The effect of filgrastim on hemodynamic parameters in naive rats

Abstract

Aims: Filgrastim, a recombinant form of granulocyte colony-stimulating factor (G-CSF), is used in neutropenic conditions. Apart from its use in neutropenia treatment, it is also employed in experimental studies due to its neuroprotective effects. This study aimed to investigate the effect of filgrastim on hemodynamic parameters in rats. Methods: 24 adult male Wistar albino rats were used. The rats were divided into three groups: control, 50 μg filgrastim group, and 100 μg filgrastim group (n=8). Filgrastim was administered intraperitoneally once daily in a dose-dependent manner for a total of 5 days. The control group received 1 ml/kg of saline, following a similar treatment protocol. After 5 days of filgrastim administration, blood pressure measurements were taken in all groups of rats using indirect tail-cuff plethysmography. A total of five measurements were taken at 1-minute intervals for each animal. Results: Systolic pressure (control: 117.40±7.93 mmHg, 50μg: 118.50±17.25 mmHg, 100 μg: 127.70±14.94 mmHg), diastolic pressure (control: 92.42±8.76 mmHg 50 ug: 95.65±8.75 mmHg, 100 μg: 101.20±8.04 mmHg) and mean arterial pressure (control: 100.70±7.61 mmHg 50μg: 103.20±10.62 mmHg 100 μg: 110.00±9.91 mmHg) were not significantly different among experiment groups (p>0.05). Heart rates showed a remarkable increase in the group administered 100 μg (366.5±22.35) compared to the control group, while no significant increase was observed in the group administered 50 μg (348±15.69). Conclusion: In our study, no consistent changes in systolic blood pressure were observed across treatment groups. However, a modest increase in heart rate was observed at the higher dose, suggesting a potential dose-related cardiovascular effect after 5 days of Filgrastim administration. Long-term effects of similar and higher doses on hemodynamic parameters can be examined.

Keywords

• Blood pressure
• filgrastim
• heart rate
• neutropenia

Filgrastimin sağlıklı sıçanlarda hemodinamik parametreler üzerindeki etkisi

Abstract

Amaç: Granülosit koloni uyarıcı faktörün (G-CSF) rekombinant bir formu olan filgrastim, nötropenik durumlarda kullanılır. Nötropeni tedavisinde kullanımının yanı sıra, nöroprotektif etkileri nedeniyle deneysel çalışmalarda da kullanılmaktadır. Bu çalışmada, filgrastimin sıçanlarda hemodinamik parametreler üzerindeki etkisi araştırılmıştır. Yöntemler: 24 yetişkin erkek Wistar albino sıçan kullanılmıştır. Sıçanlar kontrol, 50 μg filgrastim grubu ve 100 μg filgrastim grubu olmak üzere üç gruba ayrılmıştır (n=8). Filgrastim, doz bağımlı bir şekilde günde bir kez intraperitoneal olarak toplam 5 gün boyunca uygulanmıştır. Kontrol grubuna benzer bir tedavi protokolü izlenerek 1 mL/kg salin verildi. Filgrastim uygulamasının 5. gününde, tüm sıçan gruplarında dolaylı kuyruk manşet pletismografisi kullanılarak kan basıncı ölçümleri yapıldı. Her hayvan için 1 dakikalık aralıklarla toplam beş ölçüm yapıldı. Sonuç: Sistolik basınç (Kontrol: 117,4±7,93, 50 ug: 118,5±17,25 100 ug: 127,7±14,94), diyastolik basınç (Kontrol: 92,42±8,76 50 ug: 95,65±8,75 100 ug: 101,2±8,04) ve ortalama arter basıncı (Kontrol: 100,7±7,61 50 ug: 103,2±10,62 100 ug: 110,0±9,91) deney grupları arasında önemli bir fark göstermedi (p>0,05). Kalp atış hızları, kontrol grubuna kıyasla 100 μg uygulanan grupta (366,5±22,35) belirgin bir artış gösterirken, 50 μg uygulanan grupta (348±15,69) önemli bir artış gözlenmemiştir. Sonuç: Filgrastim'in 5 günlük uygulamasından sonra kısa vadeli hemodinamik parametrelerde önemli bir değişiklik gözlenmemiştir. Benzer ve daha yüksek dozların hemodinamik parametreler üzerindeki uzun vadeli etkileri incelenebilir.

Keywords

• kan basıncı
• filgrastim
• kalp atım hızı
• nötropeni

References

1. Aoki H, Matsumura R, Nishida Y, Nakamichi K, Yokota T, Sanjo N. Efficacy of filgrastim therapy for patients with progressive multifocal leukoencephalopathy: two case reports. Int J Infect Dis. 2025;158:107950. doi:10.1016/j.ijid.2025.107950
2. Crobu D, Spinetti G, Schrepfer R, et al. Preclinical and clinical phase I studies of a new recombinant Filgrastim (BK0023) in comparison with Neupogen®. BMC Pharmacol Toxicol. 2014;15(1):7. doi:10.1186/2050-6511-15-7
3. Höglund M. Glycosylated and non-glycosylated recombinant human granulocyte colony-stimulating factor (rhG-CSF)—what is the difference? Med Oncol. 1998;15(4):229-233. doi:10.1007/BF02787205
4. Theyab A, Alsharif KF, Alzahrani KJ, et al. New insight into strategies used to develop long-acting G-CSF biologics for neutropenia therapy. Front Oncol. 2023;12:1026377. doi:10.3389/fonc.2022.1026377
5. Azam S, Eliwan H, Hago FE, Hammoudi AHMC. Neupogen (filgrastim) induced acute hematuria/proteinuria with 3 days of use in a 7-year-old boy diagnosed as aplastic anemia. Dr Sulaiman Al Habib Med J. 2020; 2(3):92-94. doi:10.2991/dsahmj.k.200704.001
6. Arslan S, Berber I, Kuku I, et al. When should I use filgrastim after autologous transplantation in MM patients? Transfus Apher Sci. 2025; 64(4):104171. doi:10.1016/j.transci.2025.104171
7. Lyman GH, Kuderer NM. Filgrastim in patients with neutropenia: potential effects on quality of life. Drugs. 2002;62(Suppl 1):65-78. doi:10. 2165/00003495-200262001-00005
8. Schmitz N, Dreger P, Linch D, et al. Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet. 1996;347(8998):353-357. doi:10.1016/s0140-6736(96)90536-x

9. Dale DC, Crawford J, Klippel Z, et al. A systematic literature review of the efficacy, effectiveness, and safety of filgrastim. Supportive Care Cancer. 2018;26(1):7-20. doi:10.1007/s00520-017-3854-x
10. Gheita HA, El-Sabbagh WA, Abdelsalam RM, Attia AS, El-Ghazaly MA. Promising role of filgrastim and α-tocopherol succinate in amelioration of gastrointestinal acute radiation syndrome (GI-ARS) in mice. Naunyn Schmiedebergs Arch Pharmacol. 2019;392(12):1537-1550. doi:10.1007/s00210-019-01702-6
11. Bayoumi H, Mohamed MA, Shalan HT, Beder E, Elgendy EM. Filgrastim protects the cerebellar cortex against TNF-α/bax enhanced apoptosis after aluminum toxicity in albino rats. Histological and immunohistochemical study. Egyptian J Histol. 2024;47(4):1490-1509. doi:10.21608/ejh.2024.255554.1986
12. Meuer K, Pitzer C, Teismann P, et al. Granulocyte-colony stimulating factor is neuroprotective in a model of Parkinson's disease. J Neurochem. 2006;97(3):675-686. doi:10.1111/j.1471-4159.2006.03727.x
13. Schabitz W-R, Kollmar R, Schwaninger M, et al. Neuroprotective effect of granulocyte colony–stimulating factor after focal cerebral ischemia. Stroke. 2003;34(3):745-751. doi:10.1161/01.STR.0000057814.70180.17
14. Clarke J, Ploughman M, Corbett D. A qualitative and quantitative analysis of skilled forelimb reaching impairment following intracerebral hemorrhage in rats. Brain Res. 2007;1145:204-212. doi:10.1016/j.brainres.2007.01.135
15. Chao PK, Lu KT, Lee YL, et al. Early systemic granulocyte-colony stimulating factor treatment attenuates neuropathic pain after peripheral nerve injury. PLoS One. 2012;7(8):e43680. doi:10.1371/journal.pone.0043680
16. Komine-Kobayashi M, Zhang N, Liu M, et al. Neuroprotective effect of recombinant human granulocyte colony-stimulating factor in transient focal ischemia of mice. J Cereb Blood Flow Metab. 2006;26(3):402-413. doi:10.1038/sj.jcbfm.9600195
17. Song S, Kong X, Acosta S, Sava V, Borlongan C, Sanchez-Ramos J. Granulocyte colony-stimulating factor promotes behavioral recovery in a mouse model of traumatic brain injury. J Neurosci Res. 2016;94(5):409-423. doi:10.1002/jnr.23714
18. Nishio Y, Koda M, Kamada T, et al. Granulocyte colony-stimulating factor attenuates neuronal death and promotes functional recovery after spinal cord injury in mice. J Neuropathol Exp Neurol. 2007;66(8):724-731. doi:10.1097/nen.0b013e3181257176
19. Gibson CL, Bath PM, Murphy SP. G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 2005;25(4):431-439. doi:10.1038/sj. jcbfm.9600033
20. Santisteban MM, Ahmari N, Carvajal JM, et al. Involvement of bone marrow cells and neuroinflammation in hypertension. Circ Res. 2015; 117(2):178-191. doi:10.1161/CIRCRESAHA.117.305853
21. Vaziri ND. Mechanism of erythropoietin-induced hypertension. Am J Kidney Dis. 1999;33(5):821-828. doi:10.1016/s0272-6386(99)70413-0
22. Ahmet I, Lakatta EG, Talan MI. Acute hemodynamic effects of erythropoietin do not mediate its cardioprotective properties. Biol Open. 2012;1(10):1049-1053. doi:10.1242/bio.20122378
23. Çalışkan H, Karabulut G. Effects of the dexamethasone-induced insulin resistance model on self-care behaviors and brain-derived growth factor in rats. J Endocrinol. 2025;265(3):e250088. doi:10.1530/JOE-25-0088
24. Hazzan AD, Shah HH, Hong S, Sakhiya V, Wanchoo R, Fishbane S. Treatment with erythropoiesis-stimulating agents in chronic kidney disease patients with cancer. Kidney Int. 2014;86(1):34-39. doi:10.1038/ki.2013.528
25. Lee MS, Lee JS, Lee JY. Prevention of erythropoietin-associated hypertension. Hypertension. 2007;50(2):439-445. doi:10.1161/HYPERTENSIONAHA. 107.090423
26. Brar SK, Perveen S, Chaudhry MR, AlBabtain S, Amreen S, Khan S. Erythropoietin-induced hypertension: a review of pathogenesis, treatment, and role of blood viscosity. Cureus. 2021;13(1):e12804. doi:10. 7759/cureus.12804
27. Hayat A, Haria D, Salifu MO. Erythropoietin stimulating agents in the management of anemia of chronic kidney disease. Patient Prefer Adherence. 2008;2:195-200. doi:10.2147/ppa.s2356
28. Care IoLARCo, Animals UoL. Guide for the care and use of laboratory animals. US Department of Health and Human Services, Public Health Service, National; 1986.
29. Hultborn R, Albertsson P, Ottosson S, et al. Radiosensitivity: gender and order of administration of G-CSF, an experimental study in mice. Radiat Res. 2019;191(4):335-341. doi:10.1667/RR15038.1
30. Sepehri H, Nasiri H. Filgrastim improved spatial memory functions in rat model of scopolamine induced alzheimer type memory dysfunction. Bulletin Pharmaceutical Sci Assiut University. 2021;44(2):579-585.
31. Werneck-de-Castro JPS, Costa-e-Sousa RH, de Oliveira PF, et al. G-CSF does not improve systolic function in a rat model of acute myocardial infarction. Basic Res Cardiol. 2006;101(6):494-501. doi:10.1007/s00395-006-0605-4
32. Koçak S, Çalışkan H, Ömercioğlu G, et al. The impact of high-intensity interval training on insulin resistance, oxidative stress, and muscle function in a PCOS rat model. Physiol Behav. 2025;291:114794. doi:10. 1016/j.physbeh.2024.114794
33. Rezende LMTd, Soares LL, Drummond FR, et al. Is the wistar rat a more suitable normotensive control for SHR to test blood pressure and cardiac structure and function? Int J Cardiovasc Sci. 2021;35:161-171. doi:10.36660/ijcs.20200367
34. Milani-Nejad N, Janssen PM. Small and large animal models in cardiac contraction research: advantages and disadvantages. Pharmacol Ther. 2014;141(3):235-249. doi:10.1016/j.pharmthera.2013.10.007
35. Taşkıran E, Erdoğan MA, Yiğittürk G, Erbaş O. Therapeutic effects of liraglutide, oxytocin and granulocyte colony-stimulating factor in doxorubicin-induced cardiomyopathy model: an experimental animal study. Cardiovasc Toxicol. 2019;19(6):510-517. doi:10.1007/s12012-019-09524-x
36. Forechi L, Baldo MP, Meyerfreund D, Mill JG. Granulocyte colony-stimulating factor improves early remodeling in isoproterenol-induced cardiac injury in rats. Pharmacol Rep. 2012;64(3):643-649. doi:10.1016/s1734-1140(12)70860-5
37. Hartung T, Doecke WD, Bundschuh D, et al. Effect of filgrastim treatment on inflammatory cytokines and lymphocyte functions. Clin Pharmacol Ther. 1999;66(4):415-424. doi:10.1053/cp.1999.v66.a101210
38. Wilde E, Aubdool AA, Thakore P, et al. Tail-cuff technique and its influence on central blood pressure in the mouse. J Am Heart Assoc. 2017;6(6):e005204. doi:10.1161/JAHA.116.005204