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Biomedical subjects

R K Shadduck

Publications and source records attributed to R K Shadduck.

At least 73 records · Page 4Linked to original sources
PubMed1991

The kinetics of cyclosporine and its metabolites in bone marrow transplant patients.

1. The pharmacokinetics of cyclosporine (CsA) and the time course of CsA metabolites were studied in five bone marrow transplant patients after intravenous (i.v.) administration on two separate occasions and once after oral CsA administration. 2. Cyclosporine and cyclosporine metabolites were measured in whole blood by h.p.l.c. 3. Cyclosporine clearance after i.v. administration decreased from 3.9 +/- 1.7 ml min-1 kg-1 to 2.0 +/- 0.6 ml min-1 kg-1 after 14 days of treatment. The mean +/- s.d. absolute oral bioavailability of cyclosporine was 17 +/- 11%. 4. Hydroxylated CsA (M-17) was the major metabolite in blood. There were no significant differences in the mean metabolite/CsA AUC ratios between the first and second i.v. studies. 5. After oral administration, the metabolite to CsA AUC ratios were higher for most metabolites compared to those observed in the second i.v. study, suggesting a contribution of intestinal metabolism to the clearance of CsA.

Adolescent↗
PubMed1991

Cyclosporine and methylprednisolone after allogeneic marrow transplantation: association between low cyclosporine concentration and risk of acute graft-versus-host disease.

A combination of cyclosporine (CSA) and methylprednisolone (MP) was used as graft-versus-host disease (GVHD) prophylaxis in 25 patients age 11-47 years (median 27 years) who received HLA-compatible sibling marrow transplants after myeloablative therapy for leukemia, myelodysplasia or lymphoma. CSA was initiated at 3 mg/kg/day in two divided doses, and the dose was adjusted to maintain a trough whole blood h.p.l.c. concentration between 200 and 800 ng/ml. While on i.v. CSA, the dose of CSA was increased for 10 of the 25 patients. The actuarial rate of grades II-IV acute GVHD was 37%. Those patients who developed moderate to severe GVHD had a significantly higher early mortality than those who did not (56% vs 12%, p = 0.02). There was a significant association between the development of acute GVHD and a mean week 2 CSA trough concentration less than 250 ng/ml. Life threatening regimen-related toxicities in the first 100 days included capillary leak syndrome, acute pancreatitis and small bowel perforation. Although the combination of CSA and MP in this dosing schedule was active in preventing acute GVHD, nephrotoxicity remained a problem, and outcome was limited by the inability to achieve the target CSA trough concentration in a substantial proportion of patients.

Acute Disease↗
PubMed1991

Complications of indwelling central venous catheters in bone marrow transplant recipients.

Complications associated with indwelling central venous catheters in patients undergoing bone marrow transplantation are presented. The study group was comprised of 123 patients who underwent transplantation from 1982 to 1988 in whom 139 catheters were placed. One hundred and fifteen of 139 catheters placed had a triple lumen, while 24 had a dual lumen. Percutaneous placement through the subclavian vein was used in 127 of 139 catheters with a low complication rate. Catheters remained in place for 65.0 +/- 55.5 days (mean +/- standard deviation). One hundred and eight catheters remained functional during the course of treatment for these patients and lasted until elective removal or until the patient died. Thirty-one catheters were removed because of a complication. Infection was the most common complication, occurring in 22 catheters. Seven infected catheters were salvaged with antibiotic therapy. Coagulase negative staphylococcus was the most frequent organism identified. Mechanical problems causing catheter malfunction, migration, thrombosis and cuff erosion occurred in 19 catheters; 15 were removed. We concluded that double and triple lumen Silastic (silicone rubber) catheters provide relatively safe and effective access for bone marrow transplant recipients. The triple lumen catheter provides an additional venous access port that facilitates intensive care. The duration of catheter function is sufficient in most patients for therapy during and after bone marrow transplantation. Infection is the most common complication; our results indicate that catheters can be maintained and salvaged in some patients with septicemia. Noninfectious complications are less frequent, although catheters with persistent mechanical problems are less likely to be salvaged.

Bone Marrow Transplantation↗
PubMed1991

Autologous bone marrow transplantation following high-dose busulfan and VP-16 for advanced non-Hodgkin's lymphoma and Hodgkin's disease.

Ten patients with non-Hodgkin's lymphoma (NHL) and nine with Hodgkin's Disease (HD) received high-dose busulfan and etoposide (VP-16) prior to autologous bone marrow transplantation (ABMT). All patients with NHL and eight with HD had poor prognostic factors. Marrows from patients with NHL were purged with 4-hydroperoxy-cyclophosphamide. Busulfan (16 mg/kg body weight) was given orally over 4 days; VP-16 was administered as a single 4-h infusion. VP-16 was initiated at a dose of 60 mg/kg but reduced to 50 mg/kg after three of the first seven patients developed fatal toxicity. The 100-day regimen-related mortality was 21% (95% confidence interval 14%-46%). An absolute neutrophil count of 500/microliters was achieved at a median of 18 days in NHL and 23 days in HD. The median time to achieve a platelet count of 50,000/microliters was slower in HD (100 days) than in NHL (31 days) (p less than 0.05). Complete remissions were documented in four of nine evaluable patients with NHL and two of eight evaluable patients with HD. Actuarial survival at 18 months was 21% (95% confidence interval 3%-39%). The combination of high-dose VP-16 and busulfan as used in this study, although comparable to other regimens in efficacy, is associated with several toxicities.

Administration, Oral↗
PubMed1991

Comparison of intravenous versus subcutaneous recombinant human granulocyte-macrophage colony-stimulating factor in patients with primary myelodysplasia.

The primary objective of this study was to compare the toxicity and hemopoietic effects of s.c. and i.v. recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in patients with primary myelodysplasia. Twenty patients were treated in this phase I crossover-designed study. In three groups of patients, the dose of rhGM-CSF was escalated from 60 to 250 micrograms/m2/day. Each patient was to receive 2 weeks of i.v. (daily 2-h infusion) and s.c. (twice daily) rhGM-CSF separated by a 2-week rest period. The decision to start with i.v. or s.c. administration was by random selection. Toxicity was comparable between i.v. and s.c. administration. At the highest dose level, 63% (five of eight) of the patients developed moderate to severe toxicity. Increases in the absolute neutrophil count showed a dose-response relationship and were more pronounced with s.c. than i.v. administration. Failure to grow in vitro granulocyte-macrophage colonies or a hypocellular marrow (less than or equal to 30%) predicted for a poor response to therapy. No patient had a platelet or a reticulocyte response. No patient progressed to acute leukemia. Compared to a 2-h infusion of i.v. rhGM-CSF, s.c. administration is more myelostimulatory without an increase in toxicity.

Adolescent↗
PubMed1990

Human macrophage colony-stimulating factor induces macrophage colonies after L-phenylalanine methylester treatment of human marrow.

Macrophage-colony stimulating factor (M-CSF) has well-known effects on murine bone marrow, but its colony stimulating activity for human bone marrow is controversial. After treatment of human bone marrow with L-phenylalanine methylester (PME), macrophage-colonies (CFU-M) were induced by M-CSF in a dose-dependent fashion. The optimal concentration of recombinant human-macrophage colony stimulating factor (rhM-CSF) was 1,000 U/mL. Purified human urine M-CSF had colony stimulating activity similar to rhM-CSF. Further studies were performed to determine the factors responsible for the enhanced CFU-M formation from PME treated marrow. Compared with nylon wool and carbonyl iron monocyte depletion methods, PME eliminated significantly more monocytes and myeloid cells. This observation suggested that these cells may release hematopoietic inhibitory factors for CFU-M. Low concentrations (1%) but not normal (10%) concentrations of blood monocytes were inhibitory (mean inhibition, 48%) to CFU-M. High concentrations of monocytes (50%) augmented CFU-M colonies. HL-60 conditioned media was used to simulate secretory products of early myeloid cells. HL-60 conditioned media (1%) inhibited CFU-M formation but not granulocyte macrophage or granulocyte colonies. We conclude that M-CSF has colony stimulating activity for human marrow that can be recognized after removal of inhibitory cells by PME treatment.

Bone Marrow↗
PubMed1990

High-dose cytosine arabinoside and L-asparaginase therapy for poor-risk adult acute nonlymphocytic leukemia. A retrospective study.

The effectiveness and toxicities of high-dose cytosine arabinoside with L-asparaginase (HiDAC-ASNase) were evaluated in 41 patients with "poor risk" acute nonlymphocytic leukemia (ANLL). Twenty-four patients had either refractory or relapsed primary ANLL, and 17 had ANLL secondary to prior cytotoxic chemotherapy or an underlying hematologic disorder. The overall complete remission (CR) rate was 37%. The CR rates for primary and secondary ANLL were almost identical. Furthermore, advanced age alone did not adversely influence the CR rate. The median CR duration was 302 days with no differences between primary and secondary ANLL. The induction death rate was 24%. Predictors for induction deaths included poor initial performance status, fever at the time of presentation, low cholesterol and/or albumin, and an initial bone marrow aspirate with greater than 50% blasts. These data indicate that HiDAC-ASNase is a moderately effective regimen for patients with poor prognosis ANLL including secondary ANLL.

Adolescent↗
PubMed1990

Use of granulocyte-macrophage colony-stimulating factor in patients with malignancy and bone marrow failure.

Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to 10 patients with refractory malignancies, 2 patients who had myelodysplastic syndromes with severe neutropenia and to a patient who had delayed marrow recovery after 3 cycles of therapy for acute leukemia. A marked neutropenia and monocytopenia was observed within 5 min after an i.v. injection of GM-CSF. This persisted for 1-2 h and seemed related to activation of an adhesive glycoprotein (MO1) on the surface of these cells. With continued daily i.v. administration of GM-CSF, all patients with refractory malignancies developed a striking leukocytosis. Total leukocyte counts reached 75,000/microliters within 2 weeks of treatment. This was due to an increase in band and segmented neutrophils, eosinophils and monocytes. Accelerated myelopoiesis required the continuous presence of GM-CSF; with pump failure for 24 h or discontinuation after 14 days, leukocyte counts returned to normal levels in 24-48 h. GM-CSF also increased myelopoiesis in the patients with myelodysplastic syndromes or following anti-leukemic treatment. These observations suggest that this growth factor should prove a useful adjunct in the treatment of patients with malignancies and bone marrow failure.

Aged↗
PubMed1990

Jejunal vasculitis with protein-losing enteropathy after bone marrow transplantation.

A 37-yr-old white man experienced crampy abdominal pain beginning 21 days after successful bone marrow transplantation for chronic myelogenous leukemia. Generalized edema and hypoproteinemia developed. Symptoms persisted until 61 days post-transplant, when the patient developed an acute abdomen. At laparotomy, an edematous segment of jejunum was resected. Pathological examination showed submucosal vasculitis and necrotizing enteritis. Serum protein and albumin levels returned to normal within a few weeks after surgery. Vasculitis of the gastrointestinal tract should be considered in the differential diagnosis of protein-losing enteropathy after bone marrow transplantation.

Abdominal Pain↗
PubMed1990

Chimerism studies using in situ hybridization for the Y chromosome after T cell-depleted bone marrow transplantation.

In situ hybridization for the Y chromosome (Y-ISH) was used to monitor engraftment in 10 patients with hematological malignancies who had received T cell-depleted marrow transplants from sex-mismatched donors, seven of whom were only partially HLA-matched. In the three patients who engrafted, as the peripheral counts rose, the percentage of host peripheral blood and marrow mononuclear cells decreased steadily, although host cells (less than 1%) could still be detected as late as day 252. The percentage of host granulocytes fell rapidly to less than 0.2%. Seven patients did not achieve full engraftment by day 28. Those with a low percentage of host cells (less than 1%) improved with observation or treatment with steroids, while those with a high or increasing percentage of host cells did not improve even after treatment with GM-CSF or with repeat marrow infusion without reconditioning. In one patient with graft failure, the residual host cells were predominantly CD8+ CD57+ and CD3+ CD56+, phenotypes consistent with non-MHC-restricted cytotoxic T cells. Lack of full engraftment in recipients of T cell-depleted marrow is not always associated with autologous reconstitution and does not always require retransplantation. Y-ISH may be useful for monitoring patients at high risk for graft failure in order to detect adverse trends in mixed chimerism that will alter therapy early after transplantation.

Adolescent↗
PubMed1989

Granulocyte-macrophage colony-stimulating factor is an endogenous regulator of cell proliferation in juvenile chronic myelogenous leukemia.

Juvenile chronic myelogenous leukemia (JCML) is a rare myeloproliferative disorder of early childhood that is clinically and cytogenically distinct from the well-recognized adult type of chronic myeloid leukemia. Unlike the adult disease, growth of hematopoietic progenitors from peripheral blood (PB) occurs in the absence of exogenous stimulus even at low cell densities. This so-called "spontaneous" growth can be abrogated by adherent cell depletion and appears to depend on production of endogenous growth factors. We studied seven children with JCML to determine the nature of endogenous stimulators. With isolated PB mononuclear cells (PBMNCs) and a 3H-thymidine (3H-TdR) incorporation assay, JCML cells were shown to incorporate high levels of 3H-TdR when cultured in the absence of stimulus even at low cell densities. When neutralizing antisera prepared against each of the four known colony-stimulating factors (CSFs), GM-CSF, G-CSF, M-CSF, and interleukin-3 (IL-3), as well as antisera against interleukin-1 (alpha and beta) and tumor necrosis factor (TNF) were added to these cultures, only the antisera against recombinant human GM-CSF (rhGM-CSF) consistently resulted in significant inhibition of cell proliferation, achieving up to 72% inhibition of 3H-TdR incorporation in one case. Monoclonal antibodies (MoAbs) against rhGM-CSF resulted in a similar and highly significant degree of inhibition. A marked inhibitory effect of rhGM-CSF antiserum on "spontaneous" growth of PB CFU-GM derived colonies in semisolid medium was also demonstrated in four of five patients studied (87% to 90% inhibition). Production of growth factors by highly enriched JCML monocytes was variable. When initially studied in five of the seven patients, the monocytes from three of the patients revealed increased release of IL-1-like activities; two patients had levels similar to those of controls. One patient with normal levels when initially studied was later shown to have markedly increased amounts of IL-1-like activities in a second preparation of monocyte-conditioned medium (MCM). High levels of GM-CSF were detected in the initial MCM from one patient, but this may have indirectly reflected elevated IL-1-like activities present in the MCM. IL-3 and M-CSF levels were either low or undetectable in the patients studied as compared with MCM prepared with normal adult monocytes. These results clearly implicate GM-CSF as the primary endogenous regulator of JCML cell proliferation in culture and suggest that this malignant myeloproliferative disease may in part result from paracrine stimulation of marrow progenitor cells by growth factors/cytokines secreted by the malignant monocytes.

Bone Marrow↗
PubMed1989

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purged marrows for acute nonlymphocytic leukemia in late remission or early relapse.

Twenty-four patients with acute nonlymphocytic leukemia (ANLL) were treated with high-dose chemotherapy or chemoradiotherapy followed by infusion of autologous marrow purged with 100 micrograms/mL of 4-hydroperoxycyclophosphamide (4HC). The marrow harvests were performed when there were less than 5% blasts in the marrow. Seven patients were transplanted in second complete remission (CR), eight in third CR, one in fourth CR, and eight in early relapse. The median time to achieve 500 neutrophils/microL or 1,000 leukocytes/microL was 30 days. A platelet count of 20,000/microL and 50,000/microL was achieved at a median of 67 and 91 days, respectively. One patient failed to engraft by day 58. There were five other transplant-related deaths: sepsis (one), intracerebral hemorrhage (one), veno-occlusive disease (one), and interstitial pneumonia (two). Four of seven evaluable patients transplanted in early relapse obtained a CR lasting 112, 143, 189, and greater than 615 days. Eight of 11 evaluable patients transplanted in CR have relapsed at a median of 153 days (range, 104 to 311). The actuarial survival for all patients was 19%. There was a trend toward improved relapse-free survival for patients transplanted in remission as opposed to those transplanted in relapse (P = .11).

Actuarial Analysis↗
PubMed1989

Effect in vivo of multiple injections of purified murine and recombinant human macrophage colony-stimulating factor to mice.

Hematopoietic efficacy in vivo of multiple injections of purified murine L-cell and recombinant human macrophage colony-stimulating factors (M-CSF; specific activity, greater than 2 x 10(7) units/mg) was assessed in mice. Injections i.v. of sterile saline or 20,000 units of M-CSF were administered once (at 0 h), twice (at 0 and 12 h), or three times (at 0, 12, and 24 h) to C57BL/6 x DBA/2 F1 mice. Numbers and cycling rates of marrow and spleen granulocyte-macrophage, erythroid, and multipotential progenitor cells were assessed 32-36 h after the first injection. Marrow, spleen, and peripheral blood cellularity was assessed at intervals of up to 105 h. Progenitor cell cycling rates were significantly increased after one and two injections of M-CSF but were reduced to a slow or noncycling state after three injections. For marrow cells, the third injection resulted in a significant suppression of hematopoietic progenitor cell cycling compared to the control group. No significant changes were noted for number of progenitors per femur or spleen, for marrow, spleen, or peripheral blood cellularity, or for differential cell counts in these organs after any of the M-CSF treatment schedules. Suppression of progenitor cell proliferation noted after three injections of M-CSF may at least partially explain why repeated injections of 20,000 units of M-CSF fails to increase bone marrow, spleen, or blood cellularity even though one injection of M-CSF increases cycling rates of the hematopoietic progenitors.

Animals↗
PubMed1989

Recombinant human granulocyte/macrophage colony-stimulating factor enhances monocyte cytotoxicity and secretion of tumor necrosis factor alpha and interferon in cancer patients.

The colony-stimulating factors (CSFs) promote the proliferation and differentiation of hematopoietic precursors and more recently have been shown to amplify the functions of mature phagocytes in vitro. In this study recombinant human granulocyte/macrophage colony-stimulating factor (rGM-CSF) was administered to cancer patients to determine whether the cytotoxic and secretory activity of their blood monocytes could be enhanced. Patients with refractory neoplastic disease were treated with rGM-CSF either as a single bolus or as a constant infusion for 14 days at either 100 or 500 micrograms/m2 per day. As has been reported by others, the number of peripheral blood monocytes and granulocytes rose markedly in a dose-response fashion during infusion with rGM-CSF. The functional capacity of monocytes was increased by rGM-CSF, since the cytotoxicity of monocytes against antibody-coated xenogeneic cells was increased during the constant infusion compared to baseline. In addition, monocytes harvested during the constant infusion and stimulated with lipopolysaccharide (LPS) in vitro secreted increased quantities of tumor necrosis factor alpha (TNF-alpha) and interferon (IFN). These data indicate that rGM-CSF can enhance both the number and the function of peripheral blood monocytes in vivo.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1989

The effect of recombinant human granulocyte macrophage colony-stimulating factor on neutrophil activation in patients with refractory carcinoma.

Patients with refractory carcinoma were treated with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) by intravenous (IV) infusion. During the period of treatment, studies of polymorphonuclear leukocyte superoxide (O2-) release in response to formylmethionylleucylphenylalanine (fMLP) and phorbol myristate acetate (PMA) and studies of chemotaxis in response to fMLP and C5a were performed. We observed that patients receiving rhGM-CSF in vivo exhibited primed O2- release after stimulation both with fMLP and PMA. Chemotaxis, however, was not enhanced by the treatment. These data suggest that host defenses may be enhanced by this treatment and that rhGM-CSF may be a useful therapeutic adjunct in compromised patients.

Carcinoma↗