Preclinical Safety of Recombinant Human Interleukin-18

2003 ◽  
Vol 31 (5) ◽  
pp. 554-561 ◽  
Author(s):  
Danuta J. Herzyk ◽  
Peter J. Bugelski ◽  
Timothy K. Hart ◽  
Patrick J. Wier
Keyword(s):  
Cell Mass ◽  
Lymphoid Hyperplasia ◽  
Red Cell ◽  
Interleukin 18 ◽  
Cast Nephropathy ◽  
Cell Counts ◽  
Red Cell Mass ◽  
Spleen And Lymph Nodes ◽  
Pharmacologically Active ◽  
Preclinical Safety

Recombinant human interleukin-18 (rHuIL-18) is currently in clinical trials for treatment of cancer. This report presents results of preclinical toxicity studies with rHuIL-18 in cynomolgus monkeys and recombinant murine IL-18 (rMuIL-18) in mice. The rHuIL-18 was administered intravenously in 1 or 2 different 5-day cycles at doses 0.3 to 75 mg/kg/day in monkeys. Decreases in red cell mass, neutrophil, and platelet counts, increases in monocyte and large unstained cell counts, and lymphoid hyperplasia in spleen and lymph nodes were mild, reversible, and likely related to the pharmacologic activity of IL-18. The only toxic effect was protein cast nephropathy, secondary to coprecipitation of administered IL-18 and Tamm-Horsfall protein in the distal nephron, that only occurred at 75 mg/kg/day. Other adverse effects of rHuIL-18 were related to strong immunogenicity in monkeys and were manifest only during a second dosing cycle. The rMuIL-18, at similar dosing levels and cycles in mice, resulted in reduced red cell mass, increased white blood cell counts, spleen and lymph node hyperplasia, and mild, reversible changes in intestine, liver, and lungs. Protein cast nephropathy occurred in mice at doses ≥30 mg/kg/day. In conclusion, preclinical safety studies showed that rIL-18 was well tolerated at pharmacologically active doses in both monkeys and mice.

Hematological measurements in rats flown on Spacelab shuttle, SL-3

1987 ◽  
Vol 252 (2) ◽  
pp. R216-R221 ◽  
Author(s):  
R. D. Lange ◽  
R. B. Andrews ◽  
L. A. Gibson ◽  
C. C. Congdon ◽  
P. Wright ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Life Science ◽  
Bone Marrow Cells ◽  
Cell Mass ◽  
Red Cell ◽  
Cell Counts ◽  
Animal Bone ◽  
Red Cell Mass ◽  
And Control ◽  
First Time

Previous studies have shown that a decrease in red cell mass occurs in astronauts, and some studies indicate a leukocytosis occurs. A life science module housing young and mature rats was flown on shuttle mission Spacelab 3 (SL-3), and the results of hematology studies of flight and control rats are presented. Statistically significant increases in the hematocrit, red blood cell counts, and hemoglobin determinations, together with a mild neutrophilia and lymphopenia, were found in flight animals. No significant changes were found in bone marrow and spleen cell differentials or erythropoietin determinations. Clonal assays demonstrated an increased erythroid colony formation of flight animal bone marrow cells at erythropoietin doses of 0.02 and 1.0 U/ml but not 0.20 U/ml. These results agree with some but vary from other previously published studies. Erythropoietin assays and clonal studies were performed for the first time.

Troglitazone has no effect on red cell mass or other erythropoietic parameters

1999 ◽  
Vol 55 (2) ◽  
pp. 101-104 ◽  
Author(s):  
M. M. R. Young ◽  
L. Squassante ◽  
J. Wemer ◽  
S. P. van Marle ◽  
P. Dogterom ◽  
...  
Keyword(s):  
Cell Mass ◽  
Red Cell ◽  
Red Cell Mass

Should Whole-Body Red Cell Mass Be Measured or Calculated?

2000 ◽  
Vol 26 (1) ◽  
pp. 25-31 ◽  
Author(s):  
Ingrid Balga ◽  
Max Solenthaler ◽  
Miha Furlan
Keyword(s):  
Cell Mass ◽  
Whole Body ◽  
Red Cell ◽  
Red Cell Mass

Analysis of Red Cell Mass and Plasma Volume in Patients With Polycythemia

2005 ◽  
Vol 129 (1) ◽  
pp. 89-91 ◽  
Author(s):  
Mordechai Lorberboym ◽  
Naomi Rahimi-Levene ◽  
Helena Lipszyc ◽  
Chun K. Kim
Keyword(s):  
Body Weight ◽  
Plasma Volume ◽  
Cell Mass ◽  
Mean Value ◽  
Whole Body ◽  
Red Cell ◽  
Volume Data ◽  
Red Cell Mass ◽  
The Mean ◽  
Iodine 125

Abstract Context.—Polycythemia describes an increased proportion of red blood cells in the peripheral blood. In absolute polycythemia, there is increased red cell mass (RCM) with normal plasma volume, in contrast with apparent polycythemia, in which there is increased or normal RCM and decreased plasma volume. In order to deliver the appropriate treatment it is necessary to differentiate between the two. Objective.—A retrospective analysis of RCM and plasma volume data are presented, with special attention to different methods of RCM interpretation. Design.—The measurements of RCM and plasma volume in 64 patients were compared with the venous and whole-body packed cell volume, and the incidence of absolute and apparent polycythemia was determined for increasing hematocrit levels. Measurements of RCM and plasma volume were performed using chromium 51–labeled red cells and iodine 125–labeled albumin, respectively. The measured RCM of each patient was expressed as a percentage of the mean expected RCM and was also defined as being within or outside the range of 2 SD of the mean. The results were also expressed in the traditional manner of mL/kg body weight. Results.—Twenty-one patients (13 women and 8 men) had absolute polycythemia. None of them had an increased plasma volume beyond 2 SD of the mean. When expressed according to the criteria of mL/kg body weight, 17 of the 21 patients had abnormally increased RCM, but 4 patients (19%) had a normal RCM value. Twenty-eight patients had apparent polycythemia. The remaining 15 patients had normal RCM and plasma volume. Conclusions.—The measurement of RCM and plasma volume is a simple and necessary procedure in the evaluation of polycythemia. In obese patients, the expression of RCM in mL/kg body weight lacks precision, considering that adipose tissue is hypovascular. The results of RCM are best described as being within or beyond 2 SD of the mean value.

Failure of prolonged exercise training to increase red cell mass in humans

1996 ◽  
Vol 270 (1) ◽  
pp. H121-H126 ◽  
Author(s):  
J. K. Shoemaker ◽  
H. J. Green ◽  
J. Coates ◽  
M. Ali ◽  
S. Grant
Keyword(s):  
Exercise Training ◽  
Prolonged Exercise ◽  
Cell Mass ◽  
Hemoglobin Concentration ◽  
Red Cell ◽  
Total Blood ◽  
Mean Cell Volume ◽  
Red Cell Mass ◽  
Mean Cell Hemoglobin

The purpose of this study was to investigate the time-dependent effects of long-term prolonged exercise training on vascular volumes and hematological status. Training using seven untrained males [age 21.1 +/- 1.4 (SE) yr] initially consisted of cycling at 68% of peak aerobic power (VO2peak) for 2 h/day, 4-5 days/wk, for 11 wk. Absolute training intensity was increased every 3 wk. Red cell mass (RCM), obtained using 51Cr, was unchanged (P > 0.05) with training (2,142 +/- 95, 2,168 +/- 86, 2,003 +/- 112, and 2,080 +/- 116 ml at 0, 3, 6, and 11 wk, respectively) as were serum erythropoietin levels (17.1 +/- 4.3, 13.9 +/- 3.5, and 17.0 +/- 2.0 U/l at 0, 6, and 11 wk, respectively). Plasma volume measured with 125I-labeled albumin and total blood volume (TBV) were also not significantly altered. The increase in mean cell volume that occurred with training (89.7 +/- 0.95 vs. 91.0 +/- 1.0 fl, 0 vs. 6 wk, P < 0.05) was not accompanied by changes in either mean cell hemoglobin or mean cell hemoglobin concentration. Serum ferritin was reduced 73% with training (67.4 +/- 13 to 17.9 +/- 1 microgram/l, 0 vs. 11 wk, P < 0.05). Total hemoglobin (HbTot) calculated as the product of hemoglobin concentration and TBV was unaltered (P > 0.05) at both 6 and 11 wk of training. The 15% increase in VO2peak (3.39 +/- 0.16 to 3.87 +/- 0.14 l/min, 0 vs. 11 wk, P < 0.05) with training occurred despite a failure of training to change TBV, RCM, or HbTot.

Chronic Deficits in Red-Cell Mass in Patients with Orthopaedic Injuries (Stress Anemia)

1972 ◽  
Vol 54 (5) ◽  
pp. 1001-1014 ◽  
Author(s):  
P. E. BIRON ◽  
J. HOWARD ◽  
M. D. ALTSCHULE ◽  
C. R. VALERI
Keyword(s):  
Cell Mass ◽  
Red Cell ◽  
Red Cell Mass ◽  
Orthopaedic Injuries

scholarly journals Effect of Prolactin on Erythropoiesis in the Mouse

Blood ◽  
1964 ◽  
Vol 24 (6) ◽  
pp. 726-738 ◽  
Author(s):  
J. H. JEPSON ◽  
L. LOWENSTEIN
Keyword(s):  
Growth Hormone ◽  
Cell Mass ◽  
Pregnant Mouse ◽  
Red Cell ◽  
Intact Mouse ◽  
Mouse Plasma ◽  
Red Cell Mass

Abstract The effect of prolactin, growth hormone, progesterone, testosterone, lactating mouse plasma (fifth postpartum day), pregnant mouse plasma (sixteenth to nineteenth day of pregnancy) on erythropoiesis in the polycythemic mouse has been studied and compared. Prolactin was found to stimulate erythropoiesis in the intact mouse. Also, pregnant mouse plasma and lactating mouse plasma had an erythropoietic stimulating effect. Prolactin produced an increase in the red cell mass when administered over a prolonged period to normal and orchidectomized mice. This suggests that the testes are not necessary for the action of prolactin. It is suggested that prolactin could function as an erythropoietic stimulatory component in pregnant and lactating mouse plasma.

Erythropoietin production in exhypoxic polycythemic mice

1989 ◽  
Vol 256 (4) ◽  
pp. C925-C929 ◽  
Author(s):  
I. Seferynska ◽  
J. Brookins ◽  
J. C. Rice ◽  
J. W. Fisher
Keyword(s):  
Body Weight ◽  
Ambient Pressure ◽  
Cell Mass ◽  
Rapid Decline ◽  
Red Cell ◽  
Erythropoietin Production ◽  
Hypobaric Chamber ◽  
Red Cell Mass ◽  
Posthypoxic Period ◽  
Serum Erythropoietin

Our present study was undertaken to determine the serum erythropoietin concentration (radioimmunoassay), hematocrit, red cell mass, and body weight of mice exposed to hypoxia in a hypobaric chamber (0.42 atm, 22 h/day) for 14 days and during the 10 posthypoxic days at ambient pressure to clarify the correlation of the red cell mass and erythropoietin production during hypoxia. The mean serum erythropoietin titer was 326.23 +/- 77.04 mU/ml after 2 days, reached the highest level after 3 days (452.2 +/- 114.5 mU/ml), then gradually declined to a level of 36.5 +/- 11.4 mU/ml after 14 days of hypoxia, and was undetectable during the 10-day posthypoxic period. The hematocrit values were significantly increased from 41.09 +/- 0.50% at day 0 to 51.65 +/- 1.08% after 3 days and to 72.20 +/- 1.53% after 14 days of hypoxia. The red cell mass (calculated from initial body weight) increased from 3.24 +/- 0.1 ml/100 g at day 0 to 7.32 +/- 0.46 ml/100 g after 14 days of hypoxia and declined to 6.66 +/- 0.53 ml/100 g at the end of the 10-day posthypoxic period. The mice lost weight while they were in the hypobaric chamber and showed a significant increase in body weight during the 10-day posthypoxic period. These studies support the concept that chronic intermittent hypoxia causes an early increase, followed by a rapid decline, in erythropoietin production, which is correlated with the gradual increase in red cell mass.

scholarly journals Improving Autologous Blood Harvest: Recovery of Red Cells from Sponges and Suction

1987 ◽  
Vol 15 (4) ◽  
pp. 421-424 ◽  
Author(s):  
A. K. Ronai ◽  
J. J. Glass ◽  
A. S. Shapiro
Keyword(s):  
Blood Loss ◽  
Autologous Blood ◽  
Cell Mass ◽  
Haemoglobin Concentration ◽  
Red Cells ◽  
Red Cell ◽  
Cell Salvage ◽  
Donor Blood ◽  
Red Cell Mass ◽  
Free Haemoglobin

The efficacy of red cell salvage was assessed under circumstances which simulated blood loss managed with sponges or suction. Expired banked blood was equally divided and processed by either suction, or absorbing the blood on a sponge followed by rinsing the sponge in saline. These two techniques were used to harvest washed, centrifuged erythrocytes. The volume, haematocrit and free haemoglobin concentration of the banked blood and the processed units were measured, and smears from all units were examined microscopically. The red cell mass was calculated as the product of the volume and haematocrit. The red cell mass recovered by suction and from sponges averaged 93% and 87% respectively. Blood lost in sponges can be recovered and used to increase the available autologous blood, thereby reducing the need for donor blood.

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