Effect of intravenous fructose-1,6-diphosphate on myocardial contractility in patients with left ventricular dysfunction.

STUDY OBJECTIVE: To examine the effects of fructose-1,6-diphosphate on myocardial performance using nuclear scintigraphy. DESIGN: Prospective, randomized, single-blind, parallel study. SETTING: Urban teaching hospital clinical research center. PATIENTS: Individuals with New York Heart Association functional class II-III heart failure (mild to moderate). INTERVENTIONS: Subjects received either intravenous fructose-1,6-diphosphate 125 mg/kg or normal saline 1.3 ml/kg every 12 hours over 10 minutes for four consecutive doses. Left ventricular performance was assessed by radionuclide ventriculography at baseline and within 60 minutes after the fourth infusion. Vital signs were monitored throughout the study period. MEASUREMENTS AND MAIN RESULTS: Fructose-1,6-diphosphate resulted in a modest 7% increase in left ventricular ejection fraction (p < 0.05). Peak ejection rate and peak diastolic filling rate did not change significantly. There were no changes in blood pressure or heart rate with either fructose-1,6-diphosphate or placebo. CONCLUSIONS: Fructose-1,6-diphosphate produces a modest but significant increase in left ventricular ejection fraction in patients with mild to moderate heart failure.

Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects.

The capability of pravastatin and lovastatin, HMG-CoA reductase inhibitors likely to be taken chronically for hypercholesterolemia, to cross the blood-brain barrier was investigated in normal male volunteers. Lovastatin, which is lipophilic, was detected in cerebrospinal fluid (CSF) at concentrations that may have a pharmacologic effect. Pravastatin, which is hydrophilic, was not detected in CSF. It is concluded that pravastatin may have less potential for causing CNS-related side effects than lovastatin.

An in vitro method which assesses corneal epithelial toxicity due to antineoplastic, preservative and antimicrobial agents.

We developed an in vitro model for studying the cytotoxicity of pharmacologic agents on corneal epithelium employing 3H-thymidine incorporation. Primary rabbit corneal epithelial cell cultures were established, and the cells plated prior to each experiment. 3H-thymidine incorporation was measured after the addition of drug or vehicle to these confluent cells, and dose-response curves were generated. Marked inhibition of 3H-thymidine incorporation was reached at chemotherapeutic concentrations achieved clinically for cytosine arabinoside (10(-7) M), methotrexate (10(-3) M), and 5-fluorouracil (10(-6) M). A 10(-4) M concentration of 2-deoxycytidine, a naturally occurring competitive inhibitor of cytosine arabinoside, protected cells up to a concentration of 10(-5) M. We utilized these data to undertake an in vivo prophylaxis study in 13 leukemia patients receiving high-dose iv cytosine arabinoside. Topical deoxycytidine 10(-4) M and 1% prednisolone phosphate, given 12 hours prior to the start of antileukemic therapy, were effective in reducing symptoms and signs of keratitis; both were better than historical placebo-treated eyes. Ophthalmic preservatives were studied in vitro at concentrations used clinically: benzalkonium chloride (BAC) (0.004-0.02%) was the most toxic, thimerosal (TMS) (0.001-0.004%) intermediate, and chlorobutanol (CHB) (0.2-0.5%) the least toxic. Antiviral agents (final concentration) included: trifluridine (TFT) (1.0%), ethyldeoxuridine (EDU) (2.0%), and idoxuridine (IDU) (0.1%). Dose but not time-dependent concentrations of these 3 agents were noted to cause toxicity; however, (E)-5(2-bromovinyl)-2'-deoxyuridine (BVDU) (0.1%) was non-toxic. Similarly, tobramycin and amikacin were significantly less toxic than gentamicin and neomycin in this system. These in vitro cytotoxicity data correlate well with previous in vivo and pre-clinical corneal epithelial toxicity studies. Our model may be useful in the toxicologic study of future topical ophthalmic agents.

Magnetic resonance imaging of the heart.

Magnetic resonance (MR) has noninvasively imaged the proximal coronary arteries, areas of infarction, and a variety of congenital heart lesions. Further technical improvement may extend cardiac MR from the realm of research to clinical utility.

Gated magnetic resonance imaging of the normal and diseased heart.

Gated cardiac magnetic resonance (MR) images were obtained in two normal volunteers and 21 adults with a variety of cardiovascular abnormalities. The images were correlated with data from clinical examinations, electrocardiograms, and cardiac catheterization. Gated cardiac images were superior to nongated images. Combined cardiac and respiratory gated images were superior to images obtained with cardiac gating only, but acquisition time was longer. Portions of the coronary arteries were visualized in seven of 23 examinations (30%), and subacute and old myocardial infarcts were seen in five of nine patients (55%) as areas of thinned myocardium. No signal changes were observed in the patients with subacute infarctions or the patient with myocarditis. Coronary atherosclerotic lesions were not visualized in any of the patients. Normal cardiac anatomy (chambers, valves, and papillary muscles) was well visualized. Examples of aortic stenosis and atherosclerosis of the abdominal aorta are shown.

Identification of an ATP-activated endopeptidase from rat kidney which catalyzes cleavage of parathyroid hormone to fragments identical to those produced in the rat kidney in vivo.

An endopeptidase catalyzing cleavage of parathyroid hormone to specific C-terminal and N-terminal fragments was identified in a partially purified membrane fraction from rat kidney. Fractionation on sucrose gradient showed that this activity is present primarily in a light membrane fraction rather than in the basal-lateral membranes, or in the classic lysosomal fraction. The endopeptidase can be extracted from the membranes by freezing and thawing, it has an acid pH optimum, and it catalyzes production of specific fragments of PTH. The major C-terminal fragment produced has its N-terminus at residue 39 of the native hormone. This fragment is identical to the primary PTH fragment found in kidney tissue following injection of iodinated PTH into the systemic circulation of rats (D'Amour et al., 1979). Finally, the cleavage of PTH by this acid endopeptidase is activated by physiological concentration of ATP (10(-4) - 10(-3)M). These results suggest that this enzyme may be involved in PTH catabolism by the kidney, that it may be located in a specialized cell fraction and that hormone catabolism may be regulated by the energy status of the cell.

Specific cleavage of bovine parathyroid hormone catalyzed by an endopeptidase from bovine kidney.

Cleavage of parathyroid hormone (PTH) is catalyzed by an endopeptidase associated with a partially purified membrane preparation from bovine kidney cortex. This enzyme was found to have an acid pH optimum and to be easily extracted from the membranes by a single freeze-thaw cycle. The cleavage is remarkable in that it appears to be restricted to a small region of the PTH peptide chain, generating fragments which are not further degraded. The dominant products are a large fragment, COOH-terminal in origin, and a small fragment from the NH2 terminus. The small fragment is biologically active and its activity establishes that it contains at least the first 29 amino acids in PTH. The large fragment has no biological activity. The cleavage of PTH was demonstrated both with iodinated PTH and with unlabeled hormone by immunoassay and by labeling the large fragment after its production. Microsequencing of the large fragment showed that, in fact, two products are produced: one with its NH2 terminus at position 38 of PTH and one with its NH2 terminus at position 35. These fragments are remarkably similar to those generated in both the liver and the kidney in vivo.

Innominate aterial arteriovenous fistula complicating retrograde brachial arterial catheterization.

Arteriovenous fistula of the innominate artery occurred in a patient 3 weeks after retrograde brachial arterial catheterization was performed 1 day before aortocoronary bypass surgery. Intramural dissection was noted at catheterization, and a mediastinal hematoma at operation. Exploration of the hematoma in the course of catheterization might have prevented the arteriovenous fistula, which necessitated a second operation 3 weeks after the first. To our knowlege this complication of retrograde brachial catheterization has not previously been described. We recommend that known injuries to cervical or thoracic arteries occurring just before operations requiring extracorporeal circulation be explored to prevent late complications. Recent injuries to the cervical and thoracic arteries that are not acessible to external compression should be exposed and treated during sternotomy to prevent late complications if heparinization is contemplated.

Management of aortocaval fistula due to abdominal aortic aneurysm.

Anasarca and intractable congestive heart failure were the presenting signs of an abdominal aortic aneurysm with aortocaval fistula. Management with careful monitoring of cardiovascular function using a Swan-Ganz catheter before, during, and after surgery resulted in an uneventful recovery.

Analysis of radiohippuran renogram by subtraction of extrarenal radioactivity.

A method is presented for the simple, non-computerized analysis of the radiohippuran renogram by subtraction of the extrarenal radioactivity as monitored simultaneously by a detector centered over the manubrium sterni. This method requires the application of a calibration factor, relating the level of radioactivity recorded by the sternal detector to that over each kidney area at the end point of the phase of initial rise on each side separately. The results in 15 normal individuals showed a narrow range of values, indicating a high degree of resolution. Verification of the basis of this method of analysis was obtained by accounting for all of the counting rate as extrarenal sources in the tracings of nephrectomized subjects. A further advantage is that the tracing recorded by the sternal detector may be used to calculate renal blood flow.

Right ventricular infarction with tricuspid insufficiency and chronic right heart failure.

A patient with chronic right heart failure and probable tricuspid insufficiency associated with an inferior myocardial infartion is described. Angiograms demonstrated total occlusion of the right coronary artery at its origin, a patent venous bypass graft to the mid-right coronary artery and hypokinesia of the inferior wall of both the right and left vebtricles. Clinical data indicated a greater impairment of right than of left ventricular function. It is proposed that infarction of the right ventricle resulted in chronic right heart failure and tricuspid insufficiency.