Response of dogs to repeated intravenous injection of polyethylene glycol 4000 with notes on excretion and sensitization

doi:10.1016/0041-008X(71)90312-7

Toxicology and Applied Pharmacology

Volume 18, Issue 1, January 1971, Pages 35-40

https://doi.org/10.1016/0041-008X(71)90312-7 Get rights and content

Abstract

Repeated intravenous injections of sterile 10% polyethylene glycol 4000 in 0.85% aqueous NaCl caused no detectable ill effects in groups of 9 beagles on dosages of 90, 30, 10, and 0 mg/kg/day. Two dogs from each level were killed after 43 daily injections in 2 months, 2 more after 99 injections in 6 months, and the remaining 5 after 178 injections in 12 months. There were no statistically significant differences between any of the injected groups and the control group that received the 0.85% NaCl vehicle in an amount equivalent to the volume of the highest dosage, i.e., 9 ml. The criteria of effect included body and organ weights, hematology, biochemical tests, gross and histopathologic examination of cranial, thoracic, and abdominal organs. Two importantly related studies reveal that PEG 4000 is not a sensitizing agent in guinea pigs and that the major routes of excretion of ¹⁴C equivalents by rats after iv and po administration are via urine in the first instance and feces in the second. Its proposed use as a complexing agent in the preparation of a high purity antihemophilic factor for human intravenous use prompted these studies.

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These interventions typically involve either modifying a uricase enzyme with different polymers [9–16], and/or combining a uricase molecule with some form of immunosuppression [17,18]. When searching for a solution to overcome the challenges presented by APA, we were drawn to the safety and relative immunological inertness of free PEG (i.e., unmodified PEG molecules) administered intravenously [19–24]. This contrasts to when PEG is conjugated to select proteins or liposomes, which can be inherently immunogenic [15,23,25,26].
Pegloticase is an enzyme used to reduce serum uric acid levels in patients with chronic, treatment-refractory gout. Clinically, about 40% of patients develop high titers of anti-PEG antibodies (APA) after initial treatment, which in turn quickly eliminate subsequent doses of pegloticase from the systemic circulation and render the treatment ineffective. We previously found that pre-infusion with high MW free PEG (40 kDa) can serve as a decoy to saturate circulating APA, preventing binding to a subsequently administered dose of PEG-liposomes and restoring their prolonged circulation in mice, without any detectible toxicity. Here, we investigated the use of 40 kDa free PEG to restore the circulation of radio-labeled pegloticase in mice using longitudinal Positron Emission Tomography (PET) imaging over 4 days. Mice injected with pegloticase developed appreciable APA titers by Day 9, which further increased through Day 14. Compared to naïve mice, mice with pegloticase-induced APA rapidly cleared ⁸⁹Zr-labeled pegloticase, with ~75% lower pegloticase concentrations in the circulation at four hours after treatment. The 96-h AUC in APA+ mice was less than 30% of the AUC in naïve mice. In contrast, pre-infusion of free PEG into PEG-sensitized mice restored the AUC of pegloticase to ~80% of that seen in naïve mice, resulting in a similar biodistribution to pegloticase in naïve mice over time. These results suggest that pre-infusion of free PEG may be a promising strategy to enable the safe and efficacious use of pegloticase and other PEGylated drugs in patients that have previously failed therapy due to induced APA.
Building the design, translation and development principles of polymeric nanomedicines using the case of clinically advanced poly(lactide(glycolide))–poly(ethylene glycol) nanotechnology as a model: An industrial viewpoint
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Liposomal drugs are already commercially available and are safely used in humans [29–31]. Polyethylene glycol is also considered nontoxic and is excreted unmetabolized in the urine [32]. The RGD peptide is an octapeptide and is considered to be non-toxic and non-immunogenic [26,27].
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Over 100 mg/kg body weight in mice, liposomes induce hepatomegaly, granulomas, and splenomegaly [133–136]. PEG, used to prepare stealth liposomes with a molecular weight ranging from 1900 to 5000 Da, are considered to be non-toxic compounds [137]. However, Krause et al. observed allergy-like side effects induced by liposome injections in mice.
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This assessment focusses on polyethylene glycols (PEGs) and on anionic or nonionic PEG derivatives, which are currently used in cosmetics in Europe. These compounds are used in a great variety of cosmetic applications because of their solubility and viscosity properties, and because of their low toxicity. The PEGs, their ethers, and their fatty acid esters produce little or no ocular or dermal irritation and have extremely low acute and chronic toxicities. They do not readily penetrate intact skin, and in view of the wide use of preparations containing PEG and PEG derivatives, only few case reports on sensitisation reactions have been published, mainly involving patients with exposure to PEGs in medicines or following exposure to injured or chronically inflamed skin. On healthy skin, the sensitising potential of these compounds appears to be negligible. For some representative substances of this class, information was available on reproductive and developmental toxicity, on genotoxicty and carcinogenic properties. Taking into consideration all available information from related compounds, as well as the mode and mechanism of action, no safety concern with regard to these endpoints could be identified. Based on the available data it is therefore concluded that PEGs of a wide molecular weight range (200 to over 10,000), their ethers (laureths. ceteths, ceteareths, steareths, and oleths), and fatty acid esters (laurates, dilaurates, stearates, distearates) are safe for use in cosmetics. Limited data were available for PEG sorbitan/sorbitol fatty acid esters, PEG sorbitan beeswax and PEG soy sterols. Taking into account all the information available for closely related compounds, it can be assumed that these compounds as presently used in cosmetic preparations will not present a risk for human health. PEG castor oils and PEG hydrogenated castor oils have caused anaphylactic reactions when used in intravenous medicinal products. Their topical use in cosmetics is, however, considered safe as they are not expected to be systemically available. As all PEGs and PEG derivatives, they must not be applied to damaged skin. Manufacturers of PEGs and PEG derivatives must continue their efforts to remove impurities and by-products such as ethylene oxide and 1,4-dioxane. Overall, it is concluded, that the PEGs covered in this review are safe for use in cosmetics under the present conditions of intended use.
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^☆: This study was supported by Union Carbide Corporation to aid the American Red Cross in the development of a High Purity Antihemophilic Factor.

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Response of dogs to repeated intravenous injection of polyethylene glycol 4000 with notes on excretion and sensitization☆

Abstract

J. Amer. Pharm. Ass., Sci. Ed.

Biochim. Biophys. Acta

J. Amer. Pharm. Ass., Sci. Ed.

J. Amer. Pharm. Ass., Sci. Ed.

J. Amer. Pharm. Ass., Sci. Ed.

J. Amer. Pharm. Ass., Sci. Ed.

Management of comprehensive dental surgery in severe hemophilia with a high purity human antihemophilic factor (AHF) concentrate

Clin. Res.

Two large-scale procedures for purification of human antihemophilic factor (AHF)

Blood