Effect of influenza immunization on CYP3A4 activity.

A number of clinical reports of drug interactions with influenza vaccine have been made. We hypothesized that CYP3A4 activity would decrease following influenza immunization. Fifteen healthy subjects had erythromycin breath tests (ERMBT) and influenza antibody titer hemagglutinin inhibition assay (HIA) before and after receiving influenza vaccine. The mean age of the subjects was 31.9 years (S.D. 10.2). The change in ERMBT following influenza immunization was not significant (mean -4%, S.D. 17%, P=0.25). Influenza immunization does not significantly change CYP3A4 activity. Changes in serum drug concentrations noted previously after influenza immunization are either due to very small changes in CYP3A4 activity or other pharmacokinetic interactions.

A randomized placebo-controlled trial of lisofylline in HLA-identical, sibling-donor, allogeneic bone marrow transplant recipients. The Lisofylline Marrow Transplant Study Group.

The purpose of the study was to evaluate the effect of lisofylline (LSF) on engraftment, regimen-related toxicities (RRT), and mortality in patients undergoing allogeneic bone marrow transplantation (BMT). We performed a multicenter, randomized placebo-controlled trial in 60 patients with hematologic malignancies receiving BMT from HLA-identical sibling donors. Patients were randomized to receive either placebo, 2 mg/kg LSF or 3 mg/kg LSF every 6 h, beginning before conditioning and continuing to day 21 or hospital discharge. Treatment groups were balanced with respect to conditioning regimen and disease stage. However, significantly more patients in the 2 mg/kg LSF group were at high risk for RRT due to performance status >/=1, age >/=40 years, and prior exposure to CMV. Nausea and vomiting were the only adverse events observed in a higher proportion of LSF-treated patients that led to study withdrawal in six of 42 patients (14%). The times to neutrophil recovery to >/=500/microl and platelet recovery (>20 000/microl) were not improved by LSF treatment. Nevertheless, no patient who received treatment with 3 mg/kg LSF developed a documented infection between day 0 and 35 or had a serious or fatal infection between day 0 and 100 (P = 0.003 vs placebo for both). The day-100 survival rate was also significantly improved in the 3 mg/kg LSF group (89%), compared with either the 2 mg/kg LSF (48%) or placebo (61%) groups (log-rank test, 3 mg/kg LSF vs placebo, P = 0. 026). We conclude that treatment with LSF 3 mg/kg reduced the incidence of infections and improved 100-day survival in patients receiving related-donor allogeneic bone marrow transplantation. Bone Marrow Transplantation (2000) 25, 283-291.

Measurement of coronary blood flow and flow reserve using magnetic resonance imaging.

PURPOSE: It was the purpose of this study to demonstrate the feasibility of performing coronary artery flow and coronary flow reserve (CFR) measurements in normal human volunteers using a magnetic resonance (MR) phase contrast technique. MATERIALS AND METHODS: Coronary flow rate, flow velocity, peak flow and CFR were determined at rest and during pharmacologically induced hyperemia in 10 healthy volunteers. The flow measurements were obtained during a single breath-hold by using a fast, prospectively gated, segmented k-space gradient-echo phase contrast acquisition with view sharing (FASTCARD PC) that was modified to improve sampling of the diastolic flow. Data were processed using the standard phase difference (PD) processing techniques as well as a new complex difference (CD) flow measurement method intended to improve the accuracy of flow measurements in small vessels. RESULTS: Mean hyperemic flow velocity (40 +/- 16 cm/s) and blood flow (3.9 +/- 1.5 ml/s) rates differed significantly from resting velocity (13 +/- 6.6 cm/s) and flow (1.1 +/- 0.4 ml/s) measurements (p < 0.0001). PD methods consistently measured larger flow rates at rest (24% larger, p < 0.0005) and stress (29% larger, p < 0.0001). CFR, calculated as the ratio of the mean PD flows (4.7 +/- 2.8), was higher than CFR calculated as the ratio of mean CD flows (4.2 +/- 1.8); however, the differences did not reach statistical significance (p = 0.07). Flow measurements performed in adjacent slices of the same vessel correlated well (r = 0.88). CONCLUSIONS: Coronary flow and CFR measurements using the MR techniques are feasible and are similar to those reported in the literature for healthy volunteers.

Physiologic and clinical significance of myocardial blood flow quantitation: what is expected from these measurements in the clinical ward and in the physiology laboratory?

In this essay we review data on absolute quantitation of myocardial blood flow (MBF) in humans. Earlier work established that coronary heart disease (CAD) can be detected by coronary angiography and that this disease has characteristic features at rest and during stress, which indicate the linkage between regional metabolic needs and myocardial perfusion. In the 1970s myocardial perfusion was mapped in patients with radioxenon, but this method had significant technical limitations. About the same time, radioactive microspheres were introduced for cardiovascular research and investigations; these particles provided insights on MBF in acute infarction and ischemia, myocardial reperfusion, collateral circulation, myocardial blood flow during exercise, coronary flow reserve (CFR), and layer-to-layer distribution of MBF. Studies with microspheres also permitted investigators to establish the presence in the heart of MBF heterogeneity. Currently, there are several techniques that aim at extending these concepts into clinical investigation. Two of these techniques, i.e. Doppler coronary flow velocity and fast magnetic resonance imaging assess epicardial flow dynamics and CFR. Contrast myocardial echocardiography is another novel technique which has been useful in mapping the area at risk, reperfusion, myocardial viability and collateral circulation. This essay also considers the emerging technique of intracoronary ultrasound which has shown evidence of disease underestimation by conventional contrast angiography. Positron emission tomography (PET) is a noninvasive technique that uniquely and quantitatively maps myocardial perfusion and CFR. The latter can be computed before and after angioplasty. PET studies have further demonstrated that chronic myocardial ischemia does not exist as a distinct state in patients with CAD. From the above investigations the concept has arisen that not only is CAD an entity involving epicardial vessels but also, in a significant portion of patients, an abnormal microcirculation plays an important role in the pathogenesis of ischemic syndromes. PET studies have relatively low spatial resolution since they cannot resolve layer-to-layer absolute MBF.

Preferential radiosensitization of G1 checkpoint-deficient cells by methylxanthines.

PURPOSE: To develop a checkpoint-based strategy for preferential radiosensitization of human tumors with deficient and/or mutant p53. METHODS AND MATERIALS: A549 human lung adenocarcinoma cell lines differing in their expression of the p53 tumor suppressor gene were produced by transduction with the E6 oncogene from human papilloma virus type 16. The cells expressing E6 (E6+) lack a G1 arrest in response to ionizing radiation, are deficient in p53 and p21 expression, and exhibit a fivefold greater clonogenic survival following 10 Gy radiation. RESULTS: Postirradiation incubation with millimolar concentrations of the methylxanthine pentoxifylline (PTX) results in preferential radiosensitization of the E6+ cells compared to the LXSN+ vector transduced controls. There is a threefold sensitization of the LXSN+ cells and a 15-fold sensitization of the E6+ cells, which results in equal clonogenic survival of the two lines. Flow cytometry reveals PTX abrogation of the radiation induced G2 arrest for both cell lines. PTX also prolongs G1 transit for both cell lines. Preliminary results are presented using a novel methylxanthine, lisofylline (LSF), which has similar cell cycle effects on G1 and G2 and achieves differential radiosensitization at micromolar concentrations that are sustainable in humans. CONCLUSION: This checkpoint-based strategy is a promising approach for achieving preferential radiosensitization of p53- tumors relative to p53+ normal tissues.

An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome.

OBJECTIVE: No means exist for predicting the acute respiratory distress syndrome (ARDS), which complicates sepsis, trauma, and a variety of clinical disorders. Because activation of phospholipid-signaling pathways involving the acyl chains oleate and linoleate may initiate and amplify the inflammatory response, and thereby lead to the development of ARDS, we examined whether serum concentrations of these bioactive lipids increase and are predictive of ARDS in at-risk patients. DESIGN: Part I: A prospective, single-blind trial. Part II: A prospective, randomized, double-blind trial. SETTING: General intensive therapy units in five university teaching hospitals. SUBJECTS: Part I: Thirty-nine healthy control patients were studied to determine normal distribution of serum acyl values, followed by 30 patients admitted with onset of sepsis, trauma, or development of ARDS (within 24 hrs of admission) over a 1-yr period. Part II: Eight patients admitted with sepsis syndrome over a 2-month period. INTERVENTIONS: Part II: Patients were randomized to receive the substituted methylxanthine, lisofylline (CT1501R), or an identically presented placebo. MEASUREMENTS AND MAIN RESULTS: We measured the serum free fatty acid concentrations in the 39 healthy control subjects, and then we prospectively examined the serum free fatty acid concentrations in 30 age-matched patients in samples obtained within 24 hrs from the onset of sepsis, trauma, or development of ARDS. We then prospectively studied eight septic, at-risk patients who were matched for age, Acute Physiology and Chronic Health Evaluation II scores, Multiple Organ Failure index, and Glasgow Coma Score, in a double-blind, placebo-controlled, pilot study. These patients included four patients who received no treatment and four patients who received lisofylline, a compound that decreases serum unsaturated free fatty acids and diminishes acute lung injury in animals caused by sepsis and/or trauma. The calculated ratios of serum free fatty acids (Le., the ratio of C18 unsaturated fatty acids linoleate and oleate to fully saturated palmitate, C16:0) increased and predicted the development of ARDS in at-risk patients. Serum samples from the 30 patients, obtained within 24 hrs from the onset of sepsis, trauma, or development of ARDS, had significantly increased mean acyl chain ratios (1.42 +/- 0.35 [SD]) compared with healthy control subjects (0.86 +/- 0.25; p < .01). Sera from 13 patients with sepsis or trauma who did not develop ARDS (group A [at-risk, non-pre-ARDS]) also had increased acyl ratios (1.23 +/- 0.27) compared with sera from healthy control subjects (0.86 +/- 0.25; p < .01). Sera from seven patients who subsequently developed ARDS (group B [at-risk, pre-ARDS]) had higher acyl ratios (1.70 +/- 0.21) than group A at-risk patients who did not develop ARDS (1.23 +/- 0.27; p < .01) or healthy control subjects (0.86 +/- 0.25; p < .001). Sera from ten group C patients with ARDS at the time of admission to the study had the highest acyl ratios (1.80 +/- 0.75), which exceeded values for healthy control subjects (p < .001) and group A at-risk patients without ARDS (p = .01), but were not significantly different then group B at-risk, pre-ARDS patients (p = .17). Prospective study of eight septic, at-risk patients demonstrated significantly (p < .05) increased serum acyl ratios in the four untreated patients (findings consistent with the first study) but a significantly (p = .02) reduced ratio in the four at-risk patients treated with lisofyline. CONCLUSIONS: Increases in unsaturated serum acyl chain ratios differentiate between healthy and seriously iII patients, and identify those patients likely to develop ARDS. Thus, the serum acyl ratio may not only prospectively identify and facilitate the assessment of new treatments in patients at highest risk for developing ARDS, but may also lead to new insights about the pathogenesis of ARDS.

Blood flow distribution in necrotic versus nonnecrotic rabbit hearts.

The spatial myocardial blood flow heterogeneity of the normal heart was previously investigated by means of the standard microsphere-defined regional myocardial blood flow in nonischemic hearts. We determined the probability density functions of coronary blood flows in the rabbit heart at selected macroautoradiographic 20-microns cross-sections of the left ventricle in nonischemic as well as infarcted hearts. Macroautoradiography gave us spatial resolutions of 0.1-0.2 mm. As a tracer we used 14C-iodoantipyrine given into the root of the aorta. We report here for the first time a systematic study of the shape of the flow probability density functions during acute regional myocardial necrosis. As the hearts became progressively and extensively necrotic, the distribution of flows changed its characteristics showing two independent components. The first component was the peak representing the nonischemic regions in the hearts subjected to acute ischemia. The second component was a monotonically decreasing component associated with very low flows and necrosis in the severely hypoperfused portion of the hearts. This monotonically decreasing component became larger as the extent of ischemia increased and was well separated from the peak attributable to the nonischemic regions. We could not demonstrate a leftward shift of the nonischemic central peak in the ischemic hearts. Our research shows that in transaxial radionuclide cardiac sections, such as those that might be obtained and analyzed in clinical SPECT and clinical PET, variable amounts of myocardial necrosis will result in a composite curve of myocardial blood flow heterogeneities. One portion of the curve will indicate the distribution of flows in the nonischemic zones. The other portion will vary in magnitude with the extent of ischemia, exhibit the shape of monotonically decreasing curve. Depending upon the spatial resolution of the radionuclide imaging technique utilized, a border zone will exist representing the interface between normally perfused and occluded vascular beds. In our investigation, it was found that the border zone determined statistically was consistently and significantly smaller than the border zone determined visually.

Lisofylline inhibits transforming growth factor beta release and enhances trilineage hematopoietic recovery after 5-fluorouracil treatment in mice.

The effectiveness of endogenous or exogenously administered colony-stimulating factors may be modulated by the presence of hematopoietic inhibitory molecules. Cytotoxic therapy may result in the induction of hematopoietic inhibitors contributing to prolonged myelosuppression, whereas preventing the induction of such inhibitors may accelerate multilineage recovery. Lisofylline [LSF; (R)-1-(5-hydroxyhexyl)-3,7, dimethyl-xanthine], inhibits the signaling and/or release of certain hematopoietic inhibitory molecules such as tumor necrosis factor alpha, macrophage inflammatory protein 1 alpha, transforming growth factor beta, and IFN-gamma. Treatment of murine bone marrow cells with the cytotoxic agent 5-fluorouracil (5-FU) results in the release of a nondialyzable inhibitor of progenitor (colony-forming unit-granulocyte macrophage; CFU-GM) proliferation. When murine bone marrow cells were treated with 5-FU plus LSF, release of this inhibitor of CFU-GM proliferation was blocked. Neutralizing antibody and Western blot analysis indicated that the inhibitor was TGF-beta. We tested the effect of LSF (100 mg/kg i.p., b.i.d.) on multilineage regeneration after high-dose 5-FU or thiotepa treatment in BALB/c mice. In 4 of 5 experiments, LSF significantly accelerated neutrophil recovery (P < or = 0.05, Wilcoxon paired-signed test). In addition, platelet, reticulocyte, and CFU-GM regeneration were significantly accelerated in mice treated with LSF compared to control mice (P < or = 0.05). LSF had no significant effects on the ability of 5-FU to kill hematopoietic progenitor cells, nor did LSF stimulate or inhibit proliferation of CFU-GM. LSF had no effect on chemotherapy-induced killing of tumor cells in vitro, nor on the antitumor activity of 5-FU or thiotepa in BALB/c mice implanted with P388 leukemia cells. Inhibition of hematopoietic inhibitor release may accelerate multilineage recovery after cytotoxic therapy and, as such, may represent an alternative or additional therapy to the use of positively acting lineage specific colony-stimulating factors.

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.

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.

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.

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.

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.

Gallbladder sludge formation after bone marrow transplant: sonographic observations.

We prospectively studied 12 patients before and after bone marrow transplantation (BMT) with serial sonography to evaluate gallbladder sludge formation. Patients were studied on four separate occasions to assess the gallbladder for sludge and stones: prior to BMT and conditioning chemoradiation, and on days 3, 13, and 28 after BMT. During two of the sonographic studies, gallbladder volume measurements were made before and after administration of cholecystokinin octapeptide (CCK-OP) and the ejection fraction (EF) was calculated. Medical records were reviewed for symptoms of cholecystitis, narcotic use, and dietary intake. Sludge and/or stones developed in eight of 12 patients (67%), and in four patients sludge was observed by day 3 post-BMT. Ejection fraction was normal (> 50%) pre-BMT in six of the eight patients who developed sludge, and in four of these six post-BMT. Furthermore, five of the eight patients developed sludge and/or stones in the absence of fasting and/or narcotic use. We conclude that gallbladder sludge develops frequently and early in BMT patients and may resolve or progress to stone formation. We did not demonstrate a relationship between impaired contractility and the development of sludge and/or stones, nor did we find a strong association between sludge formation and conditions presumed to cause gallbladder stasis, such as narcotic use and fasting. These findings suggest that other factors apart from impaired gallbladder contractility may play a role in the formation of sludge in the BMT patient.

A randomized controlled trial of pentoxifylline for the prevention of regimen-related toxicities in patients undergoing allogeneic marrow transplantation.

This study evaluated the effect of pentoxifylline (PTX) on the incidence of regimen-related toxicity in patients receiving allogeneic marrow transplants from related donors. All patients received a regimen of methotrexate and cyclosporine as prophylaxis against acute graft-versus-host disease (GVHD). Patients were randomized to receive PTX or a placebo for 70 days and the outcome was examined in a blinded fashion. Forty-four patients were evaluate in each study arm. PTX had no significant effect on engraftment, the incidence of GVHD, venocclusive disease of the liver, infection, the need for oxygen, posttransplant survival, or the duration of hospitalization. Patients receiving PTX were significantly more likely to develop major elevations of serum creatinine levels. PTX was poorly tolerated and induced significantly more vomiting than the placebo. PTX as administered in this randomized study was associated with significant toxicity and offered no benefit in reducing transplant-related morbidity or mortality.