van der Bijl Pieter, van Eyk Armorél D, Seifart Heiner I, Meyer David
Departments of Pharmacology and Ophthalmology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
Cornea. 2004 May;23(4):386-9. doi: 10.1097/00003226-200405000-00014.
To investigate the in vitro permeation of metronidazole through rabbit and human corneas in the presence and absence of 0.01% benzalkonium chloride and to suggest its use as adjunct therapy in the treatment of Acanthamoeba keratitis.
Metronidazole permeation through rabbit and human corneas, the latter being unsuitable for transplantation, were used for all permeability experiments. Flux rates for metronidazole from 0.5% and 1.0% aqueous solutions in the presence and absence of 0.01% benzalkonium chloride (BZCL) were determined. ANOVA and the Duncan multiple range test were used to test for steady state and an unpaired t test with the Welch correction was used to test for differences between the mean flux values at each time point. A significance level of 5% was used for all the statistical tests. In the clinical cases described, 0.5% aqueous solution was used.
Steady-state flux rates for metronidazole from 0.5% and 1.0% solutions across both rabbit and human corneas were achieved after 6 and 4 hours, respectively. No statistically significant differences were obtained in the presence and absence of 0.01% BZCl (P < 0.05) between the steady state flux values at both concentrations of metronidazole of human and rabbit corneas, except for 0.5% metronidazole across rabbit corneas. Flux rates of metronidazole across human corneas were 12%-33% higher than those across rabbit corneas. For both rabbit and human corneas, flux rates of metronidazole from 0.5% and 1.0% solutions were reduced by between 4% and 11%, respectively, in the presence of 0.01% benzalkonium chloride.
Although statistically significant differences in flux values were obtained between human and rabbit corneas, the study supports the suitability of the in vitro rabbit cornea as a model for investigating permeation of drugs through human corneas. However, direct extrapolation of animal data to humans must be approached cautiously. The metronidazole from a 1% solution had a steady-state flux rate approximately double that from the 0.5% solution. Higher concentrations of up to 1% may be considered for clinical use for treating Acanthamoeba keratitis infections. It would appear to be prudent to omit benzalkonium chloride as a preservative from preparations of metronidazole formulated for topical ophthalmologic use. Early clinical experience with the topical solution as adjunct therapy in the treatment of Acanthamoeba keratitis is encouraging.
研究在有和没有0.01%苯扎氯铵存在的情况下甲硝唑透过兔角膜和人角膜的体外渗透情况，并建议将其用作棘阿米巴角膜炎治疗的辅助疗法。
所有渗透性实验均使用甲硝唑透过兔角膜和人角膜（后者不适用于移植）的情况。测定了在有和没有0.01%苯扎氯铵（BZCL）存在的情况下，0.5%和1.0%水溶液中甲硝唑的通量率。采用方差分析和邓肯多重极差检验来检验稳态，采用经韦尔奇校正的非配对t检验来检验每个时间点平均通量值之间的差异。所有统计检验的显著性水平均为5%。在所描述的临床病例中，使用的是0.5%水溶液。
分别在6小时和4小时后，0.5%和1.0%溶液中甲硝唑透过兔角膜和人角膜的通量率达到稳态。除了0.5%甲硝唑透过兔角膜外，在有和没有0.01% BZCl的情况下（P < 0.05），人角膜和兔角膜在两种浓度甲硝唑下的稳态通量值之间没有统计学上的显著差异。甲硝唑透过人角膜的通量率比透过兔角膜的通量率高12% - 33%。对于兔角膜和人角膜，在有0.01%苯扎氯铵存在的情况下，0.5%和1.0%溶液中甲硝唑的通量率分别降低了4% - 11%。
虽然在人角膜和兔角膜之间获得了通量值的统计学显著差异，但该研究支持体外兔角膜作为研究药物透过人角膜渗透模型的适用性。然而，必须谨慎地将动物数据直接外推至人类。1%溶液中的甲硝唑稳态通量率约为0.5%溶液的两倍。治疗棘阿米巴角膜炎感染的临床应用中可考虑使用高达1%的更高浓度。对于用于局部眼科用途的甲硝唑制剂，省略苯扎氯铵作为防腐剂似乎是谨慎的做法。局部溶液作为棘阿米巴角膜炎治疗辅助疗法的早期临床经验令人鼓舞。
