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Biomedical subjects

W Sheridan

Publications and source records attributed to W Sheridan.

At least 19 recordsLinked to original sources
PubMed2001

Thrombopoietin therapy increases platelet yields in healthy platelet donors.

The recombinant thrombopoietins have been shown to be effective stimulators of platelet production in cancer patients. It was therefore of interest to determine if one of these, pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), could be used to increase platelet counts and consequently platelet yields from apheresis in healthy platelet donors. In a blinded, 2-cycle, crossover study, 59 platelet donors were randomized to receive a single subcutaneous injection of PEG-rHuMGDF (1 microg/kg or 3 microg/kg) or placebo and 15 days later undergo platelet apheresis. Donors treated with placebo had a median peak platelet count after PEG-rHuMGDF injection of 248 x 10(9)/L compared with 366 x 10(9)/L in donors treated with 1 microg/kg PEG-rHuMGDF and 602 x 10(9)/L in donors treated with 3 microg/kg PEG-rHuMGDF. The median maximum percentage that platelet counts increased from baseline was 10% in donors who received placebo compared with 70% in donors who received 1 microg/kg and 167% in donors who received 3 microg/kg PEG-rHuMGDF. There was a direct relationship between the platelet yield and the preapheresis platelet count: Placebo-treated donors provided 3.8 x 10(11) (range 1.3 x 10(11)-7.9 x 10(11)) platelets compared with 5.6 x 10(11) (range 2.6 x 10(11)-12.5 x 10(11)) or 11.0 x 10(11) (range 7.1 x 10(11)-18.3 x 10(11)) in donors treated with 1 microg/kg or 3 microg/kg PEG-rHuMGDF, respectively. Substandard collections (<3 x 10(11) platelets) were obtained from 26%, 4%, and 0% of the placebo, 1 microg/kg, and 3 microg/kg donors, respectively. No serious adverse events were reported; nor were there events that met the criteria for dose-limiting toxicity. Thrombopoietin therapy can increase platelet counts in healthy donors to provide a median 3-fold more apheresis platelets compared with untreated donors.

Adult↗
PubMed2000

Effects of megakaryocyte growth and development factor on platelet production, platelet life span, and platelet function in healthy human volunteers.

The effects of thrombopoietic stimulation on megakaryocytopoiesis, platelet production, and platelet viability and function were examined in normal volunteers randomized to receive single bolus subcutaneous injections of 3 microg/kg pegylated recombinant megakaryocyte growth and development factor (PEG-rHuMGDF) or placebo in a 3:1 ratio. PEG-rHuMGDF transiently doubled circulating platelet counts, from 237 +/- 41 x 10(3)/microL to 522 +/- 90 x 10(3)/microL (P <.0001), peaking on day 12. Baseline and day-12 samples showed no differences in responsiveness of platelets to adenosine diphosphate or thrombin receptor agonist peptide (P >.4 in all cases); expression of platelet ligand-induced binding sites or annexin V binding sites (P >.6 in both cases); or density of platelet TPO-receptors (P >.5). Platelet counts normalized by day 28. The life span of autologous (111)In-labeled platelets increased from 205 +/- 18 hours (baseline) to 226 +/- 22 hours (P <.01) on day 8. Platelet life span decreased from 226 +/- 22 hours (day 8) to 178 +/- 53 hours (P <.05) on day 18. The theoretical basis for senescent changes in mean platelet life span was illustrated by biomathematical modeling. Platelet turnover increased from 43.9 +/- 11.9 x 10(3) platelets/microL/d (baseline) to 101 +/- 27.6 x 10(3) platelets/microL/d (P =.0009), and marrow megakaryocyte mass expanded from 37.4 +/- 18.5 fL/kg to 62 +/- 17 x 10(10) fL/kg (P =. 015). Although PEG-rHuMGDF initially increased megakaryocyte volume and ploidy, subsequently ploidy showed a transient reciprocal decrease when the platelet counts exceeded placebo values. In healthy human volunteers PEG-rHuMGDF transiently increases megakaryocytopoiesis 2-fold. Additionally, peripheral platelets expand correspondingly and exhibit normal function and viability during the ensuing 10 days. The induced perturbation in steady state thrombopoiesis resolves by 4 weeks. (Blood. 2000;95:2514-2522)

Blood Platelets↗
PubMed1998

Overview of the safety and biologic effects of PEG-rHuMGDF in clinical trials.

Completed randomized placebo-controlled phase I/II studies of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) have demonstrated that this recombinant Mpl ligand has potent and lineage-dominant effects on megakaryopoiesis and platelet production. Platelets produced after PEG-rHuMGDF administration display normal ultrastructure and functional attributes. In these early studies, PEG-rHuMGDF accelerated the recovery of baseline platelet counts after cytotoxic chemotherapy in cancer patients by six to seven days, indicating the potential for clinical benefit in this setting. PEG-rHuMGDF has been well-tolerated in clinical trials, with similar adverse events in placebo and PEG-rHuMGDF populations, and an observed adverse event profile consistent with the effects of underlying malignancy and chemotherapy. The lack of inflammatory cytokine effects in the clinic is consistent with results of animal studies, the narrow tissue distribution of Mpl and the lineage-dominant effect of PEG-rHuMGDF on megakaryopoiesis. Additional phase I/II studies have commenced in the fields of cancer chemotherapy and augmentation of platelet donation, and a phase III study is underway in patients undergoing bone marrow transplantation.

Clinical Trials as Topic↗
PubMed1997

Chronic thrombocytopenia is induced in dogs by development of cross-reacting antibodies to the MpL ligand.

The MpL ligand (ML) is a potent stimulus for thrombocytopoiesis. To create an in vivo model of ML deficiency, we injected dogs with a recombinant human ML (rhML) to determine whether cross-reacting antibodies would develop and cause thrombocytopenia. RhML was administered subcutaneously for 8 weeks to three normal dogs (mean platelets, 197 +/- 5.5 x 10(3)/microL). Within 5 days their platelet counts were twice baseline and greater than 4 times baseline by day 21. Then, uniformly, chronic thrombocytopenia developed. At 1 week after terminating rhML, mean platelets were 0.5 times baseline and at 2 months 0.25 times baseline. Early in treatment, marrow biopsies showed increased megakaryocyte number and ploidy, which decreased as platelets declined. Paralleling these changes, high titer anti-rhML antibodies developed. Autologous 51Cr-labeled platelet recovery and survival measurements indicated that the thrombocytopenia was principally due to decreased production. Infusion of plasma from the thrombocytopenic dogs into two normal dogs and one dog previously made thrombocytopenic with rhML caused platelet counts to fall gradually. These studies show that dogs with anti-rhML antibodies develop thrombocytopenia, presumably because the cross-reacting antibodies neutralize endogenous canine ML. The results strongly suggest that ML plays an essential role in maintaining normal platelet levels.

Administration, Cutaneous↗
PubMed1997

Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer.

BACKGROUND: Polyethylene glycol (PEG)-conjugated recombinant human megakaryocyte growth and development factor (MGDF, also known as PEG-rHuMGDF), a recombinant molecule related to thrombopoietin, specifically stimulates megakaryopoiesis and platelet production and reduces the severity of thrombocytopenia in animals receiving myelosuppressive chemotherapy. METHODS: We conducted a randomized, double-blind, placebo-controlled dose-escalation study of MGDF in 53 patients with lung cancer who were treated with carboplatin and paclitaxel. The patients were randomly assigned in blocks of 4 in a 1:3 ratio to receive either placebo or MGDF (0.03, 0.1, 0.3, 1.0, 3.0, or 5.0 microg per kilogram of body weight per day), injected subcutaneously. No other marrow-active cytokines were given. RESULTS: In the 38 patients who received MGDF after chemotherapy, the median nadir platelet count was 188,000 per cubic millimeter (range, 68,000 to 373,000), as compared with 111,000 per cubic millimeter (range, 21,000 to 307,000) in 12 patients receiving placebo (P = 0.013). The platelet count recovered to base-line levels in 14 days in the treated patients as compared with more than 21 days in those receiving placebo (P<0.001). Among all 40 patients treated with MGDF, 1 had deep venous thrombosis and pulmonary embolism, and another had superficial thrombophlebitis. CONCLUSIONS: MGDF has potent stimulatory effects on platelet production in patients with chemotherapy-induced thrombocytopenia.

Adult↗
PubMed1994

Peripheral blood lymphocyte surface antigen expression and prognosis in myeloma: Australian Leukaemia Study Group Study.

The Australian Leukaemia Study Group myeloma study (MM1) aimed to determine the prognostic significance of clinical and immunophenotypic markers in patients with multiple myeloma. All patients were treated with standard dose melphalan and prednisone. Seventy-four patients were entered and the median survival was 27 months. Serum beta 2-microglobulin (beta 2M) and albumin levels were the only significant clinical factors influencing survival (p = 0.007 and p = 0.008, respectively). Patients with raised levels of CD38+ lymphocytes at presentation had a significantly shorter survival than patients with normal levels (p = 0.01, logrank test, median 19 months vs 33 months). CD38 antigen expression was independent of beta 2M but patients with raised levels of CD38 had significantly lower levels of albumin than patients with normal levels (p = 0.001) which may explain their poorer survival. Salmon and Durie stage was not associated with antigen expression. No other B-cell antigens (CD10, CD19, CD20, CD21, CD22, CD23, FMC1 or FMC7) or plasma cell antigens tested (PCA-1) were found to be associated with prognosis. Patients who achieved plateau phase had a better prognosis than those who did not (p = 0.04 in a landmark analysis). Patients who achieved plateau phase following an objective response appeared to have a better prognosis than those who were in plateau phase at presentation (p = 0.09 in a landmark analysis). Light chain isotype suppression (LCIS) was not associated with a significant survival advantage and did not correlate with any known prognostic indicator.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Plasma fatty acid profiles in benign breast disorders.

Breast pain (mastalgia) and macroscopic breast cysts present commonly. Mastalgia may be improved by dietary manipulation to reduce saturated fat or supplement essential fatty acid intake. Fatty acid profiles were measured in women with mastalgia and breast cysts, before and during treatment with evening primrose oil, a rich source of essential fatty acids. The fatty acid profiles of both groups of patients were abnormal, with increased proportions of saturated fatty acids and reduced proportions of essential fatty acids. Treatment with evening primrose oil improved the fatty acid profiles towards normal, but this was not necessarily associated with a clinical response.

Breast Diseases↗
PubMed1992

Studies of oral neutrophil levels in patients receiving G-CSF after autologous marrow transplantation.

Patients are at risk of mucositis and infections in the oral cavity during the neutropenic period after chemotherapy, which are significant causes of morbidity. In phase I/II studies with the haemopoietic growth factor granulocyte colony stimulating factor (G-CSF), a reduction in post-chemotherapy mucositis has been observed in addition to haematologic effects. To understand this phenomenon better in patients receiving G-CSF following high-dose chemotherapy with autologous bone marrow transplantation (ABMT), we studied the effects of G-CSF on levels of neutrophils recoverable from the oral cavity using a quantitative mouthrinse assay. In normal subjects, mouthrinses contained 472 +/- 329 x 10(3) neutrophils/mouthrinse. After chemotherapy followed by ABMT, mouthrinse neutrophil levels decreased to undetectable levels during the neutropenic period, but recovered 1-2 and 3-9 d before circulating neutrophil levels reached 0.1 and 1 x 10(9)/l respectively, whether or not patients received G-CSF. In patients who received G-CSF, the mean cumulative mucositis score was reduced from 35 +/- 9 to 21 +/- 12 (P < 0.05), and the maximum mean daily mucositis score was reduced from 2.8 +/- 0.5 to 1.7 +/- 0.9 (P < 0.01), compared to patients who did not receive G-CSF after ABMT. These studies provide in vivo evidence that neutrophils produced during G-CSF therapy are available to leave the circulation and enter tissues where their function is required for host defence. Since the usual temporal relationship between oral and peripheral blood neutrophil recovery was preserved during G-CSF administration after ABMT, these data support the hypothesis that the reduction in post-ABMT mucositis observed with G-CSF therapy may reflect a beneficial effect of G-CSF on the kinetics of oral mucosal neutrophil recovery in addition to the effect of G-CSF to accelerate peripheral blood neutrophil recovery.

Adolescent↗
PubMed1991

Pachymeningitis associated with a pulmonary nodule.

The authors report a case of hypertrophic pachymeningitis, a rare cause of spinal cord compression. In this patient, dural inflammation was associated with a histologically identical pulmonary lesion. Such an association has not been described previously and supports the hypothesis that this disease is related to other connective tissue disorders.

Humans↗
PubMed1990

Phase I study of intravenously administered bacterially synthesized granulocyte-macrophage colony-stimulating factor and comparison with subcutaneous administration.

A Phase I study of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was undertaken in 21 patients with advanced malignancy or neutropenia. rhGM-CSF was administered once daily by i.v. bolus injection (0.3 to 3 micrograms/kg/day) or 2-h i.v. infusion (3 to 20 micrograms/kg day) for 10 days. rhGM-CSF at all i.v. doses caused an immediate transient decrease in circulating neutrophils, eosinophils, and monocytes. By 6 h after rhGM-CSF, circulating leukocyte levels were restored. Daily i.v. bolus dosing (0.3 to 3 micrograms/kg/day) did not elevate leukocyte levels except in one neutropenic patient. Daily 2-h i.v. infusions (10 to 20 micrograms/kg/day) caused a dose-dependent leukocytosis with increased levels of neutrophils (up to 4.3-fold), eosinophils (up to 18-fold), and monocytes (up to 3.5-fold). Marrow aspirates showed increased proportions of promyelocytes and myelocytes during rhGM-CSF administration. Retreatment after 10 days without rhGM-CSF resulted in a more marked leukocytosis at doses greater than or equal to 10 micrograms/kg/day. Platelet levels decreased for the first 3 days and then increased during the first course of rhGM-CSF administration. Two patients with chronic lymphocytic leukemia had a transient reduction in lymphocytosis. Serum cholesterol and albumin levels decreased, and vitamin B12 levels increased during rhGM-CSF treatment. At doses of up to 15 micrograms/kg/day, rhGM-CSF was relatively well tolerated by the patients, but adverse effects included bone pain, lethargy, fever, rash, and weight gain. A first dose reaction characterized by hypoxia and hypotension was identified at dose levels greater than or equal to 1 microgram/kg. Dosing i.v. was less potent at inducing a leukocytosis than previously observed for equivalent s.c. doses and was associated with a higher incidence of generalized rash and first dose reactions. The maximal tolerated dose of i.v. rhGM-CSF was 15 micrograms/kg/day. Phase II studies in which the derived effect is to raise leukocyte levels should be undertaken at rhGM-CSF doses of 3 to 15 micrograms/kg/day.

Adult↗
PubMed1990

A randomized trial of dietary intervention with essential fatty acids in patients with categorized cysts.

Two hundred women with breast cysts proven by aspiration were entered into a randomized double-blind trial of Efamol (evening primrose oil) at a dose of 6 capsules daily or equivalent placebo dose for a year. Cysts were categorized by initial electrolyte composition, and follow-up continued for 1 year posttherapy. Recurrent cyst formation in the first year was slightly (but not significantly) lower in the Efamol group compared with the placebo-treated group. The Efamol treatment was well tolerated as the dropout rate was only 7% and equal in both the active and placebo groups. The initial electrolyte composition did not predict for cyst recurrence.

Adult↗
PubMed1989

Effects of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy.

STUDY OBJECTIVE: To define the clinical and hematologic effects of subcutaneously administered bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). DESIGN: Single arm nonrandomized dose escalation study. PATIENTS: Twenty-one patients with advanced malignancy who were not receiving concurrent myelosuppressive therapy. INTERVENTIONS: Subcutaneous administration of rhGM-CSF by once-daily injection to groups of two to four patients at doses of 0.3 to 30 micrograms/kg body weight.d for 10 consecutive days. Some patients received a second 10-day period of daily rhGM-CSF treatment after a 10-day nontreatment interval followed by alternate-day treatment. Clinical status and hematologic values were monitored frequently. MEASUREMENTS AND MAIN RESULTS: All doses of rhGM-CSF caused an immediate transient fall of 84% to 99% in circulating neutrophils, eosinophils, and monocytes. Continued daily dosing caused a leukocytosis of up to 10-fold with increases in numbers of circulating neutrophils, eosinophils, monocytes, and lymphocytes. There appeared to be a plateau in the increase in neutrophils in the dose range 3 to 15 micrograms/kg.d. Marrow aspirates showed increased proportions of promyelocytes and myelocytes. Alternate-day injection of 15 micrograms/kg maintained a leukocytosis. At doses up to 15 micrograms/kg.d, rhGM-CSF was well tolerated but adverse effects included bone pains, myalgias, rashes, and liver dysfunction. At doses exceeding 15 micrograms/kg.d, pericarditis was a dose-limiting toxicity. Idiopathic thrombocytopenic purpura was reactivated by rhGM-CSF in one patient. CONCLUSIONS: Bacterially synthesized rhGM-CSF induces a leukocytosis in the dose range of 3 to 15 micrograms/kg.d. These doses are appropriate for phase II studies.

Adult↗
PubMed1989

Pharmacology of the colony-stimulating factors.

Leukocyte production is influenced by a family of glycoproteins called colony-stimulating factors. Two of these have been purified, cloned and produced in quantities sufficient for clinical use. Granulocyte colony-stimulating factor (G-CSF) preferentially stimulates neutrophil production and has been shown to reduce the duration of neutropenia following chemotherapy. G-CSF therapy also has beneficial effects in a variety of other neutropenic states. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates neutrophil, monocyte and eosinophil production and function. GM-CSF is associated with more diverse haematological and clinical effects. George Morstyn and colleagues summarize the promising results from the early clinical trials with these new therapeutic agents.

Animals↗
PubMed1989

Treatment of chemotherapy-induced neutropenia by subcutaneously administered granulocyte colony-stimulating factor with optimization of dose and duration of therapy.

In patients who have not received extensive prior chemotherapy or radiotherapy, it has been previously demonstrated that granulocyte colony-stimulating factor (G-CSF) abrogated the leukopenia following administration of melphalan (25 mg/m2). This study examined the necessity of a prechemotherapy period of G-CSF administration and the effect of varying the timing and duration of postchemotherapy G-CSF. Initially, patients received 0.3, 1.0, 3.0, and 10 micrograms/kg/d subcutaneously on days 1 to 5 and days 10 to 18. Melphalan was given on day 9. In the next portion of the study melphalan was administered on day 1 and G-CSF, 10 micrograms/kg/d, was administered by subcutaneous infusion on five schedules: (1) days 2 to 13; (2) days 8 to 13; (3) days 2 to 18; (4) days 8 to 18; (5) days -9 to -2 and 2 to 13. G-CSF produced a rapid and sustained elevation in neutrophil levels within 24 hours even when started 8 days after melphalan. This treatment was sufficient to abrogate the neutropenia in patients who had received no prior chemotherapy. It was not necessary to continue G-CSF for more than 7 days. G-CSF did not consistently alter the course of the thrombocytopenia that followed this dose of melphalan. G-CSF was well tolerated, although mild bone pain occurred and was reduced with acetaminophen. One of 22 patients developed cellulitis at an infusion site. We conclude that after melphalan chemotherapy, G-CSF may need to be given for only a short period to prevent chemotherapy-induced neutropenia, and that G-CSF induces a rapid rise in neutrophil levels even when started 8 days after melphalan administration.

Adult↗