L., SNEED, C. K., Giacomini, K. M., Giacomini, J. C., Stauss, J., Blaschke, T. F., Cox, B. M. 1981; 24 (5): 614-617

    Abstract

    The 2R and 2S enantiomers of 4-isopropyl-2-(2-pyridyl)-2-phenylbutyramide [(2R)-2 and (2S)-2] were prepared from the respective 2R and 2S enantiomers of disopyramide [(2R)-1 and (2S)-1] by oxidation with peracid, Cope elimination, and subsequent zinc/HCl reduction of the resulting hydroxylamines (2R)-3 and (2S)-3. The enantiomers were tested as antagonists to the contraction of guinea pig ileum longitudinal muscle produced in response to electrically stimulated release of acetylcholine. The enantiomers showed IC50 values of 5.0 X 10(-6) and 14 X 10(-6) M for (2S)-2 and (2R)-2 respectively, about a 3-fold difference between enantiomers. Data are presented showing direct antagonism of acetylcholine in the guinea pig ileum assay. In a comparison of the anticholinergic effects of 2 and 1, the metabolite (2) was slightly less potent than disopyramide (1).

    View details for Web of Science ID A1981LM55600024

    View details for PubMedID 7241519

  • THE STEREOSELECTIVE DISPOSITION OF DISOPYRAMIDE IN THE DOG JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Giacomini, K. M., Giacomini, J. C., SWEZEY, S. E., HARRISON, D. C., Nelson, W. L., Burke, T. R., Blaschke, T. F. 1980; 2 (6): 825-832

    Abstract

    The disposition of d-, 1-, and d,1-disopyramide was studied in 5 conscious dogs after intravenous administration (15 mg/kg) of each compound using a balanced crossover design. The clearance of d-disopyramide (15.4 +/- 5.10 ml/min/kg) was significantly greater than that of the l-isomer (9.45 +/- 2.52 ml/min/kg) (p < 0.001). The clearance of the d,1-mixture was intermediate between that obtained for the d- and l-isomers. The steady-state volume of distribution of the three compounds was similar (approximately 1.4 liters/kg). The elimination half-life reflected differences in clearance, being 76.4 +/- 7.30 min for d-disopyramide, 112 +/- 23.4 min for 1-disopyramide, and 97.2 +/- 15.1 min for d,1-disopyramide. The effect of general anesthesia with urethane and chloralose on the disposition of the compounds was also examined. General anesthesia decreased the clearance and increased the half-life of all three compounds. No consistent differences in the volume of distribution were observed with anesthesia as compared to control. Thus, there is stereoselective elimination of the optical isomers of disopyramide in the dog, and general anesthesia decreases the clearance of d-, 1-, and d,1-disopyramide.

    View details for Web of Science ID A1980KM24300011

    View details for PubMedID 6160331

  • ABSENCE OF EFFECT OF HEPARIN ON THE BINDING OF PRAZOSIN AND PHENYTOIN TO PLASMA-PROTEINS BIOCHEMICAL PHARMACOLOGY Giacomini, K. M., Giacomini, J. C., Blaschke, T. F. 1980; 29 (24): 3337-3340

    View details for Web of Science ID A1980KX34600021

    View details for PubMedID 7213407

  • ADMINISTRATION OF HEPARIN CAUSES INVITRO RELEASE OF NON-ESTERIFIED FATTY-ACIDS IN HUMAN-PLASMA LIFE SCIENCES Giacomini, K. M., SWEZEY, S. E., Giacomini, J. C., Blaschke, T. F. 1980; 27 (9): 771-780

    View details for Web of Science ID A1980KF14500009

    View details for PubMedID 7412503