Pharmacokinetics of topically applied pilocarpine in the albino rabbit eye.

The temporal and spatial pattern of [3H]-pilocarpine nitrate distribution in the albino rabbit eye following topical administration was determined. A four-compartment caternary chain model describing this disposition corresponds to the precorneal area, the cornea, the aqueous humor, and the lens and vitreous. Simultaneous computer fitting of data from tissue corresponding to some compartments in the model supported the proposed model. Additional support was provided by the excellent correlation between predicted and observed values in multiple-dosing studies. Several important aspects of ocular drug disposition are evident from the model. The extensive parallel elimination at the absorption site gives rise to an apparent absorption rate constant that is one to two orders of magnitude larger than the true absorption rate constant. In addition, aqueous flow accounts for most of the drug removal. Thus, major effects on absorption and elimination, independent of the drug structure, suggest the possibility of similar pharmacokinetics for vastly different drugs.     

Disposition of topically applied vitamin A in the albino rabbit eye

Using radiotracer techniques, the disposition of vitamin A in the albino eye was studied following instillation of its solution in arachis oil in tear chamber, Early peak times were observed in the conjunctiva and the cornea suggesting rapid uptake of the drug by these tissues. Perhaps because of their proximity to the fear pool, these two tissues possessed the highest concentration of vitamin A. Sustained drug concentration was evident in all the ocuiar tissues studied—conjunctiva, cornea, aqueous humor and iris-ciliary body—beginning at 30 min post-instillation. This presumably was due to a reservoir for vitamin A in the precorneal area and perhaps the corneal epithelium; the nature of this reservoir has yet to be resolved. The significance was that vitamin A was available to the conjunctiva and the cornea from topical dosing, the two tissues known to undergo changes in vitamin A deficiency and dry-eye states. Unfortunately, these data as yet do not permit the formulation of a dosage regimen for topically applied vitamin A in the treatment of xerophthalmia.     

Disposition of topically applied sodium cromoglycate in the albino rabbit eye

The influence of pH, tonicity, preservatives, polymers and instilled drop size on the disposition of sodium cromoglycate, an agent used in the prophylaxis of vernal keratoconjunctivitis, in the tear chamber of the albino rabbit eye has been examined. Radiotracer techniques were used throughout. The initial decline in concentration in the tear chamber was found to be unaffected by the presence of preservatives, pH, and tonicity over the ranges studied. However, significant increases in the residence time of sodium cromoglycate in the precorneal area were noted when a smaller instilled drop size was used and when 5% polyvinyl alcohol (PVA) was added to the aqueous vehicle. Tissue uptake was found to be greatest in the conjunctiva, followed by the cornea, the iris-ciliary body and the aqueous humor. In both the conjunctiva and the cornea, the addition of 5% PVA produced an elevation in the peak concentration of sodium cromoglycate and an increase in the time at which the peak concentration was achieved, indicating improved drug delivery to these sites.     

Effect of ocular pigmentation on pilocarpine pharmacology in the rabbit eye. II. Drug response

The time course of the miotic response of pilocarpine in albino and pigmented rabbit eyes was studied after ocular application of 0.11. 0.43, 0.85 and 2.30 mg doses in eye drops and 0.85 and 2.30 mg doses in polymer matrices. When administered in eye drops ocular pigmentation delayed the onset of the peak effect of the 3 smallest pilocarpine doses. The magnitude of the peak effect was lower in pigmented than in albino eyes after 0.11 and 0.43 mg doses, but equal after larger doses. Ocular pigmentation increased the relative biophasic availability of 0.85 and 2.30 mg doses of pilocarpine. This was due to the slower elimination rate of pilocarpine from pigmented tissues. The relative biophasic availability of 0.11 and 0.43 mg doses of pilocarpine was not affected by the ocular pigmentation, because of the opposite effects of lower peak effect and slower elimination rate on biophasic availability in pigmented eyes. The administration of pilocarpine in polymer matrices increased the relative biophasic availability of the drug. When administered in polymer matrices, pilocarpine showed a typical time course of prolonged pulse-entry of the drug into the eye.     

Disposition pharmacokinetics of lorazepam in the rabbit

The disposition pharmacokinetics of the sedative and anxiolytic drug lorazepam were investigated in 8 rabbits in relation to intravenous bolus injection of 0.3 or 0.6 mg of the compound. Lorazepam showed distinct linear two-compartment characteristics with a mean biological half-life (t 1/2 beta) of only 73.7 min. +/- 17.3 S.D. The mean half-life of the alpha phase of distribution was 18.4 min. +/- 4.7 S.D. The mean apparent steady state volume of distribution was 1.64 1 kg-1 +/- 0.27 S.D., Vc-mean was 1.11 1 kg-1 +/- 0.24 S.D. and Vdarea 2.26 1 kg-1 +/- 0.16 S.D. The calculated apparent volume of the peripheral compartment amounted to 0.53 1 kg-1 +/- 0.28 S.D. Compared to human data the distribution of lorazepam takes place somewhat slower in an about two-times as great apparent volume of distribution, while the disposition of the compound proceeds with an about 20 times as high rate.     

硝酸毛果芸香碱眼用凝胶有关物质研究

目的建立高效液相色谱法测定硝酸毛果芸香碱眼凝胶有关物质的方法.方法采用C18色谱柱(150mm×4.6mm,5μm),pH=4.5的醋酸盐缓冲液(2.94g醋酸钠与稀醋酸38.4mL加水溶解成600mL,混匀,即得)-甲醇(85∶15)为流动相,检测波长为230nm.结论本方法简便、准确,适用于硝酸毛果芸香碱凝胶的有关物质检查.     

Preliminary pharmacokinetic model of pilocarpine uptake and distribution in the eye

A pharmacokinetic model that permits prediction of aqueous humor pilocarpine levels following topical application to rabbit eyes was developed. The model is able to account for changes in both instilled solution volume and drug concentration. The model, although simplified, relies mainly on experimentally verifiable and independently measured parameters. Its utility lies in its ability to account quantitatively for the large drainage loss of instilled drug solutions and its predictive ability regardless of the instilled volume or concentration. The framework established by this model will allow further sophistication as more experimental data become available and should be adaptable to other ophthalmic drugs.     

Disposition of cyclophosphamide in the rabbit and human cornea

Rabbit (dark irides and albino) and human corneas were excised and mounted in a Lucite® chamber in order to determine the permeability of cyclophosphamide-¹⁴C and to identify its metabolites. The chromatographic scans obtained from the developed thin-layer plates showed only one peak for either rabbit or human corneas which corresponded to cyclophosphamide. By measuring the permeability of cyclophosphamide across the intact cornea, stroma alone, epithelium/stroma, and stroma/endothelium, it was possible to determine the resistance to penetration for each layer. The epithelium was the rate determining barrier, whereas both the stroma and endothelium offered little resistance. The stroma behaves as an inert sieve with drug diffusing through an aqueous media of gel-like mucopolysaccharide interspersed by a matrix of collagen fibrils.     

RP-HPLC法测定硝酸毛果芸香碱滴眼液的有关物质

目的:建立反相高效液相色谱法测定硝酸毛果芸香碱滴眼液的有关物质。方法:采用色谱柱Shimadzu RP,C18柱(150 mm×4.6 mm,5μm);流动相为甲醇-含0.002 mol/L磷酸二氢铵和0.001 8 mol/L四丁基氢氧化铵的水溶液(30∶70),进行变流速梯度洗脱;检测波长为220 nm。结果:硝酸毛果芸香碱主成分峰与杂质峰的分离度均符合要求,硝酸毛果芸香碱的检出限为4 ng。结论:该方法简便、准确、灵敏度高,适用于硝酸毛果芸香碱滴眼液的有关物质分析。     

匹罗卡品脂质体与凝胶缩瞳作用的实验研究

目的　研究 1%匹罗卡品脂质体与 4 %匹罗卡品凝胶对兔眼的缩瞳作用。方法　家兔 2 4只 ,随机分为 4组 ,每组 6只 ,按 1%匹罗卡品脂质体滴眼液 ,4 %匹罗卡品凝胶 ,1%匹罗卡品滴眼液 ,空白对照分为四组 ,给药后观察兔眼的刺激反映情况并间隔一定时间测量其瞳孔大小。结果　 4组兔眼滴药前瞳孔直径左右眼比较 ,差异无显著性 (P >0 .0 5 )。 1%匹罗卡品滴眼液组滴药后 0 .2 5h ,缩瞳作用最大 (P <0 .0 1) ,滴药后 1h瞳孔开始散大 ,滴药后 5h ,左右眼差异无显著性 (P >0 .0 5 ) ;1%匹罗卡品脂质体滴眼液组 ,滴药后 0 .5h缩瞳作用最大 (P <0 .0 1) ,滴药后 3h瞳孔开始散大 ,滴药后 7h ,左右眼差异无显著性 (P >0 .0 5 ) ;4 %匹罗卡品凝胶组 ,滴药后 0 .5h缩瞳作用最大 (P <0 .0 1) ,滴药后 4h瞳孔开始散大 ,滴药后 5h左右眼差异无显著性(P >0 .0 5 ) ;空白对照组在观察的 7h内左右眼差异无显著性 (P >0 .0 5 )。结论　 1%匹罗卡品脂质体滴眼液具有缓慢释药 ,延长作用时间的优点。其作用时间长于 4 %匹罗卡品凝胶。     

一阶导数分光光度法测定1%硝酸匹鲁卡品眼膏的含量

目的：改进硝酸匹鲁卡品眼膏含量测定方法。方法：采用一阶导数分光光度法测定硝酸匹鲁卡品眼膏的含量。测定波长２２２ｎｍ,△λ为２ｎｍ。结果：样品浓度在１０～６０ｍｇ／Ｌ范围内呈良好线性关系,ｒ＝０．９９９８,平均回收率为９９．８３％,ＲＳＤ％〈１．０１％。结论：方法简便、准确,可用于测定硝酸匹鲁卡品眼膏的含量。     

二阶导数光谱法测定硝酸毛果芸香碱滴眼液的含量

本文采用二阶导数光谱法测定硝酸毛果芸香碱滴眼液的含量,以230nm 为测定波长,可排除附加剂的干扰,快速简便。平均回收率99.99%,变异系数0.16%。     

Catecholamine content of pigmented and nonpigmented tissues of the rabbit

Norepinephrine and dopamine content of various tissues from albine and nonalbino (black fur) rabbits were chemically determined. Although norepinephrine content of the nonpigmented iris (7.93 μg/g) and the pigmented iris (6.8 μg/g) did not differ significantly, the latter type contained very high amounts of dopamine (6.5 μg/g). As compared to that from the albino animal, the retina from nonalbino animals also contained slightly higher levels of dopamine. Thus, in addition to previously proposed neurotransmitter role of dopamine in the retina, it may also serve as precursor for the biosynthesis of melanin in the pigmented tissues.     

Arginine vasopressin transport and metabolism in the pigmented rabbit conjunctiva.

The purpose of this study was to evaluate the transepithelial transport and metabolism of arginine vasopressin (AVP) in the pigmented rabbit conjunctiva, both in the absence and presence of protease inhibitors. The apparent permeability coefficient, P(app), for 3H-AVP was determined in the modified Ussing chamber, and AVP metabolites were monitored by reversed phase HPLC using a C18 column. At 50 nM donor 3H-AVP, the P(app) in the mucosal-to-serosal (ms) direction was about five times higher than that in the opposite direction. Excess (0.1 mM) AVP decreased the P(app) for labelled AVP in the mucosal-to-serosal (ms) direction by about 50%. However, intact AVP transport showed neither concentration nor direction dependence. HPLC analysis revealed two subspecies of 3H-AVP in the receiver fluid and virtually no degradation products in the donor fluid following 3 h flux experiments. 3H-AVP transported in the ms direction underwent extensive hydrolysis (73%), which was decreased by 33% with mucosal application of 2 mM camostat mesylate (an aminopeptidase inhibitor) or by 27% with 0.5 mM leupeptin (a serine protease inhibitor). By contrast, 3H-AVP transported in the serosal-to-mucosal (sm) direction resulted in only 37% hydrolysis, and mucosal application of either inhibitor did not significantly affect the P(app) for intact AVP. These data suggest that intact AVP transport in the conjunctiva may be mediated mostly by passive diffusion and enzymatic degradation of AVP may be mediated by proteolytic enzymes present on the mucosal side of the conjunctiva.     

环丙沙星滴眼剂在家兔眼内组织分布及其药物动力学

环丙沙星（ｃｉｐｒｏｆｌｏｘａｃｉｎ，ＣＰＦＸ）滴眼液点入兔眼后，用ＨＰＬＣ法测定眼内各组织中药物浓度。结果在角膜、房水、虹膜－睫状体、晶体、玻璃体内峰浓度值分别为１９．４３μｇ／ｇ，１．５８μｇ／ｍｌ，１６．６８μｇ／ｇ，１．４２μｇ／ｇ和０．９６μｇ／ｍｌ；其半衰期分别为０．７６，０．６９，０．９２，０．６１和１．４０ｈ。结果表明ＣＰＦＸ能在眼内达到较高的抗菌浓度。     

匹罗卡品影响兔眼睫状体细胞凋亡的超微结构研究

目的探讨长期保守治疗应用2%匹罗卡品滴眼液对兔睫状体慢性损伤机制中的超微结构改变及其对兔睫状体细胞凋亡的作用。方法用2%匹罗卡品为兔滴眼1个月和3个月后，取下兔眼球迅速固定，分离睫状体，用光学显微镜和透射电镜观察其形态学改变。结果应用匹罗卡品后，经过一定潜伏期后，睫状体中睫状肌细胞和色素上皮细胞出现细胞凋亡改变：细胞浆空泡变性、溶解及线粒体空泡化，部分细胞皱缩和细胞核固缩、凋亡小体的形成。结论2%匹罗卡品可以诱导兔睫状体中睫状肌细胞凋亡，并且参与兔睫状肌细胞凋亡过程。     

Macromolecular drug absorption in the albino rabbit eye

Proteins as well as polymers used in topical ophthalmic preparations are generally assumed to be excluded from the interior of the eye. Nonetheless, the corneal penetration of such high molecular weight compounds is of interest from both the drug toxicity and drug delivery points of view. The objective of this study was to determine, in a qualitative way, the mechanisms by which inulin permeated the cornea following topical dosing in the albino rabbit eye. Despite its molecular size (M.W. 5,000) and low n-octanol/buffer partition coefficient (1.27 × 10⁻³), inulin was absorbed across the cornea. At 30 min post-dosing the amount of inulin recovered in the aqueous humor and anterior segment tissues of the eye was 0.12–0.37% of the topically applied dose. Results in this study suggest that the mechanism of corneal absorption of inulin is different from glucose and epinephrine. However, there is no evidence that a carrier or endocytosis is involved. It is suggested that further experiments are necessary to investigate the contribution of the paracellular pathway to the corneal absorption of inulin.     

反相高效液相色谱法测定硝酸毛果芸香碱滴眼液的含量和有关物质

目的:建立一种反相高效液相色谱法测定硝酸毛果芸香碱滴眼液的含量和有关物质。方法:用迪马ODS柱(4.6 mm×250 mm,5μm),甲醇-缓冲液(取磷酸13.5 mL,加水700 mL、三乙胺3 mL,加水稀释至1000 mL,用20%氢氧化钠溶液调节pH值至3.00±0.02)(80∶920)为流动相;流速为1.0 mL.min-1;柱温为30℃;UV检测波长220 nm。结果:该色谱条件下,毛果芸香碱与各杂质之间分离良好。毛果芸香碱在2-7μg.mL-1(r=0.9992)、50-350μg.mL-1(r=0.9996)范围内,线性关系良好;含量测定精密度试验RSD=0.50%(n=6);平均回收率为100.5%(n=9);有关物质精密度试验RSD=0.54%(n=6)。结论:本方法简便、快捷、准确、灵敏,可有效控制产品质量。