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Biomedical subjects

G S Harman

Publications and source records attributed to G S Harman.

8 recordsLinked to original sources
PubMed1992

Marked increase in veno-occlusive disease of the liver associated with methotrexate use for graft-versus-host disease prophylaxis in patients receiving busulfan/cyclophosphamide.

The use of cyclosporine-A/methotrexate (CyA/MTX) for graft-versus-host disease (GVHD) prophylaxis is safe and effective for patients undergoing allogeneic bone marrow transplantation after preparation with cyclophosphamide and total body irradiation. We report 87 patients prepared for allogeneic transplant with busulfan 4 mg/kg/d orally for 4 days, followed by cyclophosphamide 60 mg/kg/d intravenously for 2 days (Bu4Cy2). A marked increase in hepatotoxicity was observed in 20 patients administered CyA/MTX, compared with 67 historical control patients who received CyA/methylprednisolone (CyA/MP) for GVHD prophylaxis with all other treatment and support variables remaining constant. The incidence of hyperbilirubinemia (bilirubin greater than or equal to 2 mg/dL) increased from 48% to 80% (P = .02), and the mean maximal bilirubin increased from 4.67 +/- 7.27 to 8.72 +/- 8.73 mg/dL (P = .04), when CyA/MTX was used in place of CyA/MP for GVHD prophylaxis. In addition, the incidence of veno-occlusive disease (VOD) increased from 18% to 70% (P = .0001), and death caused by VOD increased from 4.5% to 25% (P = .02). Survival was not significantly different for the two groups because of a higher non-VOD death rate in patients receiving CyA/MP for GVHD prophylaxis (P = .77). We suggest caution when using Bu4Cy2 in combination with CyA/MTX for GVHD prophylaxis.

Actuarial Analysis↗
PubMed1992

Pilot trial of prophylactic ursodiol to decrease the incidence of veno-occlusive disease of the liver in allogeneic bone marrow transplant patients.

Ursodiol is a hydrophilic, non-hepatotoxic bile salt indicated for the medical treatment of cholesterol gallstones. This pilot study explored the use of prophylactic ursodiol in an attempt to decrease the incidence and severity of veno-occlusive disease (VOD) of the liver following allogeneic bone marrow transplantation (BMT). Between February 1991 and January 1992, 22 consecutive patients undergoing BMT for hematologic malignancies received the BU(4)/CY(2) preparative regimen and CSA/MTX for GVHD prophylaxis. Ursodiol, 600-900 mg daily by mouth was begun at least 1 day prior to beginning the preparative regimen. Results for this pilot group were compared to a control group of 28 consecutive patients transplanted between June 1989 and January 1991 with the same regimen without ursodiol. There were no significant differences in disease or clinical status between the groups pretransplant. However, mean baseline AST levels were significantly higher in the ursodiol group, 28.0 U/l vs 18.1 U/l in the control group (p = 0.001). The median maximum bilirubin observed post-transplant was 2.35 mg/dl (range 0.9-45) in the ursodiol group, and 5.05 mg/dl (range 0.7-29.4) in controls. The incidence of VOD was 2/22 (9.1%) in the ursodiol group and 18/28 (64.3%) in controls (p = 0.0001). Death due to VOD occurred in 1/22 patients (4.5%) in the ursodiol group and in 6/28 (21.4%) controls (p = 0.12). Our data suggest that ursodiol may decrease the incidence of VOD in allogeneic BMT patients.

Adolescent↗
PubMed1991

Phase I evaluation of crisnatol (BWA770U mesylate) on a monthly extended infusion schedule.

Crisnatol is an arylmethylaminopropanediol derivative that has shown promise as an antitumor agent in preclinical testing. In a phase I trial using a monthly six-hour infusion schedule the recommended dose for future phase II trials was found to be 388 mg/m2. Neurologic toxicity was dose-limiting in that trial and correlated with the attainment of a threshold plasma concentration of greater than 4.5 micrograms/ml. In this study we treated 15 patients with escalating doses of crisnatol from 450 mg/m2 to 900 mg/m2 administered at a rate of 50 mg/m2/hr over 9, 12, 15, and 18 hours. Toxicity was mild to moderate at all dose levels. However, serious central nervous system effects were noted in one patient at 900 mg/m2 over 18 hours whose plasma level was 6.5 micrograms/ml. This study has demonstrated higher total doses of crisnatol can be given if the drug is administered as a prolonged infusion in an attempt to avoid high plasma levels of the agent.

Aged↗
PubMed1988

Phase I clinical trial of carbetimer.

Carbetimer (carbethimer, N-137, NED-137, carboxyimamidate) is a low molecular weight polyelectrolyte with antitumor activity in a variety of tumor models. This phase I trial evaluated a single dose of carbetimer infused over 1-2 h every 28 days. Forty-three patients received 71 courses of the drug at doses ranging from 180 to 8500 mg/m2. The dose-limiting toxicity was hypercalcemia (serum calcium greater than 12.5 mg/dl) noted in two of three patients at a dose of 8500 mg/m2. Serum calcium levels between 10.5 and 12.5 mg/dl were noted in an additional three patients treated at doses greater than or equal to 1600 mg/m2. Calcium balance studies in three patients treated at 6500 mg/m2 revealed an increase in urinary cyclic AMP and phosphate excretion after treatment accompanied by a mild elevation of serum parathyroid hormone. Immunological studies in these patients revealed a statistically significant increase in the percentage of peripheral T-helper cells. An increase in the T-helper/suppressor cell ratio was observed in two of the three patients studied. Interleukin 2 production by phytohemagglutinin-stimulated peripheral mononuclear cells was increased in two of three patients. One patient with a renal cell carcinoma showed a mixed response. The recommended dose for phase II trials as assessed from this study is 6500 mg/m2 as a single dose every 28 days.

Adult↗
PubMed1988

Phase I and clinical pharmacology trial of crisnatol (BWA770U mesylate) using a monthly single-dose schedule.

Crisnatol is a novel lipophilic arylmethylaminopropanediol with significant antineoplastic activity in a variety of murine and human tumor models which functions as a DNA intercalator. In this Phase I trial, a 6-h infusion of the drug was administered i.v. in 700 to 1500 ml of 5% dextrose in water every 28 days. Eighty-five courses at doses of 7.5 to 516 mg/m2 were administered to 43 patients with refractory solid tumors. Reversible neurological toxicity was dose limiting at 516 mg/m2 and was manifested as somnolence, dizziness, blurred vision, unsteady gait, and alpha-slowing on electroencephalogram at the end of infusion. All neurological signs and symptoms were reversible. No hematological toxicity was observed. Other toxicities included phlebitis, mild to moderate nausea and vomiting, reversible sinus node arrest in one patient, and hypertension. Crisnatol plasma concentrations were determined by high-pressure liquid chromatography. After infusion, plasma concentrations declined biexponentially with a terminal t1/2 of 2.9 h. Using a two-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 58.8 liters/m2 and 18.3 liters/h/m2, respectively, indicative of extensive tissue distribution and rapid hepatic clearance. Peak plasma levels occurred at the end of infusion and correlated with the onset of neurological toxicity. The recommended Phase II dose for this schedule is 388 mg/m2.

Adult↗
PubMed1988

Recurrent hypercalcemia and elevated 1,25-dihydroxyvitamin D levels in Hodgkin's disease.

Hypercalcemia has been infrequently associated with Hodgkin's disease. When seen, most cases have been attributable to skeletal invasion by disease. Herein is described a 40-year-old man with a 15-year history of Hodgkin's disease. Each of four disease recurrences was heralded by hypercalcemia occurring in the absence of bone disease or elevation of parathyroid hormone levels. Marked elevations of 1,25-dihydroxyvitamin D levels were observed that paralleled his disease course and response to therapy. The repetitive association of hypercalcemia with an elevation of 1,25-dihydroxyvitamin D in this case provides further evidence of lymphoma-associated production of this vitamin.

Adult↗