Renal toxicity of polybrene (hexadimethrine bromide)

Ransdell, Herbert T.; Haller, Julia A.; Stowens, Daniel; Barton, Paul Bruce

doi:10.1016/s0022-4804(65)80086-5

Cited by 24 publications

(11 citation statements)

References 8 publications

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“…In our previous study, we have shown that angiogenesis resulting from viral-vector-based vascular endothelial growth factor (VEGF) transduction is important for enhancement of the regenerative potential of stem cells 46 . A possible reason is that the gene-activated scaffold is applied without the continuous presence of agents, such as Polybrene 47 , that are commonly used to enhance virus absorption and gene transfer efficiency, which may present potential safety risks for clinical application 48 , 49 . As a result, we did not achieve a level of BMP-2 production similar to that in vitro ; future optimization of viral load and judicious formulation of virus adsorption enhancing cocktails may accelerate this process.…”

Section: Discussionmentioning

confidence: 99%

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Projection Stereolithographic Fabrication of BMP-2 Gene-activated Matrix for Bone Tissue Engineering

Lin

Tang

Lozito

et al. 2017

Sci Rep

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Currently, sustained in vivo delivery of active bone morphogenetic protein-2 (BMP-2) protein to responsive target cells, such as bone marrow-derived mesenchymal stem cells (BMSCs), remains challenging. Ex vivo gene transfer method, while efficient, requires additional operation for cell culture and therefore, is not compatible with point-of-care treatment. In this study, two lentiviral gene constructs – (1) Lv-BMP/GFP, containing human BMP-2 and green fluorescent protein (GFP) gene (BMP group); or (2) Lv-GFP, containing GFP gene (GFP group) – were incorporated with human BMSCs into a solution of photocrosslinkable gelatin, which was then subjected to visible light-based projection stereolithographic printing to form a scaffold with desired architectures. Upon in vitro culture, compared to the GFP group, cells from BMP group showed >1,000-fold higher BMP-2 release, and the majority of them stained intensely for alkaline phosphatase activity. Real-time RT-PCR also showed dramatically increased expression of osteogenesis marker genes only in the BMP group. 3.5 months post-implantation into SCID mice, the micro-computed tomography imaging showed detectable mineralized areas only in the BMP group, which was restricted within the scaffolds. Alizarin red staining and immunohistochemistry of GFP and osteocalcin further indicated that the grafted hBMSCs, not host cells, contributed primarily to the newly formed bone.

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Section: Discussionmentioning

confidence: 99%

“…Constructs from the GFP or BMP group (n = 6 for each group) were then inserted into the muscle on both sides of the hind legs. Polybrene was not included for the in vivo study due to potential safety issue in the future clinical application 48 , 49 . The muscles and skin of the animals were then individually and sequentially sutured.…”

Section: Methodsmentioning

confidence: 99%

Projection Stereolithographic Fabrication of BMP-2 Gene-activated Matrix for Bone Tissue Engineering

Lin

Tang

Lozito

et al. 2017

Sci Rep

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“…During the late 1950's and early 1960's, it was utilised as an alternative agent to protamine to neutralise unfractionated heparin in patients undergoing open heart surgery and in those patients with an extracorporeal circulation [Weiss et al, 1958;Keats et al, 1959;Blumberg et al, 1960;Lillehei et al, 1960]. Although found to be as effective as protamine, its clinical application was short lived following reports of renal toxicity [Haller et al, 1962;Ransdell et al, 1965].…”

Section: Hexadimethrine Bromide (Polybrene) and Thrombin Generationmentioning

confidence: 99%

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Patel

Green

Patel

et al. 2012

Blood

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503 The optimal dosing strategy of low molecular weight heparins (LMWH) for the treatment of antenatal venous thromboembolism (VTE) is not known. The physiological changes associated with pregnancy alter the pharmacokinetic (PK) profile of LMWH, and this has led to controversy and subsequent variation in practice, when pregnant women are managed with LMWH for VTE [Voke et al., 2009]. The perceived impact of these PK changes has led to the Royal College of Obstetrics and Gynaecologists (RCOG) recommending a twice daily dose of LMWH, whilst the American College of Chest Physicians recommend that either a once or twice daily dose of LMWH can be used in this setting. We conducted a population PK modelling study of enoxaparin during pregnancy in order to address this issue. Women requiring antenatal enoxaparin, all indications and doses, referred to the specialist haematology clinic at King's College Hospital, a London teaching hospital, were eligible to enrol in the study. Recruited women were reviewed monthly in clinic during their pregnancy, and had up to three anti-Xa activities (trough, 1 hour post dose, and 3 hours post dose) drawn at each clinic attendance. This anti-Xa sampling strategy was based on d-optimal design, to ensure gestation related changes in enoxaparin clearance (CL) and volume of distribution (Vd) were captured in the PK model developed [van Hasselt et al., 2012]. Women under 18 years of age, those with impaired renal function and those non-adherent to enoxaparin were excluded. Compartmental PK modelling was conducted using non linear mixed effects modelling (NONMEM version 7.2.2). One hundred and twenty three patients contributed 795 anti-Xa activities (712 antenatal, 83 postnatal), for PK modelling purposes. A one compartment model with exponential between subject variability on CL and Vd, with a combined proportional and additive error model best fitted the data, with both enoxaparin CL and Vd found to have increased during pregnancy (table). Enoxaparin PK parameter CL (L/hr) Vd (L) Non-pregnancy (literature values) 0.5-0.7 3-7 Pregnancy (this study) 1.6 13.2 Time dependent changes during pregnancy were found to be significant covariates on both CL and Vd. A full covariate analysis identified weight to be a significant covariate for enoxaparin CL and gestation and baseline lean body weight to be significant covariates for Vd during pregnancy. The final pregnancy enoxaparin PK models for CL and Vd can be represented mathematically as: where Wt is the women's actual weight, GEST is their gestational stage, and LBW is their baseline lean body weight. Goodness of fit plots, a bootstrap analysis and a visual predictive check revealed that a robust enoxaparin model for use in pregnancy had been developed. Simulations of women injecting enoxaparin once versus twice daily demonstrate that both dosing regimens will reach RCOG target 3 hour plasma concentrations throughout the duration of the pregnancy (Figure 1). This should provide confidence to clinicians who prescribe a once daily dose of enoxaparin for the antenatal population. Perhaps the more important concentration to assess however is the trough anti-Xa activity, due to the historical thinking that during pregnancy CL increases, therefore so should the dose/dosing frequency. When the trough activity is simulated, the majority of women on a once daily dose, will have measurable anti-Xa activity; with both once and twice daily regimes demonstrating an increase in trough anti-Xa activity with the progression of pregnancy. This occurs due to the increase in Vd and demonstrates that enoxaparin never reaches a steady state during pregnancy. The measurable trough activity confirms the appropriateness of a once daily dose of enoxaparin in this setting. Our work provides compelling evidence that a once daily dose of enoxaparin for the treatment of antenatal VTE is appropriate. As a result, the current guidelines should be revised. Figure 1: Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Figure 1:. Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Disclosures: Off Label Use: Enoxaparin use during the antenatal period.

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“…During the 1950s, this polycation had its time of popularity; in certain medical centers, it almost replaced protamine as a heparin antagonist.21-23 However, several patients who received this compound developed renal failure, and as a result, polybrene manufacture for clinical purposes was discontinued in 1962. 23,24 The notion that polybrene is nephrotoxic was also supported by studies in dogs, which showed that animals treated with this polycation had renal function abnormalities and histological lesions (tubular necrosis) akin to those observed in humans.23,24 Therefore, protamine (despite its undesirable effects on the pulmonary circulation) is certainly much safer than polybrene and, for the time being, will remain the agent of choice for neutralizing heparin after extracorporeal circulation.…”

Section: Editorial Comment Neutralization Of Heparin By Protaminementioning

confidence: 99%

Neutralization of heparin by protamine. Time for a change?

Schapira¹,

Christman²

1990

Circulation

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T he DNA of eukaryotic chromosomes forms a complex called chromatin with histones and other nucleic acid-binding proteins. In certain structures like sperm heads in which chromatin is present in a very condensed form, histones are replaced by smaller proteins, the protamines.' The structure-function relations of protamines have been studied in detail: they contain between 31 and 34 amino acid residues, two thirds of them basic, most of them arginine. When complexed to nucleic acids, protamines are folded into four a-helical domains, the cross-linking of DNA double helixes being achieved through arginine-phosphate interactions.1"2 A therapeutic role for protamine was first envisioned by Hagedorn et al,3 who observed that protamine-insulin suspensions are relatively insoluble in water or serum at neutral pH. This contrasts with regular insulin, which because of its acidic isoelectric point is extremely soluble under these conditions. The relative insolubility of protamineinsulin slows the rate at which the hormone is absorbed; consquently, its biological activity persists for 24-36 hours after subcutaneous injection (for comparison, the half-life of regular insulin after subcutaneous injection is about 4 hours).3'4 Because insulin and heparin have similar electric charges, Chargaff and Olson5 speculated that protamine might also prolong the anticoagulant effect of heparin. This, however, is not the case, because protamine efficiently inhibits the action of heparin both in vitro and in vivo. cytopenia in the dog9 was followed by studies of cardiovascular protamine toxicity after extracorporeal circulation in humans.10"'1 Jastrzebski et al10 observed a 37% increase in the mean pulmonary artery pressure of 15 patients who received protamine (6 mg/kg over a period of about 5 minutes) immediately after bypass. More recently, Lowenstein et al"l described five patients who experienced severe systemic hypotension and pulmonary vasoconstriction with 20-30 mg intravenous bolus doses of this compound. Subsequent studies involving 904 consecutive patients revealed that the incidence of protamine-induced pulmonary artery vasoconstriction after bypass was about 1%12 and that this reaction was accompanied by the generation of thromboxane and C5a, the anaphylatoxin derived from the fifth component of complement.13 In nondiabetic patients, the pathogenesis of protamineinduced pulmonary artery vasoconstriction is still poorly understood. In diabetic patients who have IgE or IgG antibodies against protamine because they have been treated with protamine-insulin preparations, the syndrome of pulmonary artery vasoconstriction and systemic hypotension is probably mediated by antibody-dependent reactions.'4

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Renal toxicity of polybrene (hexadimethrine bromide)

Cited by 24 publications

References 8 publications

Projection Stereolithographic Fabrication of BMP-2 Gene-activated Matrix for Bone Tissue Engineering

Projection Stereolithographic Fabrication of BMP-2 Gene-activated Matrix for Bone Tissue Engineering

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Neutralization of heparin by protamine. Time for a change?

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