Discussion on the Effect of Omeprazole Usage on the Viability of Random Pattern Skin Flaps in Rats

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To the Editor:
We read with great interest the article by Şen et al,1 which was published in October of 2016, reporting the effect of omeprazole in flap viability. As known, although several studies have been conducted to improve flap viability by using various agents to increase blood supply and/or neovascularization, skin flap necrosis has remained as an important problem for plastic surgeons.2 The authors performed an exhaustive experiment and should be applauded for the effort put in by them. However, we think that the study has some parts to be clarified and discussed that were proposed by the authors.
When we look at the methodology of the study, the authors randomly assigned 35 rats into 5 groups: 1 control group, which was only given distilled water intraperitoneally for 14 days; 2 study groups, which received intraperitoneally 10 and 40 mg/kg omeprazole daily for 14 days; and another 2 study groups, which received intraperitoneally distilled water for 7 days before the flap elevation and 10 and 40 mg/kg omeprazole daily for 7 days after the flap elevation. As known, the aim of using control animals is to minimize the impact of extraneous or unwanted variables. Multiple types of control groups were defined in the literature including positive, negative, sham, vehicle, comparative, etc.3 In this study, the authors used only a control group, which received distilled water by intraperitoneal route before and after the flap elevation. Thus, the authors compared their experimental groups with that control group. In such studies, a control group with a small sample size, which gets no treatment at all, should be added to exclude the effect of used vehicle, procedure, and/or test substance. In other words, could the authors explain the effect of intraperitoneally used distilled water on flap viability? Although the amount of distilled water used was probably slightly less, the authors should not ignore the effect of their used vehicle in such experiments. For instance, as it is known, distilled water is a type of artificially produced demineralized waters, which makes it a kind of hypotonic solution far from physiological fluids. Kanakura et al4 reported that intraperitoneal injection of distilled water had eradicated differentiated mast cells, whereas saline solution had not. It is shown that several lines of evidence suggest a key role for mast cells in the induction of angiogenesis.5 Most importantly, mast cells are able to produce and release many potent angiogenic factors, including tryptase, chymase, vascular endothelial growth factor, basic fibroblast growth factor, and IL-8,5 the issue of which is the authors' interests. Therefore, the authors should not ignore a negative effect of distilled water on mast cells, which can be seen as a potential angiogenic producer in their control group.
Another issue that needs to be discussed is the possible clinical usage of medications increasing gastrin during flap surgeries as the authors stated.1 The authors proposed increased vascularity in random pattern skin flap via omeprazole by increased gastrin.1 It is agreed that gastrin is not only a secretagogue but also exerts growth promoting effects in normal and neoplastic tissues. They mentioned that gastrin induces angiogenesis via stimulation of heparin-binding epidermal growth factor-like growth factor (HB-EGF).1 However, in recent years, studies that provide evidence that HB-EGF exerts oncogenic potentials in vitro and in vivo have been increasing as stated in the given references by the authors.6 Ongusaha et al6 identified HB-EGF in their research as a target of v-Jun, a potent oncogene, and mentioned that HB-EGF plays a role in v-Jun-mediated oncogenic transformation. Therefore, they hypothesized that HB-EGF may behave as an oncogene and, as such, could have importance as a therapeutic target.
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