加替沙星引起血糖紊乱的可能机制

对抗菌药加替沙星引起用药者血糖紊乱的可能机制进行了分析和讨论，如干扰某些与血糖相关的内源性物质（胰岛素、肾上腺素、组胺等）的释放、影响葡萄糖转运体1的表达与功能、抑制机体糖异生途径等，以供从事临床工作和药物研发的人士参考。     

加替沙星与糖代谢紊乱

加替沙星是第四代喹诺酮类抗菌药。在临床应用中,人们发现该药可导致糖代谢紊乱,引发低血糖或高血糖。本文综述了国内外相关研究报道,提示临床医生在加替沙星用药过程中应密切监测血糖,一旦发生血糖紊乱,应立即停药并纠正血糖紊乱。     

2003～2006年866例加替沙星致不良反应报告分析

目的:了解加替沙星致不良反应的发生特点。方法:对2003年10月30日～2006年10月30日浙江省药品不良反应监测中心收集的866例加替沙星引发的不良反应报告进行Excel列表分析。结果:皮肤及其附件、消化系统、全身性及神经系统损害是加替沙星常见的不良反应,多数症状轻微,但其存在潜在的、损害人体重要器官的不良反应,如糖代谢紊乱等。结论:加强不良反应的监测工作,以减少和避免不良反应的发生。     

加替沙星相关血糖异常的警示

目的：探讨住院患者中,加替沙星疑致血糖异常的临床特点及药品安全评价的反馈预警模式。方法：回顾性分析近一年我院发生的14例加替沙星注射液疑致血糖异常的临床资料。结果：应用甲磺酸加替沙星注射液13例、加替沙星氯化钠注射液1例发生治疗相关血糖异常,用药后1～10 d血糖值均有明显波动,达3．23～51．67 mmol·L~(-1),仅1例用药1d出现低血糖后转为高血糖,其余均为高血糖。结论：糖尿病患者和非糖尿病患者均有可能发生加替沙星治疗相关性血糖异常,老年人、肝肾功能障碍者应慎用,合并应用其他影响血糖药物有协同作用。及时开展院内严重个案的监测和分析是药品不良反应信号提取的有效手段,并可依据提取信号的强弱,发布预警,协助临床降低用药潜在风险。     

Gatifloxacin-induced dysglycemia.

PURPOSE: The development of gatifloxacin-induced dysglycemia in 13 patients is described; the details of the 3 most severe cases are presented. SUMMARY: Three elderly patients developed dysglycemia after initiation of gatifloxacin therapy. Both patients who developed hypoglycemia were receiving concomitant insulin or oral antidiabetic agents. Repeated doses of dextrose were required for management. The Naranjo et al. probability rating scale revealed that gatifloxacin was the probable cause in the majority of the 13 cases, primarily because of the temporal relationship with gatifloxacin and, in some instances, resolution of dysglycemia after drug discontinuation. Although the mechanism of gatifloxacin-induced hyperglycemia is not known, in vitro studies have found that certain quinolone antimicrobials can lower serum glucose levels by blocking adenosine 5'-triphosphate-dependent potassium channels in the pancreatic beta-cell, stimulating insulin release. It is difficult to unequivocally implicate gatifloxacin as the only cause of dysglycemia in the cases presented, as there are many explanations for poor glycemic control in hospitalized patients, such as stress, infection, decreased renal function, and concomitant drug therapies. However, the patients' medication regimens appeared to be stable before gatifloxacin administration. CONCLUSION: Thirteen patients developed dysglycemia after receiving gatifloxacin. Gatifloxacin was found to be the probable cause in the majority of cases.     

加替沙星对住院患者血糖影响的随访研究

目的：研究加替沙星对住院患者血糖的影响，为临床安全应用该药提供科学依据。方法：2007年5月至10月期间接受加替沙星或左氧氟沙星治疗的475例来自13所医院的住院患者纳入随访研究。其中加替沙星组230例，左氧氟沙星组245例。患者的给药剂量均为400mg／d，静脉滴注，用药时间为7d。给药前、给药后第4天及停药后测定患者的血糖水平。结果：停药后高血糖和血糖升高的发生率，加替沙星组高于左氧氟沙星组（分别为13．91％对6．53％和18．70％对9．80％），差异有统计学意义（P〈0．01）。停药后血糖降低的发生率，左氧氟沙星组高于加替沙星组（36．73％对22．17％），差异有统计学意义（P〈0．01）。加替沙星组停药后高血糖、血糖升高及降低的发生率，糖尿病患者分别为12．90％、17．74％及22．58％，非糖尿病患者分别为14．29％、19．05％和24．40％，差异无统计学意义（均P〉0．05）。结论：加替沙星可致血糖升高或降低，因此临床使用时应予以注意，并应作血糖水平测定。     

加替沙星致血糖异常及其合理应用

目的减少加替沙星致血糖代谢紊乱的不良反应的发生,促进其合理应用。方法检索近年来国内外医药学期刊报道的加替沙星引起血糖代谢紊乱的案例,结合国外对加替沙星的评价、加替沙星致血糖代谢紊乱的机理,进行分析、总结,提出加替沙星合理应用的建议。结果与结论应加强对加替沙星引起血糖代谢紊乱的重视,临床使用中密切监测血糖,合理应用。     

Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats

Accumulating evidences have showed that gatifloxacin causes dysglycemia in both diabetic and non-diabetic patients. Our preliminary study demonstrated that gatifloxacin stimulated glucagon-like peptide 1 (GLP-1) secretion from intestinal cells. The aim of the study was to investigate the association between gatifloxacin-stimulated GLP-1 release and dysglycemia in both normal and streptozotocin-induced diabetic rats and explore the possible mechanisms. Oral administration of gatifloxacin (100 mg/kg/day and 200 mg/kg/day) for 3 and 12 days led to marked elevation of GLP-1 levels, accompanied by significant decrease in insulin levels and increase in plasma glucose. Similar results were found in normal rats treated with 3-day gatifloxacin. Gatifloxacin-stimulated GLP-1 release was further confirmed in NCI-H716 cells, which was abolished by diazoxide, a K_ATP channel opener. QT-PCR analysis showed that gatifloxacin also upregulated expression of proglucagon and prohormone convertase 3 mRNA. To clarify the contradiction on elevated GLP-1 without insulinotropic effect, effects of GLP-1 and gatifloxacin on insulin release were investigated using INS-1 cells. We found that short exposure (2 h) to GLP-1 stimulated insulin secretion and biosynthesis, whereas long exposure (24 h and 48 h) to high level of GLP-1 inhibited insulin secretion and biosynthesis. Moreover, we also confirmed gatifloxacin acutely stimulated insulin secretion while chronically inhibited insulin biosynthesis. All the results gave an inference that gatifloxacin stimulated over-secretion of GLP-1, in turn, high levels of GLP-1 and gatifloxacin synergistically impaired insulin release, worsening hyperglycemia.     

63例加替沙星不良反应分析

目的探讨喹诺酮类药物加替沙星不良反应(ADR)的一般规律和特点,为临床安全用药提供参考。方法我院2007年1月-2009年12月上报的443份药物不良反应报表,对其中63例加替沙星不良反应报告进行统计分析。结果 63例加替沙星不良反应报告中,2007年40例,2008年18例,2009年5例。男30例,女33例。患者最小年龄18岁,最大87岁;不良反应主要表现为皮肤及附件损害、消化道反应、神经系统反应以及糖代谢紊乱等方面,根据国家ADR监测中心制定的《ADR因果关系判断标准》进行评价,肯定者46例,很可能者15例,可能者2例。ADR轻度58例,中重度需要对症治疗5例,不良反应结果治愈60例(95.24%),好转3例(4.76%)。结论加替沙星引起的不良反应类型较多,临床用药时应密切观察,确保用药安全合理。     

An evaluation of the effects of gatifloxacin on glucose homeostasis

Introduction The United States labeling for gatifloxacin has been updated to include contradictions related to its reported association with dysglycemia. However, adequately controlled studies in acute care settings assessing the magnitude and clinical determinants of dysglycemia are lacking. Objectives To compare the hypoglycemic and hyperglycemic effects of gatifloxacin with ceftriaxone in hospitalized patients. Methods A retrospective cohort study of hospitalized adult (≥18 years) patients admitted with Community Acquired Pneumonia (CAP) or Acute Exacerbation of Chronic Bronchitis (AECB) in a US tertiary care hospital between 7/1/01 and 12/31/04 treated with gatifloxacin or ceftriaxone during hospital admission. Outcomes of interests were incidence of hypoglycemia (blood glucose levels <46 mg/dL) or hyperglycemia (>200 mg/dL) during up to 5 days of drug exposure. Risks for gatifloxacin and ceftriaxone were compared adjusting for variables previously reported to be independent predictors of hypoglycemia or hyperglycemia. Results 1504 patients met the study inclusion criteria. Compared to ceftriaxone, gatifloxacin was associated with an increased risk of hypoglycemia: (adjusted odds ratio (OR) 2.34, 95% confidence interval (CI) 1.4–4.0). The increased risk of hypoglycemia during exposure to gatifloxacin was similar in patients with and without a diagnosis of diabetes mellitus. Gatifloxacin was not associated with an increased risk for hyperglycemia (adjusted OR: 1.06 95% CI 0.8–1.4) considering the whole study cohort. However, stratification by diagnosis of diabetes, gatifloxacin treated patients appeared to have a reduced risk of hyperglycemia (adjusted OR: 0.4 95% CI 0.2–0.4) while non-diabetic gatifloxacin treated patients appeared to have an increased risk of hyperglycemia (adjusted OR: 1.64 95% CI 1.1–2.4). Conclusion The risk of dysglycemia with gatifloxacin in this population of hospitalized patients was not as high as previously reported in ambulatory patients. Although these results suggest gatifloxacin use is safer in acute care settings, we recommend that clinicians monitor blood glucose levels carefully or consider alternatives to gatifloxacin therapy whenever possible.     

注射用加替沙星与酚磺乙胺注射液的配伍稳定性考察

目的:考察注射用加替沙星与酚磺乙胺注射液在0.9%氯化钠注射液和5%葡萄糖注射液中配伍的稳定性。方法:在室温((20±1)℃)下,观察8h内配伍液在0.9%氯化钠注射液和5%葡萄糖注射液中的外观,测定pH值及考察紫外光谱的变化,并用紫外双波长分光光度法测定加替沙星和酚磺乙胺的含量。结果:2药配伍后,8h内的pH值及外观均无明显变化,在0.9%氯化钠注射液中8h内以及在5%葡萄糖注射液中6h内,配伍液的含量无明显变化。结论:加替沙星与酚磺乙胺注射液在0.9%氯化钠注射液和5%葡萄糖注射液中配伍稳定。     

加替沙星致高血糖2例

2例患者静脉滴注加替沙星引发高血糖。第1例为81岁男性,因慢性阻塞性肺疾病急性加重,给予加替沙星0.4g 5%葡萄糖注射液250ml静脉滴注,1次/d。3d后患者出现烦躁、多尿、口渴、疲劳,血糖由用药前6.01mmol/L升至28.84mmol/L。立即停用加替沙星,给予12U胰岛素静脉滴注,2d后血糖恢复到5.2mmol/L。第2例为61岁男性梗阻性胆管炎、胆汁淤积性肝硬化患者,给予加替沙星0.4g 5%葡萄糖注射液250ml静脉滴注,1次/d,谷胱甘肽1.2g 葡萄糖氯化钠注射液250ml静脉滴注,1次/d,消炎利胆片6片,3次/d。治疗后第4天,血糖由用药前的5.60mmol/L升为13.81mmol/L。遂停用加替沙星,改为克林霉素静脉滴注。3d后血糖降至5.84mmol/L。     

The insulinotropic effect of fluoroquinolones

Antimicrobial fluoroquinolones induce, with strongly varying frequency, life-threatening hypoglycemias, which is explained by their ability to block K_ATP channels in pancreatic B-cells and thus to initiate insulin secretion. In apparent contradiction to this, we observed that none of the fluoroquinolones in this study (gatifloxacin, moxifloxacin, ciprofloxacin, and a number of fluorophenyl-substituted compounds) initiated insulin secretion of perifused mouse islets when the glucose concentration was basal (5 mM). Only when the glucose concentration was stimulatory by itself (10 mM), the fluoroquinolones enhanced secretion. The fluoroquinolones were ineffective on SUR1 Ko islets, which do not have functional K_ATP channels. All of these fluoroquinolones depolarized the membrane potential of mouse B-cells (patch-clamping in the whole-cell mode). Using metabolically intact B-cells (perforated-patch mode) however, 100 μM of gatifloxacin, ciprofloxacin or moxifloxacin were unable to depolarize when the glucose concentration was 5 mM, whereas other K_ATP channel blockers (tolbutamide and efaroxan) remained effective. Only at a very high concentration (500 μM) gatifloxacin and moxifloxacin, but not ciprofloxacin induced repetitive depolarizations which could be antagonized by diazoxide. In the presence of 10 mM glucose all fluoroquinolones which enhanced secretion markedly elevated cytosolic calcium concentration ([Ca²⁺]_i). In the presence of 5 mM glucose gatifloxacin and moxifloxacin at 500 μM but not at 100 μM elevated [Ca²⁺]_i. It is concluded that fluoroquinolones in the clinically relevant concentration range are not initiators, but rather enhancers of glucose-induced insulin secretion. The block of K_ATP channels appears necessary but not sufficient to explain the hypoglycemic effect of fluoroquinolones.     

Moxifloxacin and glucose homeostasis: a pooled-analysis of the evidence from clinical and postmarketing studies.

BACKGROUND: Recently, clinical data has emerged suggesting that the fluoroquinolone, gatifloxacin, can affect glucose homeostosis through an unknown mechanism. In order to explore the potential effects of moxifloxacin on glucose metabolism in humans, a pooled analysis of phase II/III clinical trials and postmarketing studies was performed and compared with results from an investigation in laboratory animals. METHODS: A pooled analysis of 30 (26 controlled, 4 uncontrolled) oral and two intravenous/oral prospective, controlled phase II/III moxifloxacin studies was performed to evaluate the frequency of hyper- and hypoglycaemic episodes and glucose-related adverse events and adverse reactions (i.e. those considered to be drug related) versus comparator antimicrobials (penicillins, cephalosporins, macrolides, doxycycline, fluoroquinolones). Similar evaluations were conducted on data pooled from five postmarketing surveillance studies. In addition, potential effects of supratherapeutic doses of moxifloxacin on blood glucose and plasma insulin levels in fed and fasted rats were assessed in comparison with those of gatifloxacin, levofloxacin and glibenclamide (glyburide). RESULTS: The phase II/III database was comprised of 14,731 patients (8474 moxifloxacin, 6257 comparator antimicrobial).There were no drug-related hypoglycaemic adverse events reported for moxifloxacin in either the oral or intravenous/oral database. Two drug-related hypoglycaemic adverse events were reported in the oral comparator group, both following administration of levofloxacin and both of mild severity; one drug-related hypoglycaemic adverse event was reported in the intravenous/oral comparator group after trovafloxacin administration. Drug-related hyperglycaemic adverse events were reported in seven (<0.1%) moxifloxacin and 1 (<0.1%) comparator-treated patients in the oral study database, none of these cases were considered serious and six of the seven moxifloxacin cases were graded as mild and required no countermeasures. There were no cases of drug-related hyperglycaemic events in any patient enrolled in the intravenous/oral studies. Coadministration of oral antidiabetic drugs with moxifloxacin or comparator antimicrobials did not change the rate of blood glucose increases or decreases in diabetic patients. Data from five moxifloxacin postmarketing studies (46 130 subjects) reported no episodes of hypoglycaemia and two non-drug-related hyperglycaemic episodes. Data from animal studies revealed that supratherapeutic doses of moxifloxacin and levofloxacin did not affect blood glucose or plasma insulin levels in both fed and fasted rats, whereas gatifloxacin decreased both blood glucose and plasma insulin in a dose-dependent manner in fed rats only. The reference compound glibenclamide increased insulin and decreased glucose levels as expected. CONCLUSIONS: Hyperglycaemic or hypoglycaemic adverse reactions were reported rarely in studies with oral or sequential intravenous/oral moxifloxacin, and incidence was comparable in moxifloxacin and comparator groups. Changes in glucose metabolism were also similar in diabetic patients treated with moxifloxacin compared with those patients without diabetes mellitus. This comprehensive analysis of the datapool for moxifloxacin phase II/III clinical trials and postmarketing studies suggests that moxifloxacin administration has no clinically relevant effect on blood glucose homeostasis.     

Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy

Severe and resistant hypoglycemia occurred in two patients with diabetes mellitus who were receiving concomitant gatifloxacin and glyburide. An 84-year-old woman treated with glyburide for type 2 diabetes mellitus experienced, for the first time, a severe episode of hypoglycemia after 2 days of gatifloxacin 400 mg/day for nonproductive cough. Her blood glucose level on hospital admission was 28 mg/dl. Gatifloxacin and glyburide were discontinued, and the patient was treated with intravenous dextrose infused over 36 hours. Glyburide was restarted before her discharge, with no recurrence of hypoglycemia. A 79-year-old man with type 2 diabetes mellitus treated with glyburide was prescribed gatifloxacin 400 mg/day for pneumonia. After 1 day of therapy, the patient was admitted to the emergency department in a coma. His blood glucose level was 18 mg/dl. Despite discontinuation of gatifloxacin and oral hypoglycemic therapy, hypoglycemia was reversed only after administration of multiple boluses of intravenous dextrose, followed by intravenous dextrose infused over 48 hours. On hospital day 7, gliclazide and levofloxacin were started; the patient experienced no recurrence of hypoglycemia and was discharged on day 10. Several cases of severe and resistant hypoglycemia associated with gatifloxacin therapy have been reported in the recent literature. Although the exact mechanism is not fully understood, it may be linked to a gatifloxacin-induced closing of the adenosine 5'-triphosphate-sensitive potassium channels in the pancreatic beta cells, leading to insulin secretion. The onset of hypoglycemia in relation to the start of gatifloxacin suggests that the drug precipitated this adverse event. Patients receiving oral hypoglycemic agents are at greater risk of experiencing gatifloxacin-induced hypoglycemia than patients not receiving these agents. Clinicians should be aware of this potentially life-threatening adverse event and monitor blood glucose levels in all patients receiving concomitant oral hypoglycemic agents and gatifloxacin.     

紫外双波长分光光度法考察注射用加替沙星与头孢噻肟配伍的稳定性

目的:考察加替沙星与头孢噻肟配伍的稳定性。方法:在22℃,观察8h内加替沙星( 2g·L-1 )与头孢噻肟(5g·L-1 )配伍液的外观、pH及紫外光谱的变化,用紫外双波长分光光度法测定2种药物的含量。结果:配伍液的pH值在8h内无明显变化,但其外观,随时间的延长颜色会逐渐加深;加替沙星和头孢噻肟的含量在6h后有明显的降低。结论:加替沙星与头孢噻肟可以配伍使用,但应在4h内滴注完毕。     

A retrospective, comparative evaluation of dysglycemias in hospitalized patients receiving gatifloxacin, levofloxacin, ciprofloxacin, or ceftriaxone

STUDY OBJECTIVES: To compare rates of blood glucose abnormalities in hospitalized patients receiving fluoroquinolones or ceftriaxone, and to describe the characteristics of patients who develop blood glucose abnormalities while receiving these agents. DESIGN: Retrospective chart review. SETTING: Two community-based hospitals in the Houston, Texas, region. PATIENTS: Seventeen thousand one hundred eight patients who received fluoroquinolones or ceftriaxone; of those, 101 received levofloxacin, gatifloxacin, or ceftriaxone and also had serum glucose concentrations above 200 or below 50 mg/dl within 72 hours of receiving the drug. MEASUREMENTS AND MAIN RESULTS: Baseline demographics of patients with glucose abnormalities while receiving gatifloxacin, levofloxacin, or ceftriaxone were similar. Mean +/- SD patient age, weight, and estimated creatinine clearance were 67 +/- 17 years, 79 +/- 21 kg, and 52 +/- 32 ml/minute, respectively. Dysglycemia rates relative to treatment were as follows: gatifloxacin 76 (1.01%) of 7540 patients, levofloxacin 11 (0.93%) of 1179, ceftriaxone 14 (0.18%) of 7844, ciprofloxacin 0 (0%) of 545, and any fluoroquinolone 87 (0.94%) of 9264. Dysglycemia was more likely to occur in patients receiving any fluoroquinolone than in those receiving ceftriaxone (relative risk [RR] 3.32, 95% confidence interval (CI) 2.31-4.78, p < 0.05). The rate of dysglycemia did not differ with gatifloxacin and levofloxacin (RR 1.07, 95% CI 0.62-1.86, p = 0.8). Of the 101 patients with dysglycemias, hypoglycemia occurred in nine (9%) and hyperglycemia in 92 (91%). In a multivariate analysis of patients receiving fluoroquinolones, only concomitant sulfonylurea therapy was identified as an independent risk factor for development of hypoglycemia compared with patients who experienced hyperglycemia. CONCLUSION: In the 17,108 patients receiving a fluoroquinolone or ceftriaxone, the rate of dysglycemia was greater in those receiving levofloxacin or gatifloxacin than in those receiving ceftriaxone. However, no difference was noted in the rate of glucose abnormalities with levofloxacin versus gatifloxacin. Clinicians should be aware of dysglycemic events that may occur in patients receiving fluoroquinolones, especially in those with diabetes mellitus or those receiving sulfonylureas.     

Pioglitazone can downregulate bone morphogenetic protein-2 expression induced by high glucose in human umbilical vein endothelial cells

Bone morphogenetic protein-2 (BMP-2) plays a key role in both vascular development and pathophysiological processes. However, the effect of high glucose on BMP-2 expression remains unclear. Here we show in human umbilical vein endothelial cells that high glucose increased BMP-2 expression, associated with NF-kappaB activation, whereas pioglitazone suppressed BMP-2 expression and NF-kappaB65 activation induced by high glucose. Furthermore, the increase in MDA levels and decrease in activities of total superoxide dismutase of cell culture stimulated by high glucose were reversed by pioglitazone treatment. Our findings indicate that BMP-2 expression induced by high glucose might be closely related to NF-kappaB activation, and both effects can be suppressed by pioglitazone.     

注射用加替沙星与头孢美唑配伍的稳定性考察

目的:考察注射用加替沙星与注射用头孢美唑分别在0.9%氯化钠注射液和5%葡萄糖注射液中配伍的稳定性。方法:在室温(20±1)℃条件下,分别观察及测定8h内配伍液的外观、pH值及紫外吸收光谱的变化,并用紫外双波长分光光度法测定加替沙星与头孢美唑钠的含量。结果:2药配伍后,8h内的外观、pH值、含量及峰形均无明显变化。结论:注射用加替沙星与注射用头孢美唑可在0.9%氯化钠注射液或5%葡萄糖注射液中配伍应用。