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Biomedical subjects

J A Bianco

Publications and source records attributed to J A Bianco.

At least 19 recordsLinked to original sources
PubMed1995

Imaging of acute myocardial infarction and reperfusion.

During the last 20 years there has been a large amount of investigation designed to determine what is the best way of imaging acute myocardial infarction (AMI) using radiopharmaceuticals. 99mTc pyrophosphate is ideal for cases where the clinical diagnosis cannot be made but it is insensitive to detect subendocardial AMI and is taken up by reversibly-injured myocytes. Antimyosin antibody imaging is specific for AMI but it is flow-dependent at low myocardial flows and it distributes in a nonuniform way in reperfused infarcts requiring high nuclear imaging (SPECT or PET) spatial resolution for proper measurement. 18F fluorodeoxyglucose (FDG) is taken up by viable cells but likely by macrophages too, in the core of AMI. 99mTc glucarate has not been investigated in detail but this sugar analog is more accurate than FDG in AMI. 99mTc sestamibi has been extensively used for AMI measurement but SPECT quantitation of transmural infarcts has not been achieved. Unresolved issue is imaging of AMI during reperfusion where there is widespread microvascular injury and capillary plugging.

Animals↗
PubMed1994

Phase Ib trial of pentoxifylline and ciprofloxacin in patients treated with interleukin-2 and lymphokine-activated killer cell therapy for metastatic renal cell carcinoma.

The dose of interleukin 2 (IL-2) which can be administered to cancer patients is limited largely by a capillary leak syndrome. Pentoxifylline (PTX) is a methylxanthine which reduces IL-2 toxicity in animals. Ciprofloxacin (Cipro) modifies the metabolism of methylxanthines and, when coadministered with PTX, increases levels of PTX and certain of its metabolites. We conducted a phase Ib trial in patients receiving IL-2 and lymphokine-activated killer cell (LAK) cell therapy for metastatic renal cell carcinoma to identify the maximum tolerated dose of PTX which could be coadministered with Cipro in this setting. Eighteen patients received IL-2 (Roche) by continuous infusion at 6 x 10(6) units/m2/day on days 1-5 and underwent leukapheresis on days 7-9. LAK cells were infused on days 12-14. IL-2 was administered at 2 x 10(6) units/m2/day on days 10-20. Cohorts of patients received PTX at 2.5 (n = 3), 3.1 (n = 6), 3.9 (n = 6), and 4.9 (n = 3) mg/kg by 30 min i.v. infusion every 4 h on days 0-5 and 10-20 and Cipro (500 mg p.o. every 12 h) on days 1-5 and 10-20. Toxicity was compared with that observed in 33 historical control patients who received 37 cycles of an identical regimen of IL-2/LAK without PTX/Cipro. PTX at 2.5-3.9 mg/kg and Cipro were well tolerated. The maximum tolerated dose of PTX was 3.9 mg/kg. Dose-limiting emesis (n = 1) and atrial fibrillation (n = 2) occurred at 4.9 mg/kg and were reversible. Two complete, one partial and one minor, responses were observed. Patients treated with 3.9 mg/kg PTX received 95.0% of the planned dose of IL-2 as compared to 72.8% in the control patients (P < 0.025), primarily due to a lower incidence of azotemia and metabolic acidosis in PTX/Cipro recipients than had been seen in the historical control patients. The results of this study demonstrate that PTX/Cipro can be administered to patients receiving IL-2/LAK without apparent loss of therapeutic efficacy. Moreover, PTX/Cipro recipients exhibited less toxicity than historical controls. Therefore, treatment with PTX/Cipro may allow delivery of higher doses of IL-2, which might induce more responses in IL-2-responsive tumors and regression of tumors unresponsive to conventional doses of IL-2.

Adult↗
PubMed1994

Protection from endotoxic shock in mice by pharmacologic inhibition of phosphatidic acid.

Certain phosphatidic/plasmanic/plasmenic acid (PA) species function as lipid intermediates in cell activation and may function directly as intracellular signaling molecules. PA can also be dephosphorylated to 1,2-diradyl-sn-glycerol by phosphatidate phosphohydrolase. Treatment of various cell types, including murine P388 monocytic leukemia cells, with bacterial lipopolysaccharide rapidly stimulates large increases in PA and PA-derived diradylglycerol. Pentoxifylline, 1-(5-oxohexyl)-3,7-dimethylxanthine, inhibits lipopolysaccharide-stimulated formation of PA in P388 cells at high concentrations (IC50 = 500 microM). Lisofylline [1-(5R-hydroxyhexyl)-3,7-dimethylxanthine] is a unique metabolite of pentoxifylline in humans and is > 800-fold more active as an inhibitor of PA formation than pentoxifylline (IC50 = 0.6 microM). Lisofylline does not inhibit lipopolysaccharide-induced activation of phosphatidylinositol-specific phospholipase C and generation of phosphatidylinositol-derived diradylglycerol. Lisofylline but not pentoxifylline protects BALB/c mice from endotoxin lethality when administered 4 hr after lipopolysaccharide. This protective effect is independent of either agent's effect on suppression of plasma tumor necrosis factor alpha. These data suggest that inhibitors of PA formation may have significant clinical potential in the treatment of sepsis and septic shock.

Acyltransferases↗
PubMed1994

CT-1501R selectively inhibits induced inflammatory monokines in human whole blood ex vivo.

The effect of (R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine (CT-1501R; the nonproprietary name for CT-1501R approved by the United States Name Council is lisofylline), an inhibitor of second messenger signaling through phosphatidic acid, on release of endogenous mediators important in the systemic inflammatory response syndrome (SIRS) was studied using the human whole blood ex vivo assay system. Human blood was stimulated with various endotoxin preparations, zymosan, or protein A, and the levels of secreted monokines were measured by enzyme-linked immunosorbent assay. CT-1501R inhibited tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and IL-6 release in a dose-dependent manner and was active with all stimuli tested including Salmonella and Escherichia coli-derived endotoxin, endotoxin from both rough and smooth E. coli strains, as well as zymosan and protein A. CT-1501R inhibited monokine release by approximately 50% at 200 microM and 30% at 50 microM and was independent of the relative potency of stimulus. CT-1501R also inhibited IL-1 alpha or IL-1 beta induction of either TNF-alpha or IL-1 beta and inhibited the synergistic effects of stimulation with both human IL-1 beta and murine TNF-alpha on release of human TNF-alpha. Inhibition of monokine release following stimulation with monokine(s) was, in general, greater than that achieved with lipopolysaccharide (LPS) stimulation. Northern blot analysis showed decreased mRNA accumulation of TNF-alpha and IL-1 beta in CT-1501R-treated samples following LPS stimulation suggesting that CT-1501R acts at least in part, at the pretranslational level. In contrast, CT-1501R does not inhibit LPS-stimulated IL-8 or IL-1 receptor antagonist (IL-1ra) release in human whole blood or IL-1 alpha-induced release of PGE2 in human foreskin fibroblast cells. These data suggest that CT-1501R may be of use for clinical intervention in SIRS.

3T3 Cells↗
PubMed1994

Potential role for phosphatidic acid in mediating the inflammatory responses to TNF alpha and IL-1 beta.

Tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1 beta), and endotoxin (LPS) are potent pro-inflammatory mediators which induce multiple and diverse biological responses in a wide variety of cell types. However, these pro-inflammatory mediators also have significant overlap and redundancy in their biological effects. This suggests that there is significant diversity in second messenger signal transduction systems induced by these stimuli to explain the diversity in biological responses, as well as significant redundancy. Here we show that one such second messenger common to several proinflammatory stimuli may be phosphatidic acid (PA). Intracellular PA species, which may have intracellular signaling functions, are rapidly induced in P388 monocytic leukemia cells by TNF alpha, IL-1 beta, or LPS. These PA species vary according to the bond type (i.e., sn-1 ester vs. ether vs. vinyl ether), acyl chain length, and the degree of saturation in the sn-1 and sn-2 positions. Although PA itself may have direct second messenger activities, many of the PA species induced are converted to diacylglycerol species (DG), which are structurally distinct from the DGs generated by phosphatidylcholine-specific phospholipase C (PC-PLC). Lisofylline [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine; LSF] selectively inhibits generation of selected species of PA in P388 cells induced by TNF alpha, IL-1 beta or LPS. TNF alpha-induced sphingomyelin hydrolysis, PLC-mediated PC hydrolysis, and DG kinase-mediated PA formation or TNF alpha-induced NF-kappa B activation and apoptosis are not inhibited by LSF. LSF has a marked protective effect in a variety of acute inflammatory animal models that may be due to inhibition of this shared second messenger pathway involving PA.

Animals↗
PubMed1993

rhGM-CSF after allogeneic bone marrow transplantation from unrelated donors: a pilot study of cyclosporine and prednisone as graft-versus-host disease prophylaxis.

Cyclosporine and prednisone were administered as graft-versus-host disease (GVHD) prophylaxis to nine patients undergoing marrow transplant from HLA matched, unrelated donors. RhGM-CSF was administered at a dose of 250 micrograms/m2 daily to all patients. The median day of neutrophil recovery to > or = 500/mm3 was Day 16. Four patients developed Grade II acute GVHD and four developed Grade III acute GVHD. One patient, who survived only 25 days, did not develop GVHD at all. One patient developed systemic infection within the first 28 days after marrow infusion. Comparison of these data to a prior series of patients undergoing bone marrow transplant (BMT) from unrelated donors who were treated with rhGM-CSF along with methotrexate and cyclosporine for GVHD prophylaxis suggests that rhGM-CSF is well-tolerated, neutrophil recovery may be earlier but the severity of GVHD does not appear reduced. Selection of the GVHD prophylaxis regimen may affect the hematopoietic response to cytokine therapy. Further trials with rhGM-CSF in patients undergoing BMT from unrelated donors are required.

Adolescent↗
PubMed1992

Specific marrow ablation before marrow transplantation using an aminophosphonic acid conjugate 166Ho-EDTMP.

166Holmium ethylenediaminetetramethylene phosphonic acid (166Ho-EDTMP) is a short-lived beta-emitting radionuclide complexed to an aminophosphonate ligand that we have investigated in a canine model as a potential agent for specific marrow ablation before marrow transplantation. After intravenous injections, 166Ho-EDTMP distributed principally to bone and after 24 hours the concentrations of 166Ho-EDTMP in bone were more than 200-fold higher than in any other organ. Increasing dosages of 166Ho-EDTMP led to increasingly prolonged and severe myelosuppression, but myeloablation was not achieved. Histologic examination of recovering animals suggested that the spleen may have acted as a reservoir for circulatory hematopoietic precursors. Four splenectomized animals administered 20 to 30 mCi/kg 166Ho-EDTMP without marrow transplantation died with marrow aplasia, while four splenectomized animals administered similar dosages of 166Ho-EDTMP followed by autologous transplantation recovered. The dose-limiting toxicity of 166Ho-EDTMP appeared to be marrow stromal damage resulting in myelofibrosis, which was reversible. These results suggest that 166Ho-EDTMP can be used to specifically ablate marrow function before marrow transplantation.

Animals↗
PubMed1992

Phase II trial of recombinant human granulocyte-macrophage colony-stimulating factor in patients undergoing allogeneic bone marrow transplantation from unrelated donors.

The safety and possible efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) were evaluated in 40 consecutive patients who received transplants from unrelated donors. rhGM-CSF was administered by 2-hour daily intravenous infusion from day 0 to day 20 or day 27 after the marrow infusion. These patients were compared with 78 historical patients who received transplants from unrelated donors who did not receive rhGM-CSF. The rhGM-CSF-treated patients were older (P = .037) and were treated less frequently in laminar air flow rooms (P = .005) than were control patients. However, the rhGM-CSF-treated group had a higher proportion of "good risk" patients with chronic myelogenous leukemia in chronic phase (P = .006) than did the comparison group (P = .017), rendering comparisons of transplant-related complications not meaningful. rhGM-CSF was well tolerated and did not adversely increase the incidence of graft rejection or increase the incidence and severity of acute graft-versus-host disease. The median day the absolute neutrophil count reached 500/mm3 in patients who received rhGM-CSF was day 21, which was not different from that of historical patients. Nevertheless, the numbers of febrile days and septicemic episodes within the first 28 days in patients who received rhGM-CSF were less than in historical patients. The probability of nonrelapse mortality at 1 year in patients who received rhGM-CSF was 22%. In view of the retrospective nature of the control group, we cannot conclusively determine whether rhGM-CSF administration was beneficial. A prospective, randomized controlled study of rhGM-CSF is required to confirm these suggestive data.

Adult↗
PubMed1992

Venocclusive disease of the liver: prospective study of US evaluation.

Twenty-one bone marrow transplantation (BMT) patients were studied prospectively to determine the prevalence of sonographic hepatobiliary abnormalities and to determine if these abnormalities were associated with hepatic venocclusive disease (VOD). Baseline US was performed in all patients prior to chemoradiation therapy, with follow-up ultrasound (US) examinations at the time of BMT and 14 days and 28 days after BMT. Sonograms were reviewed for the presence of ascites, gallbladder wall thickening, hepatosplenomegaly, hepatofugal flow, hepatic vein compression, increased periportal echogenicity, and increased hepatic echotexture. The baseline scans showed 13 of 21 patients (62%) with abnormalities prior to BMT. Within 2 weeks after BMT, serial US showed interval development of hepatomegaly in five patients (three with VOD and two without), gallbladder wall thickening in one (with VOD), hepatic vein compression in two (both with VOD), hepatofugal flow in one (without VOD), and ascites in one (with VOD). US scans obtained 4 weeks after BMT in 15 of the 21 patients showed even fewer new abnormalities. No sonographic finding was strongly associated with VOD.

Adult↗
PubMed1992

Toxic epidermal necrolysis possibly linked to aztreonam in bone marrow transplant patients.

OBJECTIVE AND SETTING: After instituting aztreonam as part of antibiotic prophylaxis in bone marrow transplant (BMT) patients at the Seattle Department of Veterans Affairs Medical Center, the first two cases of toxic epidermal necrolysis (TEN) occurred in more than 250 BMT patients at this center. We have examined the possible cause-and-effect relationship between aztreonam and TEN. PATIENTS: The first patient was a 23-year-old man with acute lymphocytic leukemia receiving a BMT from a related mismatched donor. He experienced profound conjunctivitis and superficial bulla covering 60 percent of his body surface area (BSA). The second patient, a 32-year-old man with lymphoma, received a BMT from a matched unrelated donor. He exhibited lymphocytosis, acute conjunctivitis, and bullous lesions covering 60 percent of his BSA. INTERVENTIONS: Aztreonam was discontinued in both patients. The first patient was treated with pigskin grafting and the second was treated with topical silver sulfadiazine. RESULTS: Despite stabilization of symptoms, both patients eventually died of infectious complications. CONCLUSIONS: Histological data in both patients were more consistent with TEN than graft-versus-host disease (GVHD) in that dermal infiltrates were sparse or absent. The onset of cutaneous symptoms was of more acute onset than acute GVHD, and ocular complaints are uncommon in acute GVHD. Furthermore, the onset of TEN bore a closer temporal relationship to aztreonam than to other drugs administered.

Adult↗
PubMed1992

Phase I study of busulfan and cyclophosphamide in preparation for allogeneic marrow transplant for patients with multiple myeloma.

PURPOSE: To study the toxicity and potential efficacy of busulfan (BU) and cyclophosphamide (CY) as a conditioning regimen before allogeneic bone marrow transplantation (ABMT) in patients with multiple myeloma (MM). PATIENTS AND METHODS: Twenty patients with MM underwent conditioning, which was followed by ABMT from 16 HLA-identical donors, three one-antigen-mismatched donors, and one HLA A, B, D-identical unrelated donor. Four levels of BU plus CY were evaluated. RESULTS: Severe regimen-related toxicity occurred in two of five patients who received BU 16 mg/kg and CY 120 mg/kg, in none of the four patients who received BU 14 mg/kg and CY 120 mg/kg, in one of eight patients who received BU 14 mg/kg and CY 147 mg/kg, and in two of three patients who received BU 14 mg/kg and CY 174 mg/kg. Twelve of 15 (80%) assessable patients achieved a complete remission with the disappearance of M-protein and the return of normal marrow morphology. Ten patients died of complications related to the ABMT, and two patients died of progressive or relapsed MM. Overall, eight of 20 patients were alive; seven (35%) were in complete remission 190 to 1,271 days after ABMT. CONCLUSIONS: The maximum-tolerable dose given in this setting was BU 14 mg/kg and CY 147 kg/mg. These results suggest that this regimen may have significant antimyeloma activity. Further phase II studies are warranted.

Adult↗
PubMed1992

Effect of methylxanthine derivatives on T cell activation.

In a Phase I-II trial examining the effect of prophylactic administration of pentoxifylline (PTX) on bone marrow transplant-associated morbidity, there was an apparent reduction in the incidence and severity of acute graft-versus-host disease. To determine if PTX might be directly immunosuppressive, its effects on T cell activation and proliferation were examined. PTX and several cogeners were found to directly suppress T cell proliferation in response to phytohemagglutinin, to allogeneic cells in a mixed leukocyte reaction, and to cross-linking the CD3 complex. The effects were dose-related and associated with suppression of secretion of tumor necrosis factor-alpha (TNF alpha). However, the inhibition of proliferation was not solely due to this effect since adding excess recombinant TNF alpha did not restore the proliferative response. These data suggest that PTX may be clinically useful in suppressing allogeneic reactions in bone marrow transplantation.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

Assessment of function, perfusion, metabolism, and histology in hearts preserved with University of Wisconsin solution.

BACKGROUND: University of Wisconsin solution has shown promise for prolonged cardiac preservation. This study compared the effects of 24-hour cold storage and perfusion preservation techniques by assessment of function, perfusion, metabolism, and histological changes. METHODS AND RESULTS: Three groups of rabbit hearts (n = 6 each) were evaluated: 1) control with immediate reperfusion, 2) continuous perfusion preservation, and 3) cold storage. Hearts were reperfused for 30 minutes, and left ventricular systolic pressure (LVSP) was measured by isovolumetric balloon (LVEDP, 20 mm Hg). We used 201Tl to assess perfusion and 14C-acetate to assess metabolism by macroautoradiography. LVSP was similar for controls and hearts preserved with continuous perfusion (134.8 +/- 2.1 versus 112.2 +/- 6.0 mm Hg, respectively). Hearts preserved with cold storage techniques were significantly worse (36.7 +/- 6.0 versus 134.4 +/- 8.2 mm Hg, p < 0.001). Controls showed homogeneous perfusion and metabolism, whereas hearts in the continuous perfusion group showed mild hypoperfusion and histological damage (26.4 +/- 2.7% of left ventricular cross section). Hearts in the cold storage group had 51.7 +/- 1.2% of the left ventricle hypoperfused and damaged. Histology in the control group was normal; in the perfused group, there were only mild changes; and in the cold storage group, there were extensive derangements of cellular architecture. CONCLUSIONS: Continuous perfusion of the heart with 4 degrees C modified University of Wisconsin solution provided function comparable to that of control. Conversely, cold storage showed extremely poor return of function. Autoradiography confirmed mild perfusion and metabolism abnormalities in control and continuous perfusion hearts, whereas there was marked derangement of cellular architecture, perfusion, and metabolism in the cold storage hearts.

Adenosine↗
PubMed1991

Phase I-II trial of pentoxifylline for the prevention of transplant-related toxicities following bone marrow transplantation.

Disease relapse and transplant related toxicities have limited the application of bone marrow transplantation (BMT) in the treatment for hematologic malignancies. Because elevated levels of tumor necrosis factor alpha (TNF-alpha) have been correlated with the development of transplant related complications, we conducted a phase I-II trial of pentoxifylline (PTX), a xanthine derivative capable of down-regulating TNF-alpha production, in patients with hematologic malignancies undergoing BMT. Thirty consecutive adult patients (median age, 34) were entered and received either an allogeneic (n = 26) or autologous (n = 4) BMT. Patients were enrolled at increasing dose levels (1,200, 1,600, and 2,000 mg/d) from day -10 through day +100 posttransplant. PTX was well tolerated with no significant adverse side effects noted at any of the dose levels administered. The actuarial day 100 survival for these 30 patients was 90% (95% confidence interval 79% to 100%). When compared with a good risk control group, PTX recipients experienced less mucositis (3.7 +/- 1.1 v 18.7 +/- 1.1 days, P = .004), less hepatic venocclusive disease (10% v 65%, P = .001), a lower incidence of renal insufficiency (3% v 65%, P = .0003), required less days of total parenteral nutrition (TPN) (24.0 +/- 1.3 v 35.0 +/- 2.4, P = .001) and were discharged from the hospital earlier than controls (day 26.0 +/- 1.8 v 37.0 +/- 3.8, P = .01). In addition the incidence of graft-versus-host disease (GVHD) greater than or equal to grade II was also reduced among the PTX recipients (35% v 68%, P = .03). PTX at doses in excess of 1,200 mg/d further reduced the severity of mucositis, and TPN requirements resulting in earlier hospital discharge than patients receiving 1,200 mg/d of PTX. In this study oral administration of PTX in doses up to 2,000 mg/d was well tolerated and associated with a reduction in morbidity and mortality in patients undergoing BMT. Prospective randomized trials are currently in progress to test these preliminary observations.

Acute Disease↗