Kelly C P, Chetham S, Keates S, Bostwick E F, Roush A M, Castagliuolo I, LaMont J T, Pothoulakis C
Evans Memorial Department of Clinical Research, Boston City Hospital, Boston University School of Medicine, Massachusetts 02118, USA.
Antimicrob Agents Chemother. 1997 Feb;41(2):236-41. doi: 10.1128/AAC.41.2.236.
To be therapeutically active, oral hyperimmune bovine immunoglobulin concentrate (BIC) must survive its passage through the intestinal tract. This led us to study the gastrointestinal stability of orally administered BIC directed against Clostridium difficile toxins (BIC-C. difficile). BIC-C. difficile was stable at neutral pH in vitro but was degraded at low pH, particularly in the presence of pepsin. Healthy volunteers (n = 6) took BIC-C. difficile (45 or 8 g) as a single oral dose. Total bovine immunoglobulin G (IgG) and specific anti-C. difficile IgG were measured in the stool. BIC was given under the following conditions: in the fasting state, in the fed state, with antacid, during omeprazole therapy, or in enteric capsules (released at pH > 6). The mean fecal bovine IgG content of 3-day stool collections was similar in the fasting (536 mg; 3.8% of the ingested dose of BIC), fed (221 mg; 1.6%), and antacid (381 mg; 2.7%) groups. Omeprazole therapy was associated with increased fecal bovine IgG levels (1253 mg; 8.8%), but this difference did not reach statistical significance (P = 0.07). Administration of 8 g of BIC-C. difficile in enteric capsules resulted in substantially higher fecal bovine IgG levels (1,124 mg; 32.7% of the oral dose) than those obtained after administration of nonencapsulated BIC (22 MG; 0.6%; P = 0.004). An inverse relationship was noted between intestinal transit time and fecal bovine IgG content (R = 0.83; P = 0.04 [data from omeprazole group]). Filtrates of stool samples collected after oral administration of BIC-C. difficile neutralized the cytotoxicity of C. difficile toxins A and B, whereas control stool filtrates did not. Bovine colostral IgG undergoes partial degradation in the intestinal tract. Exposure to acidic gastric secretions and prolonged colonic transit may both contribute to IgG degradation. Nonetheless, humans taking BIC-C. difficile orally have neutralizing antitoxin activity in their stool.
为了具有治疗活性，口服超免疫牛免疫球蛋白浓缩物（BIC）必须在通过肠道的过程中存活下来。这促使我们研究口服针对艰难梭菌毒素的BIC（BIC - C. difficile）在胃肠道中的稳定性。BIC - C. difficile在体外中性pH条件下稳定，但在低pH值下会降解，尤其是在胃蛋白酶存在的情况下。健康志愿者（n = 6）单次口服BIC - C. difficile（45或8 g）。在粪便中测量总牛免疫球蛋白G（IgG）和特异性抗艰难梭菌IgG。BIC在以下条件下给药：空腹状态、进食状态、与抗酸剂一起、在奥美拉唑治疗期间或肠溶胶囊中（在pH > 6时释放）。3天粪便收集的平均粪便牛IgG含量在空腹组（536 mg；摄入BIC剂量的3.8%）、进食组（221 mg；1.6%）和抗酸剂组（381 mg；2.7%）中相似。奥美拉唑治疗与粪便牛IgG水平升高相关（1253 mg；8.8%），但这种差异未达到统计学意义（P = 0.07）。口服8 g肠溶胶囊装的BIC - C. difficile导致粪便牛IgG水平（1124 mg；口服剂量的32.7%）显著高于未封装BIC给药后的水平（22 mg；0.6%；P = 0.004）。肠道转运时间与粪便牛IgG含量之间存在负相关关系（R = 0.8；P = 0.04 [来自奥美拉唑组的数据]）。口服BIC - C. difficile后收集的粪便样本滤液可中和艰难梭菌毒素A和B的细胞毒性，而对照粪便滤液则不能。牛初乳IgG在肠道中会发生部分降解。暴露于酸性胃分泌物和结肠转运时间延长都可能导致IgG降解。尽管如此，口服BIC - C. difficile的人粪便中具有中和抗毒素活性。
