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Biomedical subjects

J D Horowitz

Publications and source records attributed to J D Horowitz.

At least 109 records · Page 6Linked to original sources
PubMed1989

Tissue carcinoembryonic antigen levels in benign and malignant diseases of the breast.

The peroxidase-antiperoxidase histochemical method of staining for tissue carcinoembryonic antigen (CEA) was performed on 20 samples of malignant breast tissue, 20 samples of fibroadenomatous breast tissue, and 15 samples of breast tissue that variably contained minimal fibrosis (N = 7), ductal ectasia (N = 5), and sclerosing adenosis (N = 3; the fibrocystic changes of the breast). The intensity of staining was described to be either negative, weak, intermediate, or strong and was assigned a point value of 1, 2, 3, or 4, respectively. The following weighted average values of tissue CEA were obtained: carcinoma, 3.35 +/- 0.88; fibroadenomas, 2.85 +/- 0.67; fibrocystic changes, 2.13 +/- 0.52. Carcinomatous tissue is likely (55%) to display intense tissue staining, whereas fibrocystic disease (0%) or fibroadenoma (15%) are unlikely to exhibit such a reaction. The tissue CEA content between carcinoma and fibrocystic changes (P less than 0.01), carcinoma and fibroadenoma (P less than 0.01), and fibroadenoma and fibrocystic changes (P less than 0.05) are statistically significant.

Biomarkers, Tumor↗
PubMed1989

Determinants of in vitro nitroglycerin tolerance induction and reversal: influence of dose regimen, nitrate-free period, and sulfhydryl supplementation.

The influence of dose regimen on the induction and reversal of tolerance to nitroglycerin (NTG) is not well understood despite the current widespread clinical use of both sustained and intermittent modes of NTG administration. In an isolated coronary artery preparation both the NTG preexposure concentration and the duration of the NTG preexposure period were positive and independent determinants of the extent of NTG tolerance induction. During a "nitrate-free" or washout period, NTG tolerance was at least partially reversible. The apparent rate of NTG tolerance reversal during a "nitrate-free" period was not dependent on the absolute degree of NTG tolerance induced or on the dose regimen used to induce NTG tolerance. In this isolated vascular preparation, sulfhydryl (SH) supplementation with 1 mM N-acetylcysteine produced no significant augmentation of NTG-induced relaxations in either NTG tolerant or non tolerant tissues. N-acetylcysteine was ineffectual in attenuating the development of NTG tolerance in coronary artery preparations incubated in either Krebs bicarbonate buffer or in 10% human plasma. We conclude that in this model the NTG preexposure concentration, the duration of the NTG preexposure period, and the duration of the "nitrate-free" period are critical and independent determinants of the extent of NTG tolerance but that NTG tolerance is not significantly attenuated by SH supplementation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Perhexilene: effects on hepatic lysosomal function in rats.

1. Perhexilene, a long-acting anti-anginal drug, can induce adverse effects on the liver which may be dose-dependent. At high concentrations, perhexilene causes marked morphological changes in hepatocyte lysosomes. The current study examined the effect of 'therapeutic' doses of perhexilene on hepatic lysosomal function, particularly the biliary release of lysosomal enzymes, using an isolated perfused rat liver (IPRL) model. 2. Pharmacokinetic studies demonstrated that clearance of single doses of perhexilene by the perfused rat liver was dose-dependent and established a 'therapeutic' dose of 0.6 mg using the IPRL. A 5 day pretreatment regimen of 20 mg/kg per day was shown to produce 'therapeutic' perhexilene concentrations of 150-210 ng/ml. 3. At perhexilene concentrations equating the 'therapeutic' range in man, the major effect of perhexilene was at the biliary pole of the hepatocyte. In 5 day pretreatment dose studies, lysosomal enzyme excretion into bile was markedly increased. In single dose studies, the increase in biliary lysosomal enzyme output partially reflected an increase in bile water production which was not seen with the 5 day pretreatment regimen. Hepatic and perfusate lysosomal enzyme activities were not affected. 4. This selective effect of perhexilene on hepatocyte-to-bile lysosomal excretion may reflect intracellular lysosomal drug localization.

Acetylglucosaminidase↗
PubMed1989

S-nitrosothiols as vasodilators: implications regarding tolerance to nitric oxide-containing vasodilators.

1. The formation of an S-nitrosothiol compound, S-nitroso-N-acetylcysteine (SNAC) has recently been proposed to mediate the augmentation of the anti-aggregatory and haemodynamic effects of glyceryl trinitrate observed in the presence of N-acetylcysteine. This study investigated the effects on an isolated coronary artery preparation of acute and prolonged exposure to S-nitrosothiol compounds and nitric oxide (NO). 2. Single doses of NO and of the S-nitrosothiol compounds, SNAC and S-nitroso-N-acetyl-penicillamine (SNAP), induced rapid, but transient, relaxations in U46619-contracted bovine isolated coronary artery rings. Peak relaxation responses to SNAP and NO were attenuated in the presence of N-acetylcysteine, cysteine, ascorbic acid and methylene blue. The duration of the relaxation responses to SNAC was two to three times longer than those to SNAP and NO. In the presence of N-acetylcysteine (but not cysteine, ascorbic acid or methylene blue) the duration of the relaxation responses to SNAP and NO (but not to SNAC) was markedly increased. H.p.l.c. assay confirmed that, in the presence of N-acetylcysteine, SNAP and, to a lesser degree, NO were converted to the relatively more stable and longer acting vasodilator, SNAC. 3. When compared to control rings, coronary artery rings superfused with glyceryl trinitrate were subsequently markedly less responsive to the vasodilator actions of glyceryl trinitrate, whereas responsiveness to SNAC or NO was only marginally reduced. On the other hand, coronary artery rings superfused with SNAC or NO were subsequently less responsive to glyceryl trinitrate, SNAC and NO. Thus prolonged vascular exposure to SNAC or NO induced a form of tolerance different from that induced with glyceryl trinitrate and which is possibly associated with impaired guanylate cyclase activity. 4. Coronary artery rings superfused with NO were markedly less responsive to glyceryl trinitrate and NO, whereas responses to the endothelium-dependent vasodilator A23187 and to theophylline were not significantly attenuated. 5. It is concluded that formation of the more stable vasodilator SNAC occurs on incubation of N-acetylcysteine with SNAP or NO. While coronary artery responsiveness to SNAC and NO is virtually unchanged in the presence of glyceryl trinitrate-induced tolerance, after prolonged exposure to SNAC or NO tolerance may develop to these vasodilators with cross-tolerance to glyceryl trinitrate but not A23187. Thus, formation or therapeutic utilization of SNAC may acutely circumvent the problem of glyceryl trinitrate-induced tolerance but, during prolonged vascular exposure to SNAC, attenuation of vascular responsiveness may occur to a wide range of vasodilators.

Acetylcysteine↗
PubMed1989

Nitroglycerin-induced tolerance affects multiple sites in the organic nitrate bioconversion cascade.

The effect of nitroglycerin (NTG)-induced tolerance on the spasmolytic effects of a series of vasodilators was determined to establish potential sites of tolerance. Concentration-effect curves to vasodilators were completed concurrently in U46619-contracted bovine isolated coronary artery rings pre-exposed to 100 microM NTG for 10 min (NTG-tolerant rings) and in control rings not pre-exposed to NTG. Compared to control rings, NTG-tolerant rings were markedly less responsive (P less than .01, n = 8-10) to the spasmolytic actions of NTG, isosorbide dinitrate, sodium nitroprusside (SNP) and 3-morpholinosydonimine (SIN-1), whereas the spasmolytic actions of S-nitroso-N-acetylpenicillamine and nitric oxide were only marginally attenuated in NTG-tolerant rings. On the other hand, no significant difference in the relaxant responses of NTG-tolerant and control coronary artery rings were observed to either the endothelium-dependent vasodilator, A23187 or the guanylate cyclase-independent vasodilator, theophylline. In additional cross-tolerance studies, relaxations to the organic nitrate vasodilator, NTG were significantly more attenuated (P less than .05, n = 5) by tolerance induced by NTG, than by either SNP or SIN-1, whereas the actions of the non-nitrate vasodilators, SNP and SIN-1 were attenuated more by SNP-and SIN-1-induced tolerance than by NTG-induced tolerance (P less than .05, n = 5). We conclude that, in this isolated coronary artery preparation, NTG-induced tolerance affects at least two major sites in the cascade of events between the initial site of NTG action and guanylate cyclase activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Myocardial salvage with streptokinase combined with nitroglycerine and verapamil in acute myocardial infarction.

We tested the hypothesis that preservation of left ventricular function results from treatment with intravenous streptokinase given in the first 2 hours from onset of acute transmural myocardial infarction together with nitroglycerine and verapamil. Thirty-three consecutive patients with onset of pain less than 2 hours prior to admission, received intravenous streptokinase 1.5 x 10(6) units with intravenous nitroglycerine and verapamil; 23 concurrently admitted "control" patients with pain onset 2-4 hours received intravenous nitroglycerine and verapamil only. Radionuclide ventriculographic assessment at 2 days revealed a significantly greater left ventricular ejection fraction in the streptokinase-treated patients (54.5 +/- 2.8 vs 46.1 +/- 2.9; P less than 0.05), which persisted at 28-35 days (50.1 +/- 2.3 vs 41.2 +/- 2.9; P less than 0.05). Streptokinase-treated patients had a significantly increased incidence of ischaemic events in the 35 days following infarction, but a lower incidence of death, congestive cardiac failure and non-fatal ventricular tachycardia than control group patients. Infarct-related artery patency assessed at 3-5 days was 94% in streptokinase-treated patients. We conclude that early presentation and treatment with intravenous streptokinase, nitroglycerine and verapamil is associated with a high incidence of successful thrombolysis and significant preservation of left ventricular function. Nitroglycerine and verapamil may augment the efficacy of streptokinase in this group of patients.

Acute Disease↗
PubMed1988

Nitroglycerine/N-acetylcysteine in the management of unstable angina pectoris.

N-acetylcysteine (NAC) has been shown to potentiate the haemodynamic and antiplatelet effects of nitroglycerine (NTG) in man, and to limit the development of haemodynamic tolerance to NTG. These effects may be mediated. by the formation of S-nitroso-NAC, which induces vasodilation and strongly inhibits platelet aggregation. In a randomized double-blind study in 46 patients with severe unstable angina pectoris unresponsive to standard treatment (including cutaneous nitrates and calcium antagonists in 45 patients) we compared the effects of intravenous (IV) NTG with those of IV NTG combined with IV NAC (5 g 6 hourly). Treatment with NTG/NAC (24 patients) was associated with a similar frequency of episodes of chest pain as treatment with NTG alone (22 patients), but somewhat fewer increments in infusion rate for pain control (10 vs 17; P NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (3 vs 10 patients; P = 0.013). Symptomatic hypotension occurred frequently in the NTG/NAC group (7 vs 0 patients; P = 0.006). It is concluded that combined administration of NTG and NAC in patients with unstable angina pectoris may augment the clinical efficacy of NTG, largely by reducing the incidence of acute myocardial infarction. However, the high incidence of severe hypotension with NTG/NAC suggests that this regimen should be used with some caution.

Acetylcysteine↗
PubMed1988

Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris.

The vasodilator effects of nitroglycerin (NTG) are mediated via activation of guanylate cyclase; this process is believed to require the availability of free sulfhydryl groups. Previous studies in man have shown that the sulfhydryl donor N-acetylcysteine (NAC) potentiates the systemic and coronary vasodilator effects of NTG. Furthermore, interaction of NTG and NAC may lead to the formation of S-nitroso-NAC, which strongly inhibits platelet aggregation. The effects of intravenous NTG combined with intravenous NAC (5 g 6 hourly) were compared with those of intravenous NTG alone in a double-blind trial in 46 patients with severe unstable angina pectoris unresponsive to conventional treatment, which included calcium antagonists and cutaneous nitrates in all but one patient. Treatment with NTG/NAC (24 patients) and that with NTG alone (22 patients) was associated with a similar frequency of episodes of chest pain and of increments in NTG infusion rate for pain control (10 vs 17; p = NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (three vs 10 patients; p = .013). Symptomatic hypotension occurred frequently in the NTG/NAC group (seven vs 0 patients; p = .006). Lactate-pyruvate ratios and venous NTG concentrations were not significantly affected by NAC. Subsequently, another 20 consecutive patients were treated with intravenous NTG and continuously infused NAC (10 g/day). Seven remained pain free during the first 24 hr of NTG infusion; 11 required increments in NTG infusion rate for pain control. Acute myocardial infarction occurred in one patient, while none developed symptomatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcysteine↗
PubMed1988

Verapamil in unstable angina pectoris: failure to demonstrate a relationship between efficacy and plasma levels.

Verapamil has been shown to be effective in reducing the frequency of episodes of ischemic pain in patients with unstable angina pectoris, and to be more effective than beta-adrenoceptor antagonists in such patients. However, in many patients ischemic symptoms persist despite verapamil therapy. In a group of 33 consecutive patients admitted to the Coronary Care Unit with unstable angina pectoris and treated with verapamil and nitroglycerin, we prospectively tested the hypothesis that plasma concentrations of verapamil were a direct determinant of resolution of ischemic symptoms over the initial 72-h period of admission. During this period, improvement or resolution of symptoms occurred in 23 of the 33 patients. With patients receiving 240 to 320 mg/day of verapamil, plasma verapamil concentrations varied between 8 and 487 ng/ml, rising significantly with increasing duration of therapy. Mean plasma verapamil concentrations were somewhat greater in patients who improved than in those with ongoing or worsening symptoms, but the differences were not statistically significant. Furthermore, no correlation was found between symptomatic status and plasma concentrations of norverapamil, the active metabolite of verapamil. In one patient cardiac failure worsened, possibly attributable to an elevated plasma verapamil concentration (336 ng/ml). We conclude that in this clinical setting there is little place for routine monitoring of plasma verapamil concentrations.

Adult↗
PubMed1987

Potential functions of plasma prorenin; regional activation and tissue extraction.

The fate of circulating inactive prorenin was examined in patients and volunteers. Prorenin was activated either by acid-dialysis with warming at pH 3.3 or with trypsin. The results were similar but omission of warming reduced the value by 13%. In 6 volunteers, 20 min forearm venous occlusion raised regional total (T) and inactive (I) plasma renin concentration (PRC) by 51% and 48% without change of active (A) renin. During intense forearm exercise the ratio APRC: IPRC did not change in muscle or skin venous blood. Body anaerobic exercise increased APRC 3.7-fold without change in IPRC. These procedures activate plasminogen but are without effect on prorenin. In 18 patient with stable angina, TPRC was lower in coronary sinus than arterial blood (p less than 0.001) but APRC was not affected. A-V differences were not detected across the leg. Prorenin is apparently stable in the circulation but extracted by the heart.

Adult↗
PubMed1986

Extraction of plasma prorenin by human heart.

Arterial plasma prorenin underwent 58% extraction during one passage through the coronary circulation in eleven patients undergoing myocardial metabolic studies. Active renin and renin substrate were unaffected. Changes in renin and renin substrate concentrations were not detected across the enterohepatic, femoral, or renal vascular beds. This high degree of selective extraction of prorenin by the heart accounts for its proposed half-life. Prorenin could be a cardiotropic hormone.

Cardiac Catheterization↗
PubMed1986

Usefulness of early exercise testing after non-Q-wave myocardial infarction in predicting prognosis.

The value of an early symptom-limited maximal exercise test in predicting coronary anatomy, left ventricular ejection fraction and hemodynamics was assessed prospectively in 64 patients after an acute non-Q-wave myocardial infarction (MI). Exercise tests and cardiac catheterization were performed at a median of 6 and 7 days, respectively, after non-Q MI. Forty-one percent of the patients had a negative exercise test response (no angina, less than 1 mm of ST depression and normal blood pressure responses). Twenty-five percent had a positive response (1 to 1.9 mm of ST depression or angina); 34% had a "strongly positive" exercise test response (at least 2 mm of ST depression or abnormal blood pressure responses). A negative response predicted the absence of 3-vessel disease (at least 70% stenosis) or critical stenoses (at least 90% stenosis) involving major coronary arteries (negative predictive accuracy 92%), whereas a strongly positive response predicted their presence (positive predictive value 77%, specificity 88%). Cardiac index and mean pulmonary artery wedge pressure did not vary significantly among the 3 exercise groups, whereas left ventricular ejection fraction was slightly higher in the exercise test group with a positive response (p less than 0.025). Thus, in patients who have had a non-Q MI, early exercise testing can be used to predict the extent and severity of coronary artery disease, and the decision to perform coronary angiography should be guided by the exercise test results.

Adult↗
PubMed1986

Measurement of penicillamine and N-acetylcysteine in human blood by high-performance liquid chromatography and electrochemical detection.

A rapid and precise high-performance liquid chromatographic assay for both N-acetylcysteine and penicillamine in blood samples is described using selective reductive electrochemical detection and a high-efficiency C18 reversed-phase column. The use of an internal standard compensated for changes in detector responses during a run and for variable sample recovery. The detection limits for N-acetylcysteine and penicillamine were 25 and 10 ng/ml, respectively, using 500-microliters blood samples. Reproducibility of measurement for both thiols was excellent. This method allows routine monitoring of blood levels and pharmacokinetic studies with N-acetylcysteine and penicillamine.

Acetylcysteine↗
PubMed1986

Perhexiline maleate treatment for severe angina pectoris--correlations with pharmacokinetics.

Perhexiline maleate, which causes inhibition of myocardial fatty acid catabolism with a concomitant increase in glucose utilization, is particularly useful in the management of patients with severe angina pectoris. While perhexiline exerts no significant negative inotropic or dromotropic effects, its short- and long-term use has hitherto been restricted because of complex pharmacokinetics and the eventual development, in many patients, of hepatitis and peripheral neuropathy. Correlations between perhexiline dose, plasma drug concentrations, efficacy and development of toxicity were examined prospectively in 3 groups of patients. The first group (n = 29) were patients in whom perhexiline was added to previously prescribed anti-anginal medication for short-term (pre-surgical or post-myocardial infarction) control of angina pectoris. Over a mean treatment period of 18 +/- 2 (SEM) days, 13 patients experienced a marked reduction in frequency and severity of attacks. No adverse effects occurred. A second group of patients (n = 19) were treated chronically with 50-400 mg/day of perhexiline, dosage being adjusted to minimize symptoms. Over a mean treatment period of 8.8 +/- 1.7 months, 5 patients became asymptomatic, while 9 developed evidence of hepatitis or neurotoxicity, with concomitant plasma perhexiline concentrations of 720-2680 ng/ml. Subsequently, a further group of similar patients (n = 22) were treated for 12.4 +/- 2.6 months, perhexiline dosage being adjusted to maintain plasma perhexiline concentrations below 600 ng/ml. Nine patients became asymptomatic, while none developed adverse effects. It is concluded that perhexiline is useful both as a short-term adjunct to anti-anginal therapy and in the long-term management of patients unsuitable for coronary artery bypass grafting. The risk of long-term toxicity can be reduced markedly by maintenance of plasma drug concentrations below 600 ng/ml without significantly compromising anti-anginal efficacy.

Adult↗
PubMed1986

Short-term myocardial uptake of lidocaine and mexiletine in patients with ischemic heart disease.

Determination of short-term myocardial drug uptake and subsequent redistribution was performed in 27 patients with ischemic heart disease for the antiarrhythmic agents lidocaine and mexiletine, using frequent simultaneous measurements of drug concentration in aortic and coronary sinus blood, combined with measurement of coronary sinus blood flow after intravenous bolus injection of the drug. Maximal myocardial drug content per unit resting coronary sinus blood flow (MDC:F) was significantly greater in patients in whom coronary sinus pacing at 100 beat/min was performed during the initial period of drug uptake. Maximal myocardial drug content occurred after 2.4 +/- 0.2 (SEM) for lidocaine and after 5.5 +/- 0.6 min for mexiletine (p less than .001), and pacing did not affect time to maximum myocardial drug content. In nonpaced, but not paced, patients maximal MDC:F was greater in the lidocaine group than that in the mexiletine group. The subsequent efflux of lidocaine from the myocardium was more rapid that that of mexiletine in both paced and nonpaced groups.

Adult↗
PubMed1985

Aggravation of myocardial ischaemia by nifedipine.

Three cases in which myocardial ischaemia was possibly precipitated by the administration of nifedipine are reported. It is suggested that the initial administration of nifedipine should be undertaken with caution in patients with unstable ischaemic heart disease.

Coronary Disease↗