PubMed Health⌕ Search

Biomedical subjects

W E Fitzsimmons

Publications and source records attributed to W E Fitzsimmons.

At least 37 records · Page 2Linked to original sources
PubMed1996

FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation.

FK506 (Tacrolimus) is an immunosuppressive drug that blocks the activation of antigen-specific T lymphocytes, a major component in the pathogenesis of graft-versus-host disease (GVHD). This study was designed to obtain first estimates of the safety and efficacy of FK506 monotherapy in the prevention of GVHD following HLA-identical sibling marrow transplantation. Additionally, a subset of patients was studied to define the pharmacokinetic profile of FK506. Twenty-seven adult patients with leukemia or myelodysplasia received FK506 starting the day before transplant at a dose of 0.04 mg/kg/d by continuous intravenous infusion. When clinically possible, FK506 was given orally in two divided doses starting at five times the daily intravenous dose. FK506 doses were adjusted to target a steady state or trough blood level between 10 to 30 ng/mL. These patients were followed for 6 months posttransplant. All patients had sustained marrow engraftment. Frequently noted adverse events included reversible renal dysfunction, diarrhea, fever, nausea, vomiting, and headache. Most patients required FK506 dose reductions associated with elevated serum creatinine. Two (7%) patients relapsed, one of whom died of the disease within the 6-month study period. A second patient died due to pulmonary mucor. Whole blood pharmacokinetic parameters indicated a half-life of 18.2 +/- 12.1 hours; volume of distribution of 1.67 +/- 1.02 L/kg; clearance of 71 +/- 34 mL/h/kg; and bioavailability of 32 +/- 24%. Eleven of 27 (41%) patients developed grade II to IV acute GVHD, including 10 grade II and one grade III. Six of 24 (25%) evaluable patients developed chronic GVHD. These data indicate that FK506 monotherapy has activity in preventing GVHD. Further studies of FK506 with lower doses to improve tolerability and in combination with other immunosuppressants to augment efficacy are warranted.

Adolescent↗
PubMed1996

Tacrolimus (FK506) and methotrexate regimens to prevent graft-versus-host disease after unrelated dog leukocyte antigen (DLA) nonidentical marrow transplantation.

We previously reported an synergism between methotrexate and tacrolimus (FK506) in preventing graft-versus-host disease (GVHD) in dogs given DLA-nonidentical unrelated marrow grafts after 9.2 Gy of total body irradiation (TBI). Methotrexate was given at 0.4 mg/kg i.v. on days 1, 3, 6 and 11 and FK506 at 0.15 mg/kg/day i.m. on days 0-8 and 0.5 mg/kg/day orally on days 9-90. Half of the dogs became long-term survivors. A major toxicity was gastrointestinal, and 25% of dogs died with intussusception. The current study addresses the problem of intussusception by making changes in drug doses used. In one group of dogs, FK506 was reduced to 0.075 mg/kg i.m. on days 1-8, while methotrexate was administered per original schedule. In a second group, methotrexate was reduced to a single dose on day 7, while FK506 was either administered per the original or reduced-dose schedule. None of the 17 current dogs developed intussusception, however, all but two dogs died with GVHD (n = 12) or graft failure (n = 3). Only two dogs survived after transient GVHD. Results show that there is little room for maneuvering FK506 or methotrexate doses, and hopes of reducing gastrointestinal toxicity by dose modifications while retaining the ability to prevent GVHD were not fulfilled.

Animals↗
PubMed1994

FK506 inhibits graft-versus-host disease and bone marrow graft rejection in murine recipients of MHC disparate donor grafts by interfering with mature peripheral T cell expansion post-transplantation.

FK506 was evaluated as the sole graft-vs-host disease (GVHD) preventive agent in murine recipients of fully allogeneic donor grafts. FK506 (36 mg/kg given as a suspension on days 0 through 13, then three times per wk through day 29 post-bone marrow transplantation (BMT)) reproducibly led to 50 to 90% of FK506-treated recipients surviving a 60- to 103-day observation period. High doses of cyclosporin A did not protect mice from lethal GVHD. A kinetic study performed in mice that received FK506 demonstrated that mature donor CD3+, CD4+, and CD8+ T cells in the spleen were each reduced by > or = 64%, as compared with vehicle-treated control mice, although this effect was short lived. Thymic reconstitution studies revealed a remarkable decrease in mature CD4+ cells and cells expressing the activation Ag, CD69. In contrast, less mature CD4+8+ thymocytes were not reduced significantly and total thymocyte numbers were only marginally decreased. The fact that peripheral reconstitution of CD4+8- or CD8+4- T cells was impaired significantly at this time indicated that FK506 had a major effect on thymic maturation and/or thymic emigration. In two models specifically designed to study alloengraftment, recipients of pan-T cell-depleted (TCD) donor marrow and FK506 were noted to have accelerated hemopoietic recovery and augmented long-term multilineage peripheral blood alloengraftment, in marked contrast to controls (86 to 97% mean donor cells vs 0% in controls for all lineages). These data demonstrate that FK506 prevents GVHD and graft rejection in vivo by inhibiting mature T cell expansion post-BMT.

Animals↗
PubMed1994

Cyclosporine monitoring improves graft-versus-host disease prophylaxis after bone marrow transplantation.

OBJECTIVE: The principal objective of this study was to determine whether a relationship exists between trough cyclosporine concentrations measured by HPLC and the development of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation. DESIGN: A retrospective analysis of 59 consecutive human leukocyte antigen-matched bone marrow transplants. Patients received uniform GVHD prophylaxis with cyclosporine and methotrexate. Whole blood trough cyclosporine concentrations were measured at least twice weekly during hospitalization and weekly after discharge. SETTING: A dedicated bone marrow transplant unit in an academic center. MAIN OUTCOME MEASURES: The means of cyclosporine concentrations were assessed for each patient on a weekly basis during the first 50 days after transplant. These means were compared between patients developing grade 2-4 acute GVHD and patients without significant GVHD. RESULTS: Eighteen patients developed acute GVHD at a median of 25 days after bone marrow transplant (range 10-50). There was no correlation between the development of GVHD and patient age, diagnosis, donor age, donor gender, donor-recipient gender mismatch, and time to neutrophil engraftment (> 1000 x 10(6) cells/L). Although mean weekly cyclosporine concentrations were consistently lower in patients developing acute GVHD, the difference in values compared with those of patients with GVHD was not statistically significant. Mean weekly cyclosporine concentrations at the time of neutrophil engraftment were statistically associated with the development of GVHD. Patients with GVHD had mean +/- SD concentrations of 174 +/- 69 ng/mL, significantly lower than 254 +/- 114 ng/mL in patients without GVHD. Furthermore, the rate of GVHD was 82 percent in patients with mean concentrations < 200 ng/mL at the time of neutrophil engraftment as compared with a rate of 34 percent in patients with concentrations > or = 200 ng/mL (relative risk = 2.4). Also, mean cyclosporine concentrations measured during the week of onset of GVHD were significantly lower compared with mean cyclosporine concentrations of all other patients at risk of GVHD during that week. CONCLUSIONS: Cyclosporine concentrations are associated with the development of acute GVHD. Patients with HPLC whole blood concentrations < 200 ng/mL are at significantly higher risk of developing GVHD, particularly if these concentrations are observed during the week of neutrophil engraftment. More effective GVHD prophylaxis could be achieved by careful monitoring of cyclosporine concentrations after transplant.

Adolescent↗
PubMed1991

4-Aminopyridine in multiple sclerosis: prolonged administration.

In an earlier study, we demonstrated efficacy of single oral doses of 4-aminopyridine (4-AP) in improving motor and visual signs in multiple sclerosis (MS) patients for a mean of 4.97 hours. We attempted to determine whether efficacy could safely be prolonged using multiple daily doses over several days by administering 7.5 to 52.5 mg 4-AP to 17 temperature-sensitive MS patients in one to three daily doses at 3- to 4-hour intervals over 1 to 5 days in a double-blind study. Nine of these patients were also tested with identically appearing placebo. Thirteen of the 17 patients (76%) given 4-AP showed clinically important motor and visual improvements compared with three of nine in the placebo group. Average peak improvement scores were 0.40 for 4-AP and 0.12 for placebo. Seventy percent of the daily 4-AP improvements lasted 7 to 10 hours. The improvements for two consecutive doses of 4-AP lasted a mean of 7.07 hours (83% of the average 8.53-hour treatment-observation period) compared with 2.36 hours for placebo (26% of the average 9.06-hour treatment-observation period). No serious side effects occurred. 4-AP is a promising drug for the symptomatic treatment of MS.

4-Aminopyridine↗
PubMed1990

The effect of hepatic enzyme inducers on busulfan neurotoxicity and myelotoxicity.

Anticonvulsants are commonly used empirically to prevent seizures in patients receiving high-dose busulfan in preparation for bone marrow transplantation. This study evaluates the effects of two anticonvulsants with enzyme-inductive properties, phenytoin and phenobarbital, and an enzyme inducer without anticonvulsant properties, Aroclor 1254, on the myelotoxicity and acute neurotoxicity of busulfan in a murine model. To assess the neuroprotective effects of these agents, we studied the effects of a single dose of 100 mg/kg i.p. busulfan, previously shown in this model to be uniformly lethal due to neurotoxicity. A significantly greater proportion of mice survived when pretreated with phenytoin or phenobarbital as compared with Aroclor 1254 pretreatment or an untreated control group. Busulfan myelotoxicity was studied in another group of mice treated with 135-150 mg/kg given in divided doses over 6 days. The proportion of animals surviving the otherwise myeloablative effects of this regimen were significantly improved by Aroclor 1254, high-dose phenytoin, and phenobarbital pretreatment. We conclude that anticonvulsants offer protection from the acute neurotoxicity of busulfan. However, these enzyme-inducing agents may reduce the myelosuppressive effects as well. These results suggest that an inducible enzyme system such as microsomal or glutathione S-transferases plays an important role in busulfan metabolism, warranting concern over concomitant administration of agents that either induce or inhibit these enzymes.

Animals↗
PubMed1990

Pharmacokinetics and in vivo activity of liposome-encapsulated gentamicin.

Gentamicin sulfate was encapsulated in liposomes composed solely of egg phosphatidylcholine and administered via intravenous injection to rats and mice. The total gentamicin activity (regardless of whether it was free or liposome associated) in serum and selected tissues was determined for 24 h (serum) or up to 15 weeks (tissues) by using a microbiological assay. The mean half-lives in serum of a single 20-mg/kg dose of free (nonencapsulated) gentamicin in mice and rats were estimated to be 1.0 and 0.6 h, respectively, whereas a similar dose of encapsulated drug had apparent mean half-lives of 3.8 h in mice and 4.0 h in rats. In both species, the apparent half-life in serum of the liposomal formulation increased as the dose increased. Liposome encapsulation resulted in higher and more prolonged activity in organs rich in reticuloendothelial cells (especially spleen and liver). In acute septicemia infections in mice, the liposomal formulation showed enhanced prophylactic activity (as determined by calculation of the 50% protective dose). In a model of murine salmonellosis, liposomal gentamicin greatly enhanced survival when given as a single dose (10 mg/kg) at 1 or 2 days after infection as well as up to 7 days before infection.

Animals↗
PubMed1989

Pharmacokinetic evaluation of the terfenadine-theophylline interaction.

Based on results of studies of a possible terfenadine-theophylline interaction on file with Merrell Dow, Inc., a randomized, crossover study was undertaken to determine if there were a pharmacokinetic interaction between these two medications. Seventeen normal volunteers were randomized to receive theophylline or a theophylline-terfenadine combination for 14 days, followed by a 2-week washout period, with crossover to the other treatment for 14 days. Serum theophylline concentrations were measured on the last day of each treatment phase for determination of pharmacokinetic parameters. No differences were found in elimination rate constant, elimination half-life, area under the concentration-time curve, time to peak concentration, or maximum theophylline concentration. It is concluded that concomitant terfenadine therapy does not affect the pharmacokinetic profile of theophylline in healthy male volunteers.

Adult↗
PubMed1989

Single-dose study of the effect of terfenadine on theophylline absorption and disposition.

Terfenadine, a nonsedating antihistamine, and theophylline, a methylxanthine used extensively in the treatment of asthma, have potential for frequent concomitant administration. A single-dose pharmacokinetic study was performed to investigate the potential for a drug-drug interaction affecting serum theophylline concentrations. No statistically significant effect on theophylline absorption or elimination was found when 60 mg of terfenadine was concomitantly administered with 4 mg/kg of theophylline in 17 normal healthy male volunteers. The results of this single-dose study suggest there is no significant acute pharmacokinetic interaction affecting serum theophylline concentrations when terfenadine and theophylline are administered concomitantly as single isolated doses. Further investigation is needed to determine if repeated administration of terfenadine is equally without effect on theophylline absorption or disposition.

Adult↗
PubMed1988

Pentamidine therapy in renal failure: case report and literature review.

The literature lacks adequate dosing guidelines for modifying pentamidine therapy in renal failure. This report describes a patient in renal failure undergoing intermittent peritoneal dialysis who is treated with pentamidine for Pneumocystis carinii pneumonia. Data on pentamidine's disposition are reviewed.

Amidines↗