Research article
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Highlights
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BPC157 did not show any test-related effects in the single-dose toxicity study. •
BPC157 was well tolerated in repeated-dose toxicity evaluations. •
BPC157 caused mild local irritation and showed good tolerance. •
BPC157 showed no genetic or embryo-fetal toxicity.
Abstract
BPC157 displays protective activity in various organs and tissues. This report presents preclinical toxicity studies with BPC157 in mice, rats, rabbits and dogs. The single-dose toxicity study did not show any test-related effects that could be attributed to the test article. In repeated-dose toxicity evaluations, BPC157 was well tolerated in dogs, with no abnormal changes between the BPC157-treated groups and the solvent control group, with the exception of a decrease in creatinine level at a dose of 2 mg/kg but not at lower doses. The animals recovered spontaneously after 2 weeks of withdrawal. This may be due to the pharmacological activity of BPC157. A local tolerance test showed that the irritation caused by BPC157 was mild. BPC157 also showed no genetic or embryo-fetal toxicity. In summary, BPC157 was well tolerated and did not cause any serious toxicity in mice, rats, rabbits and dogs. These preclinical safety data contribute to the initiation of an ongoing clinical study. Based on the stability and protective effect of BPC157, which has been widely reported, BPC157 may have a better application prospect than the widely used cytokine drugs in wound therapy.
Keywords
BPC157
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Single-dose toxicity study
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Repeated-dose toxicity study
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Preclinical evaluation
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Safety
Introduction
The pentadecapeptide body protective compound (BPC)157, with the sequence Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val, is the essential activity fragment of BPC peptide in human gastric juice (Sikiric et al., 1993). BPC157 is also called BPC-15, PL-10, PLD-116 or PL14736 (Keremi et al., 2009; Sikiric et al., 2013)and was demonstrated to have an obvious protective effect on the acute and chronic damage of the esophagus, stomach, duodenum and colorectal mucosa caused by various factors (Veljaca et al., 1995; Sikiric et al., 1994, 1999a, 2000a; Bilic et al., 2001; Jelovac et al., 1999; Duzel et al., 2017). The beneficial effects of BPC157 on other organs, such as the liver (Drmic et al., 2017; Prkacin et al., 2001), pancreas (Sikiric et al., 2011), ligament (Cerovecki et al., 2010), muscle (Pevec et al., 2010), cornea (Lazic et al., 2005), heart (Balenovic et al., 2009) and nerves (Sikiric et al., 2016), has also become evident. Moreover, BPC157 can promote the healing of skin wounds and even fractures caused by various traumas (Seiwerth et al., 1997; Sebecic et al., 1999; Mikus et al., 2001). BPC157 was reported to be ‘cytoprotective’ (Konturek and Brzozowski, 2008; Sikiric et al., 2018; Brzozowski et al., 2008) and supportive of epithelial integrity. Apart from its obvious protective effect on multiple organ injuries, the potentially beneficial effects of BPC157 in anti-inflammatory (Kalogjera et al., 1997; Sikiric et al., 1997; Vuksic et al., 2007), antitremor paralysis (Sikiric et al., 1999b) and antidepression (Sikiric et al., 2000b) are described. Although the detailed mechanism underlying BPC157 function remains unclear, this compound appears to be beneficial to almost all organ systems in many species and has significant effects at very low doses. As a partial sequence of the human gastric protein BPC, BPC157 has good stability, can be stored at room temperature and shows resistance to hydrolysis or enzyme digestion, even in gastric juice. In addition, BPC157 can also be easily dissolved in water and needs no carrier for its application (Chang et al., 2011). Studies have suggested that BPC157 has exceedingly good potential as a therapeutic agent for severe trauma and stress damage in organs caused by various injuries. The stability and multiple protective effects of BPC157 make this compound significantly superior to the currently widely used cytokine drugs for the treatment of wounds. However, the safety of BPC157 as a therapeutic drug has not been reported thus far. The in vitro and in vivo safety evaluation of this pentadecapeptide will be very important for its potential applications.
Previously, we synthesized and purified BPC157 (Xue et al., 2004) by solid-phase synthesis and verified its biological activity by rat gastric ulcer models and skin alkali burn models (Huang et al., 2015). For its future clinical use as a therapeutic drug, the present study was undertaken to evaluate the safety of BPC157 according to the criteria of the investigational new drug application. In this study, the single-dose toxicity, repeated-dose toxicity, local tolerance, anaphylaxis, genetic toxicity and teratogenicity of this synthetic BPC157 peptide were investigated in rats, dogs, rabbits and guinea pigs. The results of this study and interrelated studies satisfied the requirements for future clinical trials. This study is the first preclinical safety evaluation of BPC157, and the results are of considerable importance, given not only the proven safety of BPC157 but also the implication for its systemic application as a novel drug for various injuries.
Section snippets
Test article
BPC157 was synthesized and purified in our laboratory with 99% (high-performance liquid chromatography) purity. This compound was sterilized and lyophilized to meet the regulatory requirements for preclinical studies. According to our previous pharmacodynamic results in rats and mice, our recommended dosage for clinical trials is 200 μg/person/day (3.33 μg/kg/day) for 7 days. The medication route is intramuscular injection (i.m.). The dosage used in the present toxicity studies was determined
Single-dose toxicities
In the single-dose toxicity study of rats, no death was observed after 20 mg/kg BPC157 administration. The rats in all cohorts showed no obvious abnormalities in terms of general signs, body weight, behavior, food intake, skin and fur, urination or defecation during the following 14 days of observation. Fourteen days after treatment administration, all rats were euthanized and underwent autopsy. There were no significant abnormal findings in the main organs, and no differences were observed
Discussion
BPC157, as a cell/organ protectant, has obvious protective effects on various organ damages (Sikiric et al., 2018). In previous studies, our chemically synthesized BPC157 showed significant protective effects in the healing of acute and chronic gastric ulcers at a very low dose (200 ng/kg) through both i.m. And i.g. Administration (Xue et al., 2004). We also confirmed that BPC157 can enhance alkali-burn wound healing in vivo and promote proliferation, migration, and angiogenesis (Huang et al.,
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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These authors contributed equally: Chuanyang Xu, Lijuan Sun.
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