Safety of Polyethylene Glycol 3350 for the Treatment of Chronic Constipation in Children

Pashankar, Dinesh S.; Loening‐Baucke, Vera; Bishop, Warren P.

doi:10.1001/archpedi.157.7.661

Cited by 124 publications

(83 citation statements)

References 16 publications

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“…Interventions such as calcium have been proven very safe but may have minimal efficacy (26). PEG, on the other hand, is not only very efficacious but remarkably non-toxic (27). This is largely due to the fact that it is not systemically absorbed.…”

Section: Discussionmentioning

confidence: 99%

Involvement of p21cip1/waf1 in the anti-proliferative effects of polyethylene glycol in colon carcinogenesis

Roy

Koetsier²,

Tiwari³

et al. 2011

Int J Oncol

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Abstract. Polyethylene glycol (PEG) is a safe and effective chemopreventive agent against colorectal carcinogenesis in cell culture, animal models and human subjects. Although the precise molecular mechanism is unclear, we previously reported that PEG suppresses colonic epithelial proliferation. As cellular proliferation is driven by complex G1-S phase transition, we now characterize the role of PEG on cell cycle regulation. We focused our attention on the effect of PEG on the CDK inhibitor p21 cip1/waf1 , which is implicated in early colon carcinogenesis and is upregulated by non-steroidal anti-inflammatory drugs. These studies were done in the azoxymethane-treated (AOM) rat model as well as in HT-29 colon cancer cells. Immunohistochemical analysis revealed that while AOM decreased the p21 expression (75%, p<0.01) in the premalignant colonic mucosa, PEG induced p21 levels back to normal. These findings paralleled a decreased BrdUrd incorporation (78%, p<0.001) and hypophosphorylated retinoblastoma protein (Rb; by 47%) signifying PEG's antiproliferative activity. Furthermore, in HT-29 cells, PEG decreased proliferation as measured by PCNA (68% reduction), increased p21 expression (2.3-fold), induced cell cycle arrest during G0/G1 phase (45% reduction in S phase cells) and inhibited the phosphorylation of Rb (by 52% compared to untreated). PEG caused greater than a 2-fold induction of protein and mRNA level of p21 cip1/waf1 in HT-29 cells. These results demonstrate for the first time that PEG is involved in p21 regulation concomitant with G1➝S phase cell cycle arrest and it is through these effects that it can exert its anti-proliferative and hence chemopreventive role.

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Section: Discussionmentioning

confidence: 99%

Involvement of p21cip1/waf1 in the anti-proliferative effects of polyethylene glycol in colon carcinogenesis

Roy

Koetsier²,

Tiwari³

et al. 2011

Int J Oncol

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“…These studies are very difficult to conduct on the PEGylated material, and this leaves a possible concern about the PEGylated portion of the molecule and its impact on human safety. In their nonconjugated form, polyethylene glycols are widely used as excipients for a large variety of drugs and are also regularly used in children for the treatment of pediatric constipation or for colonoscopy (Pashankar et al, 2003(Pashankar et al, , 2004Bell and Wall, 2004).…”

mentioning

confidence: 99%

PEGylated Proteins: Evaluation of Their Safety in the Absence of Definitive Metabolism Studies

Webster

Didier²,

Harris³

et al. 2006

Drug Metab Dispos

311

280

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ABSTRACT:During the development of any PEGylated protein or peptide, toxicology in relevant species will be conducted prior to human exposure. Normally, comprehensive metabolism data accompany the toxicity studies for a small molecule. We have examined whether such studies would be relevant in the safety assessment of PEGylated material. Literature data indicate that the polyethylene glycol (PEG) associated with a biological molecule should provide no extra concern because the exposure-toxicity relationship of PEG in animals and humans has been thoroughly investigated and metabolism/excretion of PEG is well understood. Based on the comparisons of PEG exposure from PEGylated biological products and the exposure of PEG associated with toxicity in humans, the therapeutic index is large (approximately 600-fold or greater). Therefore, assuming that toxicological evaluation of a biological molecule of interest is complete and satisfactory therapeutic windows are achieved, the data contained in this review indicate that the PEG associated with a protein or other biological molecule does not represent an additional unquantified risk to humans.The conjugation of small proteins, peptides, and oligonucleotides with polyethylene glycol (PEG), or PEGylation, has become an increasingly common method of improving the half-life of biological products, mainly through reducing the urinary excretion of the molecule (Yang et al., 2004), but also by reducing the enzymic degradation due to the increased steric bulk (Veronese and Pasut, 2005). In addition, PEGylated biological products often exhibit a reduced affinity for the target receptor compared with the native precursor. This reduced affinity can lead to a lower clearance by target-mediated clearance mechanisms. Finally, the addition of the PEG moiety can have beneficial effects on the immunological profile of a molecule by reducing the ability of the compound to raise antibodies in humans (Mehvar, 2000).PEG is a polymer made up of identical ethylene glycol subunits. PEGs have a descriptor associated with them that represents the mean molecular weight of the molecule (i.e., PEG200 has a molecular weight of 200) (Smyth et al., 1955). The PEG molecules conjugated to proteins can also have the terminal hydroxyl group capped with a methyl group (Molineux, 2003). The structures of these PEGs are detailed in Fig. 1. Higher molecular weight PEGs can have some degree of branching. The PEGs used to conjugate biologicals are polydispersed in nature (i.e., have a range of molecular weights), and this can to lead to a range of drug molecules with potentially subtly different biological properties. The impact of polydispersity must be considered when dealing with these conjugated biological agents (Veronese and Pasut, 2005).To couple the PEG to the protein, peptide, or oligonucleotide, the PEG (generally monomethoxy PEG) is first activated. Several methods can be used to achieve this activation and coupling, including cyanuric chloride, 1,1Ј-carbonyldiimidazole, phenylchloroformate, or succi...

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“…It has been shown to be effective, safe, palatable, and with excellent compliance [149] . Because of these properties, PEG has been studied as a bowel preparation option.…”

Section: Pediatric Patientsmentioning

confidence: 99%

Achieving the best bowel preparation for colonoscopy

Parra‐Blanco¹,

Ruiz²,

Álvarez-Lobos³

et al. 2014

WJG

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Bowel preparation is a core issue in colonoscopy, as it is closely related to the quality of the procedure. Patients often find that bowel preparation is the most unpleasant part of the examination. It is widely accepted that the quality of cleansing must be excellent to facilitate detecting neoplastic lesions. In spite of its importance and potential implications, until recently, bowel preparation has not been the subject of much study. The most commonly used agents are high-volume polyethylene glycol (PEG) electrolyte solution and sodium phosphate. There has been some confusion, even in published meta-analyses, regarding which of the two agents provides better cleansing. It is clear now that both PEG and sodium phosphate are effective when administered with proper timing. Consequently, the timing of administration is recognized as one of the central factors to the quality of cleansing. The bowel preparation agent should be administered, at least in part, a few hours in advance of the colonoscopy. Several low volume agents are available, and either new or modified schedules with PEG that usually improve tolerance. Certain adjuvants can also be used to reduce the volume of PEG, or to improve the efficacy of other agents. Other factors apart from the choice of agent can improve the quality of bowel cleansing. For instance, the effect of diet before colonoscopy has not been completely clarified, but an exclusively liquid diet is probably not required, and a low-fiber diet may be preferable because it improves patient satisfaction and the quality of the procedure. Some patients, such as diabetics and persons with heart or kidney disease, require modified procedures and certain precautions. Bowel preparation for pediatric patients is also reviewed here. In such cases, PEG remains the most commonly used agent. As detecting neoplasia is not the main objective with these patients, less intensive preparation may suffice. Special considerations must be made for patients with inflammatory bowel disease, including safety and diagnostic issues, so that the most adequate agent is chosen. Identifying neoplasia is one of the main objectives of colonoscopy with these patients, and the target lesions are often almost invisible with white light endoscopy. Therefore excellent quality preparation is required to find these lesions and to apply advanced methods such as chromoendoscopy. Bowel preparation for patients with lower gastrointestinal bleeding represents a challenge, and the strategies available are also reviewed here. Core tip: Bowel preparation for colonoscopy is a central issue related to the quality of the procedure. There are different agents for bowel preparation that can be administered with different schedules. We review the most commonly used agents, as well as new agents and combinations. Moreover, certain considerations should be taken into account for special populations in order to improve safety, efficacy and tolerance. Regimens for bowel preparation in special situations are discussed, such as for pedi...

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Safety of Polyethylene Glycol 3350 for the Treatment of Chronic Constipation in Children

Abstract: Long-term PEG therapy is safe and is well accepted by children with chronic constipation with and without encopresis.

Cited by 124 publications

References 16 publications

Involvement of p21cip1/waf1 in the anti-proliferative effects of polyethylene glycol in colon carcinogenesis

Involvement of p21cip1/waf1 in the anti-proliferative effects of polyethylene glycol in colon carcinogenesis

PEGylated Proteins: Evaluation of Their Safety in the Absence of Definitive Metabolism Studies

Achieving the best bowel preparation for colonoscopy

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