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PubMed1985

Early positive technetium-99m stannous pyrophosphate images as a marker of reperfusion after thrombolytic therapy for acute myocardial infarction.

Fourteen patients with transmural acute myocardial infarction (AMI) were treated with intravenous streptokinase a mean of 4 +/- 1 hours after chest pain and underwent technetium-99m stannous pyrophosphate (Tc-99m-PPi) imaging 7 +/- 2 hours after the onset of chest pain. The early Tc-99m-PPi images were obtained to test the hypothesis that an early, strongly abnormal Tc-99m-PPi image suggests reperfusion. Eleven of 14 patients had early peaking (within 16 hours) serum creatine kinase isoenzyme levels (CK-B) at a mean of 11 +/- 3 hours. Ten of 14 patients had 3+ or 4+ acute Tc-99m-PPi images. Eight of 11 patients had patent infarct-related vessels at cardiac catheterization 15 days after AMI. One patient who had both an early positive Tc-99m-PPi image and CK-B peak level had an occluded infarct-related artery at catheterization. Acute left ventricular (LV) ejection fraction (EF) by radionuclide ventriculography was compared with LVEF on day 15, and improved from 0.37 +/- 0.13 to 0.50 +/- 0.16 (p = 0.004) in the 10 patients with strongly positive acute Tc-99m-PPi images. LVEF also improved from 0.37 +/- 0.12 to 0.49 +/- 0.15 (p = 0.003) in the 11 patients with early peaking serum CK-B values. Three patients without evidence of reperfusion failed to improve the LVEF from the initial value to the one obtained at hospital discharge. Six control patients had acute Tc-99m-PPi images 10 +/- 2 hours after chest pain; none had strongly positive acute Tc-99m-PPi images, and the mean time to peak CK-B was 19 +/- 5 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac Catheterization↗

PubMed1987

Comparison of early myocardial technetium-99m pyrophosphate uptake to early peaking of creatine kinase and creatine kinase-MB as indicators of early reperfusion in acute myocardial infarction.

The value of technetium-99m pyrophosphate (Tc-99m-PYP) scintigraphy as an indicator of reperfusion 2.8 to 8 hours after the onset of symptoms of acute myocardial infarction was compared with the value of early peak creatine kinase (CK) and CK-MB release within 16 hours after the onset of symptoms. In 29 patients who received thrombolytic therapy, recanalization was seen (group 1) and in 7 it was not (group 2). In 23 patients (79%) in group 1 scintigraphic findings were positive and in all 7 in group 2 they were negative. In 15 patients (52%) in group 1 and 1 patient (14%) in group 2, CK reached its peak level within 16 hours. In 20 patients (69%) in group 1 and 3 (43%) in group 2 the CK-MB level reached a peak within 16 hours. The sensitivity, specificity and predictive accuracy of positive results of early Tc-99m-PYP scintigraphy in predicting the reperfusion were 79%, 100% and 83%. These values are significantly higher than or similar to those of early peaking of CK and CK-MB release. In contrast to measurements of enzyme release, reperfusion data for Tc-99m-PYP scintigraphy are available immediately after thrombolytic therapy. Therefore, early Tc-99m-PYP scintigraphy (3 to 8 hours after onset of symptoms) is valuable as a noninvasive technique for early diagnosis of reperfusion.

Aged↗

PubMed1988

Usefulness of early positive technetium-99m stannous pyrophosphate scan in predicting reperfusion after thrombolytic therapy for acute myocardial infarction.

To test the hypothesis that scans with technetium-99m pyrophosphate (Tc-99m-PPi) are positive when performed early after successful thrombolytic therapy for acute myocardial infarction (AMI), 16 consecutive patients with AMI who received thrombolytic therapy within 5 hours after the onset of chest pain were studied. Patients were included if chest pain lasted for greater than 30 minutes, was unresponsive to sublingual nitroglycerin and was associated with at least 0.2 mV ST-segment elevation in at least 2 contiguous electrocardiographic leads. All patients received 1.5 million IU of streptokinase intravenously, a mean of 195 +/- 99 minutes after onset of chest pain. Tc-99m-PPi scans and coronary cineangiograms were recorded 491 +/- 156 minutes and 518 +/- 202 minutes, respectively, after the onset of symptoms. Effective reperfusion was present in 10 patients, 6 of whom had positive Tc-99m-PPi scans (sensitivity of 60% to detect reperfusion). Of the 6 patients without effective reperfusion, 3 had positive Tc-99m-PPi scans (specificity of 50%, p greater than 0.05). Analysis of the data using various definitions of effective reperfusion or artery patency yielded similar results. Thus, our findings indicate that early AMI scanning with Tc-99m-PPi does not accurately detect the presence or absence of reperfusion in patients with AMI after treatment with intravenous streptokinase. At this time, coronary cineangiography is the only reliable method to detect reperfusion promptly after thrombolytic therapy.

Aged↗

PubMed1991

Relation of technetium-99m pyrophosphate accumulation to time interval after onset of acute myocardial infarction as assessed by a tomographic acquisition technique.

Technetium-99m pyrophosphate (Tc-99m PYP) myocardial scintigraphy was performed in 110 clinically stable patients with acute or healed acute myocardial infarction (AMI). Tomography was performed 12 hours to 7 days (group A), 7 to 30 days (Group B), 1 to 6 months (Group C) and after greater than 6 months (group D) after AMI. All 40 patients in group A, 9 of 31 in group B, 1 of 22 in group C, and no patient (0 of 17) in group D had a pathologic Tc-99m PYP tomogram. Relative Tc-99m PYP accumulation within the area of infarction was measured as infarct zone to blood pool ratio, which decreased significantly (p less than 0.001) from group A (1.54 +/- 0.39) to group B (0.89 +/- 0.24), group C (0.8 +/- 0.19) and group D (0.76 +/- 0.13). These data were confirmed by sequential scintigraphy in 17 patients. It is concluded that a persisting Tc-99m PYP uptake is rarely found greater than 1 month after AMI using tomographic imaging techniques in clinically stable patients with coronary artery disease. Positive results on Tc-99m PYP tomography are a reliable indicator of AMI. Thus, Tc-99m PYP tomography is not only a sensitive but also a specific imaging technique for AMI, which might be especially useful for diagnosis of reinfarction.

Adult↗

PubMed1993

Comparison in acute myocardial infarction of anisoylated plasminogen streptokinase activator complex versus heparin evaluated by simultaneous thallium-201/technetium-99m pyrophosphate tomography.

In a subgroup of 45 patients with acute myocardial infarction (AMI) from the German multicenter trial of anisoylated plasminogen streptokinase activator complex (APSAC) (n = 20) versus heparin (n = 25), simultaneous thallium (TI)-201 technetium (Tc)-99m pyrophosphate (PYP) tomography was initiated to elucidate a possible benefit of APSAC over heparin. Findings in the 2 treatment groups were similar with respect to TI-201 defect score, relative scintigraphic infarct size, and in keeping with the main group coronary artery patency, global ejection fraction and maximal creatine kinase level. However, 2 different TI-201/Tc-99m PYP accumulation patterns within the area of infarction (homogeneous, group A; inhomogeneous, group B) were identified. Both treatment groups were similar with regard to the frequency of the homogeneous and inhomogeneous pattern. In comparing the 2 accumulation patterns, creatine kinase peaked earlier in group A than in group B, and global left ventricular ejection fraction was significantly higher in group A than in group B. In Group A, 30 of 31 patients and in group B 7 of 11 patients had a patent infarct-related vessel (p < 0.025). TI-201 defect score was lower in group A than in group B. Likewise, relative size of the infarction as determined from Tc-99m PYP images was significantly lower in group A than in group B. Fifteen patients experienced cardiogenic shock or severe heart failure. Patients in group B had a higher incidence of these in-hospital complications than patients in group A (92 vs 12%, p < 0.0005). Scintigraphic infarct size and TI-201 defect score were greater in patients with the aforementioned clinical events.(ABSTRACT TRUNCATED AT 250 WORDS)

Anistreplase↗

PubMed1993

Diagnosis of right ventricular infarction by overlap images of simultaneous dual emission computed tomography using technetium-99m pyrophosphate and thallium-201.

The validity of dual energy single-photon emission computed tomography (SPECT) with technetium-99m pyrophosphate (Tc-99m PPi) and thallium-201 for the diagnosis of right ventricular (RV) infarction, and the clinical features of RV infarction, were investigated in 190 patients with acute myocardial infarction. Diagnosis of RV infarction was performed by Tc-99m PPi accumulation in the RV myocardium on thallium-201 and Tc-99m PPi over-lay images at the dual SPECT with simultaneous imaging taken 2 to 9 days after the onset of myocardial infarction. Thirty RV infarctions were found among the 190 patients with left ventricular infarction (15.8%): 29 (97%) in association with the inferior and 1 (3%) with the lateral infarction. Tc-99m PPi accumulation was mostly observed in the posterior wall of the right ventricle. A total occlusion or a severe stenosis of the right coronary artery was demonstrated angiographically in 92% of the patients with RV infarction. The prevalence of RV infarctions was significantly lower in patients who achieved successful early reperfusion than in those who did not (26.7 vs 68.4%, respectively, p < 0.01). However, a successful early reperfusion therapy could not significantly decrease the rate of RV involvement in patients without significant collateral flow (p < 0.01). Thus, dual isotope SPECT with Tc-99m PPi and thallium-201 can be used as a reliable method for the diagnosis of RV infarction.

Aged↗

PubMed1987

A method for the determination of 5-phosphoribosyl 1-pyrophosphate concentrations in erythrocytes using high-performance liquid chromatography.

A method for the measurement of erythrocyte 5-phosphoribosyl 1-pyrophosphate (PP-ribose-P) using HPLC is described. Inosinic acid formed from the enzyme-catalyzed reaction of hypoxanthine and PP-ribose-P using partially purified hypoxanthine-guanine phosphoribosyltransferase is measured after chromatography on an ion-exchange column (Partisil 10 SAX). The average recovery of PP-ribose-P added to erythrocytes was 96.6%. Normal values found were 1.3 +/- 0.6 nmol PP-ribose-P/ml packed RBC (20 individuals). Replication experiments gave a coefficient of variation of 4.4%. Elevated levels in the range 4.4-7.9 nmol PP-ribose-P/ml packed RBC were found in four patients with gout and partial deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase.

Chromatography, High Pressure Liquid↗

PubMed1987

A coupled optical assay for adenine phosphoribosyltransferase and its extension for the spectrophotometric and radioenzymatic determination of 5-phosphoribosyl-1-pyrophosphate in mixtures and in tissue extracts.

A reliable assay was developed to characterize crude cell homogenates with regard to their adenine phosphoribosyltransferase activities. The 5-phosphoribosyl-1-pyrophosphate (PRPP)-dependent formation of AMP from adenine is followed spectrophotometrically at 265 nm by coupling it with the following two-stage enzymatic conversion: AMP + H2O----adenosine + Pi (5'-nucleotidase); adenosine + H2O----inosine + NH3 (adenosine deaminase). The same principle was applied to develop a spectrophotometric and a radioenzymatic assay for PRPP. The basis of the spectrophotometric assay is the absorbance change at 265 nm associated with the enzymatic conversion of PRPP into inosine, catalyzed by the sequential action of partially purified adenine phosphoribosyltransferase, commercial 5'-nucleotidase, and commercial adenosine deaminase, in the presence of excess adenine. In the radiochemical assay PRPP is quantitatively converted into [14C]inosine via the same combined reaction. Tissue extracts are incubated with excess [14C]adenine. The radioactivity of inosine, separated by a thin-layer chromatographic system, is a measure of PRPP present in tissue extracts. The radioenzymatic assay is at least as sensitive as other methods based on the use of adenine phosphoribosyltransferase. However, it overcomes the reversibility of the reaction and the need to use transferase preparations free of any phosphatase and adenosine deaminase activities.

Adenine Phosphoribosyltransferase↗

PubMed1976

Preparation of Escherichia coli pyruvate oxidase utilizing a thiamine pyrophosphate affinity column.

An improved procedure is reported for the purification of Escherichia coli pyruvate oxidase (pyruvate:ferricytochome b1 oxidoreductase, EC 1.2.2.2), a peripheral membrane flavo-enzyme, which is much more reproducible and requires considerably less time than the original purification scheme. The key element in this protocol is a new Sepharose-based affinity resin designed for the isolation of thiamine pyrophosphate-requiring enzymes. The synthesis, partial characterization, and use of two such affinity resins is described. Pyruvate oxidase is a pure, homogenous protein as it is eluted from the affinity resin. The enzyme is a tetramer with a subunit molecular weight of approx. 60 000. The subunits appear to be identical. The isoelectric point of pyruvate oxidase is 5.6.

Chromatography, Affinity↗

PubMed1976

The effect of ribose 5-phosphate and 5-phosphoribosyl-1-pyrophosphate availability on de novo synthesis of purine nucleotides in rat liver slices.

The effect of increasing cellular ribose 5-phosphate (ribose-5-P) availability by methylene blue-induced acceleration of the oxidative pentose phosphate pathway on the rate of 5-phosphoribosyl-1-pyrophosphate (P-ribose-PP) generation, was studied in slices of rat liver at varying Pi concentration. It was found that at Pi concentration prevailing in the tissue of extracellular physiological Pi concentration, ribose-5-P availability is saturating for P-ribose-PP generation, as gauged by the rate of adenine incorporation into tissue nucleotides. The effect of altering P-ribose-PP availability on the rate of de novo purine production gauged by the rate of formate incorporation into purines, was also studied. It was found that the physiological P-ribose-PP concentration in rat liver tissue is limiting for purine synthesis de novo. Depletion of cellular P-ribose-PP, achieved by increase of P-ribose-PP consumption, decelerated purine synthesis, while increase of P-ribose-PP availability, achieved by activation of P-ribose-PP synthetase occurring at elevated Pi concentration, resulted in acceleration of purine synthesis.

Animals↗

PubMed1982

Effect of L-glutamine antagonists on 5-phosphoribosyl 1-pyrophosphate levels in P388 leukemia and in murine colon adenocarcinomas in vivo.

The intratumoral content of 5-phosphoribosyl 1-pyrophosphate (PRPP) and the activity of the enzymes anabolizing and catabolizing the sugar phosphate were determined following i.p. administration of an LD10 dose of an L-glutamine antagonist or saline to tumor-bearing animals. Elevation of PRPP pool size following administration of L-[alpha S,5S]-alpha-amino-3-chloro-4,5-dihydro-5-isopazoleacetic acid (NSC-163501) (AT-125) was maximal at 8 hr and returned to pretreatment levels by 24 hr. In P388 leukemia, dose for dose, at 4 hr, 6-diazo-5-oxo-L-norleucine (NSC-7365) (DON) was the most potent of the L-glutamine antagonists in elevating basal PRPP pool size (50% above control) followed by AT-125 and azaserine, 300 and 100% above control respectively. Moreover, such augmentation in PRPP pool size preferentially affected P388 tumor rather than the small intestine. Following i.p. administration of LD10 doses of AT-125, DON and azaserine, the specific activities of PRPP anabolizing and catabolizing enzymes were determined. A significant inhibition of PRPP amidotransferase was demonstrated with DON and AT-125 (P less than 0.05), and no inhibition with azaserine. A similar modulation of PRPP pool size demonstrated in vivo following administration of 250 mg/kg of ART-125 in mice bearing colonic adenocarcinoma lines. It was suggested that a significant increase of PRPP pool size might cause the possible synergism of a selected L-glutamine antagonist and 5-fluorouracil as reported after the appropriately scheduled administration of methotrexate and 5-fluorouracil.

Adenocarcinoma↗

PubMed1987

Effects of uridine diphosphoglucose (UDPG) infusion on 5-phosphoribosyl pyrophosphate (PRPP) levels of mouse tissues.

Uridine diphosphoglucose (UDPG) has been shown to have tissue-specific effects that have proved to be of clinical value in the treatment of some liver ailments. In an effort to determine something about the mechanism of action, we investigated the effect of UDPG on the levels of 5-phosphoribosyl pyrophosphate (PRPP) and PRPP synthetase in mouse liver, spleen and transplanted tumors. Three strains of mice were studied with and without tumors under various experimental conditions. Balb/c mice were infused with UDPG intraperitoneally at levels of 0.16 g/kg/day (0.28 mmole) to 1.6 g/kg/day (2.8 mmoles) for 5 days. At the low dose rate the PRPP level in the liver was found to increase 3-fold. A slight increase was noted in the activity of PRPP synthetase. However, when the UDPG was infused at a level of 2.8 mmoles/kg/day, the increases in both the synthetase and PRPP were inhibited. Both CRF1 and CD8 mice were less sensitive to the effects of UDPG per se. However, the high level of PRPP in the tumors they carried was greatly affected by the UDPG infusion. The tumor-specific inhibition of PRPP suggests that this action might prove to be useful combination therapy with inhibitors of purine and pyrimidine nucleotide synthesis in various rescue regimens. UDPG was found to enter cells intact before it was cleaved into glucose phosphate and UMP. The fact that UDPG was also found in the membrane fraction suggests that either there is a specific transport mechanism or UDPG exerts its action via interaction with the cell membrane.

Adenine↗

PubMed1975

An improved method for the determination of 5-phosphoribosyl 1-pyrophosphate.

A spectrophotometric method for the determination of 5-phosphoribosyl 1-pyrophosphate (PRPP) is presented which shows several advantages in comparison to the radiochemical techniques, such as a relatively simple, rapid and less expensive procedure. This technique has been used to evaluate PRPP content in erythrocytes, leukocytes and lymphocytes of normal subjects and individuals with partial hypoxanthine guanine phosphoribosyltransferase (EC 2.4.2.8) deficiency. The results obtained proved to be completely reliable in both groups of subjects examined, with values of PRPP similar to those observed by radiochemical techniques.

Adult↗

PubMed1977

A simple and sensitive method for estimating the concentration and synthesis of 5-phosphoribosyl 1-pyrophosphate in red blood cells.

A method is presented for the determination of 5-phosphoribosyl 1-pyrophosphate (PRPP), which is based on the release of 14CO2 from [carboxyl-14C]-orotic acid by the consecutive action of orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase. The assay is simpler and less time-consuming than most methods currently employed and is equally sensitive. The method proved to be suitable for measuring low concentrations of PRPP such as found in human erythrocytes and fibroblasts. An increased PRPP concentration was observed in erythrocytes from patients with partial or complete deficiency of hypoxanthine-guanine phospho-ribosyltransferase. frp, sp,e (but not all) gouty patients and from a patient with deficiency of purine nucleoside phosphorylase. PRPP synthetase activity was measured with a method similar to the assay for PRPP. In erythrocytes with an increased PRPP concentration, PRPP synthetase activity was found to be normal at both optimal and suboptimal substrate concentrations.

Carbon Radioisotopes↗

PubMed1984

Fluctuations in phosphoribosyl pyrophosphate levels in monolayer tumor cell lines. Effects of drugs.

The concentration of PRPP (phosphoribosyl pyrophosphate) measured in tumor cells grown in monolayer showed a large variation with the various harvesting methods examined, including trypsinization. This variation could be reduced by a 1-h incubation of trypsinized cells as a suspension in Dulbecco's medium. After this preincubation these cell suspensions were suitable for the study of modulation of PRPP. One microM methotrexate caused a 2-3-fold increase and 1 mM N- phosphonoacetyl -L-aspartate a slight increase, but inosine and deoxyinosine drastically reduced PRPP concentrations. 5-Fluorouracil had no effect. This study demonstrates that metabolic parameters such as PRPP concentrations can be studied conveniently in suspensions of cells which are commonly cultivated as monolayers.

Animals↗

PubMed1989

A common structural motif in thiamin pyrophosphate-binding enzymes.

The amino acid sequences of a wide range of enzymes that utilize thiamin pyrophosphate (TPP) as cofactor have been compared. A common sequence motif approximately 30 residues in length was detected, beginning with the highly conserved sequence -GDG- and concluding with the highly conserved sequence -NN-. Secondary structure predictions suggest that the motif may adopt a beta alpha beta fold. The same motif was recognised in the primary structure of a protein deduced from the DNA sequence of a hitherto unassigned open reading frame of Rhodobacter capsulata. This putative protein exhibits additional homology with some but not all of the TPP-binding enzymes.

Amino Acid Sequence↗

PubMed1985

The concentration of 5-phosphoribosyl 1-pyrophosphate in monolayer tumor cells and the effect of various pyrimidine antimetabolites.

5-Phosphoribosyl 1-pyrophosphate (PRPP) was determined in several murine and human cancer cell lines grown in monolayer, and harvested by trypsinization. For all cell lines a large variation in the PRPP concentration (5-1300 pmol/ 10(6) cells was found. A 1-hr incubation in Dullbecco's medium reduced the variation in PRPP concentration. After this incubation the highest concentration was found in the murine B16 melanoma cell line (about 200 pmol/10(6) cells). The human melanoma cell lines IGR3 and M5 and the human colon carcinoma cell line WiDr contained about 100 pmol/10(6) cells. After this preincubation of 1-hr these cell suspensions were used to study the effect of several antimetabolites on PRPP concentration. A 2-hr incubation with 1mM N-(phosphonacetyl)-L-aspartate (PALA) increased the PRPP concentration only in M5 cells, whereas methotrexate caused an increase in all cell lines. When 5-fluorouracil (5FU) was added, no significant decrease was found in any cell line. Addition of 5FU after a 2-hr preincubation with PALA resulted in a lower concentration in B16, M5 and WiDr cells. The prodrug, 5-fluoro-5' deoxyuridine altered the PRPP concentration only in in WiDr cells when it was added after PALA. The activity of the 5FU metabolizing enzyme orotate phosphoribosyl transferase was comparable in B16, M5 and WiDr cells, but much lower in IGR3 cells.

Animals↗

PubMed1988

Studies on the nature of thiamine pyrophosphate binding and dependency on divalent cations of transketolase from human erythrocytes.

1. The binding kinetics for [35S]thiamine pyrophosphate to transketolase and the dependency of transketolase on divalent cations for activity were investigated. 2. With Scatchard analysis, dissociation constant (Kd) and n value were calculated to be 0.2 x 10(-6) M and 0.66 respectively. 3. The activity of the reconstituted enzyme increased in the order of Co2+ less than Mn2+ less than Ca2+ less than Mg2+. The native transketolase contained Mg2+ in its molecular structure.

Binding Sites↗