Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients
Abstract
:1. Introduction
2. Results
2.1. Participants
2.2. Laboratory Measurements
2.3. Clinical Outcomes
3. Discussion
4. Materials and Methods
4.1. Study Design and Ethics
4.2. Participant Screening and Enrollment
4.3. Drug Administration
4.4. Laboratory Measures
4.5. Clinical Outcomes
4.6. Statistical Analysis
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
BG | Basal ganglia |
CR | Corona radiata |
CRP | C-reactive protein |
DBP | Diastolic blood pressure |
EPO | Erythropoietin |
F-P | Fronto-parietal cortex |
G-CSF | Granulocyte-colony stimulating factor |
MBI | Modified Barthel index |
MMSE | Mini-mental status examination |
MRI | Magnetic resonance imaging |
RBC | Red blood cell |
Reti count | Reticulocyte count |
SBP | Systolic blood pressure |
WBC | White blood cell |
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Characteristics | Open-Label Pilot Study | Exploratory Double-Blind Study | |
---|---|---|---|
EPO+G-CSF (n = 3) | EPO+G-CSF (n = 3) | Placebo (n = 3) | |
Age (years; range) | 30.00 (25.00–32.00) | 45.00 (44.00–45.00) | 34.00 (31.50–34.50) |
Sex (male/female) | 3/0 | 3/0 | 2/1 |
Height (cm) | 172.00 (166.50–173.50) | 169.00 (167.00–172.00) | 170.00 (167.50–172.00) |
Weight (kg) | 50.60 (49.95–64.30) | 65.00 (57.50–72.15) | 79.80 (71.40–82.15) |
Body Mass Index (kg/m2) | 19.50 (18.10–22.50) | 22.80 (20.60–24.35) | 27.60 (25.35–27.75) |
Etiology (ischemic/hemorrhagic) | 2/1 | 1/2 | 2/1 |
Damaged Region (BG †/F-P ‡/CR §) | 2/1/0 | 2/1/0 | 2/0/1 |
Modified Barthel Index | 57.00 (57.00–75.00) | 93.00 (82.50–94.00) | 96.00 (90.50–98.00) |
Mini-Mental Status Examination | 29.00 (20.50–29.50) | 25.00 (24.50–26.50) | 30.00 (30.00–30.00) |
SBP ¶ (mmHg) | 135.00 (135.00–135.50) | 134.00 (128.00–139.50) | 135.00 (128.00–136.50) |
DBP ** (mmHg) | 82.00 (79.50–84.50) | 82.00 (76.50–82.00) | 87.00 (82.50–90.00) |
Heart Rate (pulse/min) | 80.00 (75.00–85.50) | 64.00 (61.50–83.00) | 79.00 (74.50–82.50) |
Body Temperature (°) | 37.00 (36.85–37.15) | 36.50 (36.50–36.65) | 36.70 (36.70–36.75) |
Adverse Effects (number) | |||
Back Pain | 3 | 1 | 0 |
Headache | 2 | 0 | 1 |
Vomiting | 1 | 0 | 0 |
EPO+G-CSF (n = 3) | ||||
---|---|---|---|---|
Parameter | Normal Range | Pre-Treatment | Day 5 | Day 30 |
Glucose (mg/dL) | 70–110 | 96.00 (90.50–103.50) | 86.00 (81.50–89.00) | 86.00 (83.00–92.50) |
Creatinine (mg/dL) | 0.49–1.19 | 0.89 (0.77–1.06) | 0.92 (0.85–1.03) | 0.74 (0.70–0.96) |
CRP † (mg/L) | 0–8 | 2.85 (1.43–9.76) | 3.03 (2.79–4.08) | 2.84 (1.42–5.90) |
Reti count ‡ (cells/μL) | 20.8–109.6 | 53.80 (50.90–69.95) | 76.40 (71.15–88.85) | 41.50 (40.95–49.80) |
RBC § (cells/μL) | 4.5–6.1 × 106 | 4.69 (4.37–4.87) | 4.94 (4.73–5.18) | 4.85 (4.74–5.08) |
Hemoglobin (g/dL) | 13–17 | 15.00 (14.45–15.15) | 14.20 (14.15–14.35) | 14.30 (13.80–14.35) |
Hematocrit (%) | 40–52 | 43.00 (42.95–43.05) | 43.00 (42.45–43.45) | 43.50 (43.05–43.60) |
WBC ¶ (cells/μL) | 4–10.8 × 103 | 6.91 (5.48–8.36) | 44.36 (40.27–46.16) | 6.39 (5.14–6.98) |
Neutrophil (%) | 20–70 | 65.40 (63.75–65.85) | 84.20 (79.60–86.90) | 51.80 (46.90–64.40) |
Lymphocyte (%) | 15–40 | 26.80 (25.75–27.10) | 9.50 (6.95–10.25) | 34.20 (24.55–40.70) |
Monocyte (%) | 2–8 | 5.90 (5.50–6.35) | 4.80 (4.45–5.90) | 6.50 (6.25–7.50) |
EPO ** (mIU/mL) | 3.5–16.2 | 16.80 (10.74–16.95) | 767.00 (469.00–1032.00) | 9.24 (7.09–12.32) |
CD34+ (cells/μL) | - | 2.00 (1.50–4.00) | 40.00 (27.00–63.00) | 1.00 (1.00–2.00) |
EPO+G-CSF (n = 3) | |||||||||
Parameter | Normal Range | Day 0 | Day 5 | Day 30 | Day 35 | Day 60 | Day 65 | Day 90 | Day 180 |
Glucose (mg/dL) | 70–110 | 89.00 (82.50–93.50) | 108.00 (97.00–113.00) | 90.00 (90.00–92.50) | 80.00 (77.00–88.00) | 90.00 (86.50–135.00) | 113.00 (106.00–125.00) | 100.00 (96.50–103.50) | 107.00 (105.00–122.00) * |
Creatinine (mg/dL) | 0.49–1.19 | 1.06 (0.89–1.13) | 1.09 (0.94–1.17) | 0.95 (0.86–1.08) | 1.05 (0.92–1.10) | 1.07 (0.96–1.11) | 1.23 (0.99–1.24) | 0.95 (0.87–1.07) | 1.17 (0.97–1.22) |
CRP † (mg/L) | 0–8 | 0.40 (0.20–2.00) | 8.20 (6.84–13.70) | 0.50 (0.25–0.50) | 10.70 (6.99–12.40) | 0.60 (0.30–0.60) | 5.40 (5.33–13.55) * | 0.60 (0.30–0.85) | 1.40 (0.95–1.49) |
Reti count ‡ (cells/μL) | 20.8–109.6 | 61.20 (56.00–65.45) | 92.90 (82.40–95.50) * | 31.10 (26.95–41.30) | 82.00 (74.80–82.15) | 20.00 (18.85–26.10) | 58.50 (47.35–70.90) | 25.20 (24.50–30.60) | 81.20 (73.80–86.60) |
RBC § (cells/μL) | (4.5–6.1) × 106 | 4.18 (4.11–4.44) | 4.20 (4.18–4.35) | 4.60 (4.37–4.81) | 4.67 (4.61–4.83) | 4.64 (4.60–4.66) | 4.81 (4.75–5.01) | 4.94 (4.91–5.04) | 4.32 (4.24–4.58) |
Hemoglobin (g/dL) | 13–17 | 12.80 (12.40–13.65) | 12.70 (12.60–13.35) | 14.20 (13.25–15.05) | 14.50 (14.20–15.00) | 14.00 (13.70–14.15) | 14.70 (14.35–15.40) | 14.90 (14.45–15.10) | 13.20 (12.90–14.10) |
Hematocrit (%) | 40–52 | 38.20 (36.80–41.15) | 38.10 (37.95–40.70) | 42.70 (40.00–45.25) | 42.80 (42.45–45.30) | 42.00 (41.85–43.00) | 44.20 (44.05–46.75) | 46.20 (44.40–46.25) | 38.90 (37.95–41.25) |
WBC ¶ (cells/μL) | (4–10.8) × 103 | 7.52 (6.15–7.53) | 32.56 (29.59–45.68) * | 5.39 (4.99–6.71) | 41.96 (39.51–48.73) * | 5.17 (4.69–5.65) | 43.79 (37.16–49.95) * | 5.98 (5.73–7.50) | 6.55 (5.71–7.44) |
Neutrophil (%) | 20–70 | 56.50 (55.70–60.55) | 85.80 (85.40–86.75) * | 55.00 (44.55–62.85) | 86.40 (85.10–87.20) * | 51.20 (47.55–52.95) | 88.40 (85.30–89.50) * | 58.70 (51.85–63.55) | 56.20 (53.10–60.95) |
Lymphocyte (%) | 15–40 | 31.10 (29.15–33.50) | 6.90 (6.80–8.45) * | 30.40 (26.50–41.65) | 6.80 (6.20–8.60) * | 35.50 (33.30–41.15) | 7.10 (6.30–9.80) * | 25.90 (25.85–35.15) | 29.50 (27.50–35.15) |
Monocyte (%) | 2–8 | 5.80 (5.05–6.75) | 4.90 (3.90–4.95) | 6.10 (5.45–6.40) | 4.20 (3.45–4.25) | 5.70 (4.80–6.25) | 2.40 (2.35–3.10) * | 4.70 (4.15–7.10) | 6.90 (6.05–7.10) |
EPO ** (mIU/mL) | 3.5–16.2 | 7.30 (5.65–9.40) | 547.00 (419.50–601.00) * | 4.28 (3.64–6.89) | 421.00 (325.00–570.00) * | 5.30 (4.40–7.46) | 420.00 (361.00–590.00) * | 5.20 (4.10–6.15) * | 10.60 (9.65–11.75) |
CD34+ (cells/μL) | - | 1.00 (0.50–2.50) | 50.00 (33.00–61.00) * | 1.00 (1.00–3.50) | 28.00 (18.00–78.50) * | 2.00 (1.50–4.00) | 56.00 (30.00–73.00) | 4.00 (2.50–4.00) | 2.00 (2.00–2.50) |
Placebo (n = 3) | |||||||||
Parameter | Normal Range | Day 0 | Day 5 | Day 30 | Day 35 | Day 60 | Day 65 | Day 90 | Day 180 |
Glucose (mg/dL) | 70–110 | 87.00 (84.50–89.50) | 100.00 (95.50–122.00) | 99.00 (94.00–99.50) | 90.00 (85.50–97.00) | 95.00 (94.50–106.50) | 89.00 (88.50–95.50) | 98.00 (95.50–98.00) | 90.00 (88.00–94.00) |
Creatinine (mg/dL) | 0.49–1.19 | 1.09 (1.02–1.12) | 1.04 (0.99–1.12) | 1.12 (1.02–1.15) | 1.13 (0.98–1.14) | 1.13 (1.01–1.22) | 1.07 (0.91–1.25) | 1.14 (1.02–1.15) | 1.02 (1.00–1.08) |
CRP † (mg/L) | 0–8 | 0.00 (0.00–0.00) | 1.65 (0.83–16.25) | 0.50 (0.25–0.94) | 0.50 (0.25–1.04) | 0.50 (0.25–0.79) | 0.50 (0.25–1.24) | 2.02 (1.01–2.05) | 0.44 (0.22–1.26) |
Reti count ‡ (cells/μL) | 20.8–109.6 | 84.10 (71.60–97.05) | 48.80 (44.45–52.75) | 53.20 (52.15–95.95) | 80.00 (54.00–85.10) | 89.10 (69.00–107.95) | 58.80 (58.00–101.75) | 82.70 (58.45–86.45) | 74.50 (68.75–82.35) |
RBC § (cells/μL) | (4.5–6.1) × 106 | 5.02 (4.55–5.14) | 4.89 (4.44–4.96) | 5.09 (4.66–5.23) | 4.49 (4.39–4.82) | 5.08 (4.74–5.26) | 4.83 (4.51–5.06) | 4.73 (4.59–5.26) | 5.10 (4.71–5.45) |
Hemoglobin (g/dL) | 13–17 | 14.60 (13.55–15.00) | 14.80 (13.35–14.85) | 15.40 (14.10–15.45) | 13.80 (13.35–14.55) | 15.10 (14.25–15.45) | 14.60 (13.65–15.35) | 14.30 (13.85–16.10) | 15.00 (13.95–16.45) |
Hematocrit (%) | 40–52 | 44.00 (39.95–44.15) | 42.50 (38.85–42.75) | 43.70 (40.55–44.90) | 38.40 (38.30–41.60) | 44.00 (41.40–45.20) | 41.80 (39.35–43.85) | 40.60 (40.15–45.55) | 43.80 (40.95–47.15) |
WBC ¶ (cells/μL) | (4–10.8) × 103 | 9.57 (7.63–9.60) | 6.41 (5.93–7.44) | 9.33 (8.29–10.23) | 10.48 (8.11–10.58) | 10.06 (8.01–10.45) | 7.01 (6.53–8.49) | 11.11 (7.66–11.20) | 7.32 (6.53–9.22) |
Neutrophil (%) | 20–70 | 56.90 (56.45–60.50) | 59.30 (55.85–60.50) | 66.40 (60.50–71.85) | 66.60 (59.50–69.90) | 65.70 (60.05–68.90) | 65.60 (55.40–73.25) | 67.40 (58.80–69.55) | 67.40 (56.65–68.10) |
Lymphocyte (%) | 15–40 | 30.70 (28.25–31.55) | 29.70 (28.60–32.25) | 24.70 (20.36–30.30) | 23.70 (20.95–27.40) | 26.10 (23.30–28.30) | 23.80 (22.25–30.90) | 24.10 (21.65–29.45) | 24.10 (23.00–30.60) |
Monocyte (%) | 2–8 | 6.30 (5.55–6.30) | 6.60 (5.40–6.80) | 4.40 (4.30–4.85) | 4.90 (3.95–5.30) | 4.60 (4.60–4.70) | 5.30 (5.20–6.05) | 5.40 (5.35–5.90) | 5.30 (4.90–5.55) |
EPO ** (mIU/mL) | 3.5–16.2 | 7.93 (7.52–9.42) | 8.89 (7.46–13.35) | 8.65 (7.36–9.93) | 11.10 (10.41–12.55) | 6.60 (3.72–10.70) | 12.90 (11.15–13.25) | 11.80 (11.60–13.80) | 11.40 (10.95–12.10) |
CD34+ (cells/μL) | - | 2.00 (2.00–3.00) | 1.00 (1.00–3.00) | 2.00 (1.50–4.50) | 2.00 (1.50–4.00) | 1.00 (1.00–4.00) | 2.00 (1.50–5.50) | 1.00 (1.00–3.50) | 2.00 (1.50–4.00) |
Adverse Effects (Number) | Open-Label Pilot Study | Exploratory Double-Blind Study | |
---|---|---|---|
EPO+G-CSF (n = 3) | EPO+G-CSF (n = 3) | Placebo (n = 3) | |
Shock | 0 | 0 | 0 |
Seizure | 0 | 0 | 0 |
Dyspnea | 0 | 0 | 0 |
High blood pressure | 0 | 0 | 0 |
Hemorrhagic accident | 0 | 0 | 0 |
Myocardial/cerebral infarction | 0 | 0 | 0 |
Jaundice | 0 | 0 | 0 |
Allergy | 0 | 0 | 0 |
Itching and rash | 0 | 0 | 0 |
Stomachache | 0 | 0 | 0 |
Dyspepsia | 0 | 0 | 0 |
Vomiting | 1 | 0 | 0 |
Diarrhea | 0 | 0 | 0 |
Headache | 2 | 0 | 1 |
Dizziness | 0 | 0 | 0 |
Fever | 0 | 0 | 0 |
Chill | 0 | 0 | 0 |
Insomnia | 0 | 0 | 0 |
Fatigue | 0 | 0 | 0 |
Skeletal muscle pain | 3 | 1 | 0 |
Hand Side | Evaluation Contents | Normal Range | Day 0 | Day 180 | ||
---|---|---|---|---|---|---|
EPO+G-CSF (n = 3) | Placebo (n = 3) | EPO+G-CSF (n = 3) | Placebo (n = 3) | |||
Affected Hand | Grip Power (kg) | 46.9–48.3 | 0.00 (0.00–17.00) | 1.00 (0.50–23.50) | 0.00 (0.00–22.00) | 4.00 (2.00–16.50) |
Tip Pinch Power (kg) | 5.1–6.7 | 0.00 (0.00–2.25) | 0.00 (0.00–2.00) | 0.00 (0.00–2.75) | 0.00 (0.00–2.00) | |
Lateral Pinch Power (kg) | 7.6–9.5 | 0.00 (0.00–4.25) | 2.50 (1.25–6.75) | 0.00 (0.00–5.25) | 2.00 (1.00–3.50) | |
Palmar Pinch Power (kg) | 9.3–9.8 | 0.00 (0.00–3.75) | 0.00 (0.00–2.50) | 0.00 (0.00–4.50) | 0.00 (0.00–2.50) | |
Box and Block (numbers) | 81–83 | 0.00 (0.00–29.00) | 0.00 (0.00–25.00) | 0.00 (0.00–37.00) | 12.00 (6.00–32.00) | |
Dominant Hand | Grip Power (kg) | 46.9–48.3 | 42.00 (39.00–47.00) | 38.00 (35.00–43.00) | 46.00 (44.00–49.00) * | 39.00 (33.50–39.50) |
Tip Pinch Power (kg) | 5.1–6.7 | 7.50 (6.75–8.00) | 4.50 (4.00–5.50) | 7.50 (6.50–8.25) | 4.50 (4.25–6.75) | |
Lateral Pinch Power (kg) | 7.6–9.5 | 11.00 (10.00–11.50) | 10.00 (8.00–11.00) | 9.50 (9.25–9.75) | 5.50 (5.25–8.25) | |
Palmar Pinch Power (kg) | 9.3–9.8 | 10.00 (9.50–10.00) | 5.50 (5.00–6.50) | 12.00 (10.50–12.00) | 5.00 (5.00–7.50) | |
Box and Block (numbers) | 81–83 | 67.00 (62.00–69.00) | 58.00 (55.00–61.00) | 79.00 (71.00–80.50) | 62.00 (58.00–65.00) |
© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
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Shin, Y.-K.; Cho, S.-R. Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients. Int. J. Mol. Sci. 2016, 17, 463. https://doi.org/10.3390/ijms17040463
Shin Y-K, Cho S-R. Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients. International Journal of Molecular Sciences. 2016; 17(4):463. https://doi.org/10.3390/ijms17040463
Chicago/Turabian StyleShin, Yoon-Kyum, and Sung-Rae Cho. 2016. "Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients" International Journal of Molecular Sciences 17, no. 4: 463. https://doi.org/10.3390/ijms17040463