Sikiric P, Seiwerth S, Grabarevic Z, Balen I, Aralica G, Gjurasin M, Komericki L, Perovic D, Ziger T, Anic T, Prkacin I, Separovic J, Stancic-Rokotov D, Lovric-Bencic M, Mikus D, Staresinic M, Aralica J, DiBiaggio N, Simec Z, Turkovic B, Rotkvic I, Mise S, Rucman R, Petek M, Sebecic B, Ivasovic Z, Boban-Blagaic A, Sjekavica I
Department of Pharmacology, Medical Faculty, University of Zagreb, Salata 11, POB 916 Zagreb, Croatia.
J Physiol Paris. 2001 Jan-Dec;95(1-6):261-70. doi: 10.1016/s0928-4257(01)00036-5.
Recently, we showed cysteamine-duodenal lesions without gastric acid, since they were induced also in gastrectomized rats, as in naive rats, and they were inhibited by the novel stomach pentadecapeptide BPC 157 as well as standard antiulcer drugs (i.e. cimetidine, ranitidine, omeprazole, bromocriptine, atropine). Therefore, as an advantage of considering cysteamine as a directly acting cytotoxic agent and mentioned agents as direct cytoprotective agents, the present focus was on the ulcerogenic effect of cysteamine and protective effect of gastroduodenal antiulcer agents outside upper gastrointestinal tract (i.e. in colon). Intrarectal administration of the cysteamine (200 or 400 mg/kg b.w) produced severe colon lesions (i.e. transmural inflammation with serosal involvement) in rats (30 min-72 h-experimental period), apparently distinctive from smaller lesions after non-specific irritant enema [diluted HCl solution, pH 3.8 (adjusted to pH of cysteamine solution (pH 3.8)]. All of the tested antiulcer agents were applied simultaneously with cysteamine enema (8 cm from the anus, in a volume of the 1.0 ml/rat) intraperitoneally (i.p.), intragastrically (i.g.) or intrarectally (i.r.). Pentadecapeptide BPC 157 (10 microg or 10 ng/kg b.w.), given in either regimen, previously shown to have, besides others, a particular beneficial activity just in the intestinal mucosa, inhibited these cysteamine colon lesions (assessed after 30 min, 60 min, 180 min, 24 h, 48 h, 72 h following cysteamine in a dose of either 200 or 400 mg/kg i.r.). Cysteamine-colon lesions were also attenuated by standard antiulcer agents (mg/kg b.w.), given i.p., i.g., or i.r., such as ranitidine (10), cimetidine (50), omeprazole (10), atropine (10), together with methylprednisolone (1), and sulphasalazine (50, i.r.), assessed 30 min following application of 200 mg of cysteamine. Finally, standard cysteamine duodenal lesions (assessed 24 h after a subcutaneous application of 400 mg/kg of cysteamine) were also attenuated by these agents application (given in the same doses, i.p., 1 h before cysteamine), with only exception to sulphasalazine. Thus, the extended cysteamine specific ulcerogenic effect, cysteamine colon/duodenum lesion-link and an extenuation of agents protection from upper to lower part of gastrointestinal tract (i.e. stomach pentadecapeptide BPC 157, standard antiulcer agents, cimetidine, ranitidine, atropine, omeprazole) and vice versa (remedies for inflammatory bowel disease) evidenced in the present study may be potentially important for both further experimental and clinical research.
最近，我们发现半胱胺可导致十二指肠损伤，且无需胃酸参与，因为在胃切除大鼠中也会像正常大鼠一样引发此类损伤，并且新型胃十五肽BPC 157以及标准抗溃疡药物（即西咪替丁、雷尼替丁、奥美拉唑、溴隐亭、阿托品）均可抑制这种损伤。因此，鉴于将半胱胺视为直接作用的细胞毒性剂以及将上述药物视为直接细胞保护剂的优势，目前的重点在于研究半胱胺在上消化道以外部位（即结肠）的致溃疡作用以及胃肠道抗溃疡药物的保护作用。经直肠给予半胱胺（200或400mg/kg体重）可在大鼠中（30分钟至72小时的实验期）引发严重的结肠损伤（即伴有浆膜受累的透壁性炎症），这明显有别于非特异性刺激性灌肠（稀释的HCl溶液，pH 3.8（调整至半胱胺溶液的pH值（pH 3.8））后产生的较小损伤）。所有受试抗溃疡药物均与半胱胺灌肠剂（距肛门8cm，每只大鼠1.0ml）同时经腹腔内（i.p.）、胃内（i.g.）或直肠内（i.r.）给药。十五肽BPC 157（10μg或10ng/kg体重），无论采用哪种给药方案，先前已证明其除其他作用外，尤其在肠黏膜中具有特殊的有益活性，可抑制这些半胱胺诱导的结肠损伤（在以200或400mg/kg体重经直肠给予半胱胺后30分钟、60分钟、180分钟、24小时、48小时、72小时进行评估）。标准抗溃疡药物（mg/kg体重）经腹腔内、胃内或直肠内给药，如雷尼替丁（10）、西咪替丁（50）、奥美拉唑（10）、阿托品（10），以及甲基泼尼松龙（1）和柳氮磺胺吡啶（50，经直肠给药），在给予200mg半胱胺后30分钟进行评估，也可减轻半胱胺诱导的结肠损伤。最后，标准的半胱胺十二指肠损伤（在皮下给予400mg/kg半胱胺后24小时进行评估）在给予相同剂量的这些药物（经腹腔内给药，在给予半胱胺前1小时）后也可减轻，但柳氮磺胺吡啶除外。因此，本研究中证明的半胱胺特异性致溃疡作用的扩展、半胱胺结肠/十二指肠损伤联系以及药物保护作用从胃肠道上部到下部（即胃十五肽BPC 157、标准抗溃疡药物、西咪替丁、雷尼替丁、阿托品、奥美拉唑）的减弱以及反之亦然（炎症性肠病的治疗药物），对于进一步的实验和临床研究可能具有潜在的重要意义。
