Mechanism of prostaglandin E2-, F2α- and latanoprost acid-induced relaxation of submental veins

The mechanism of prostaglandin E₂-, prostaglandin F_2α- and latanoprost acid (13,14-dihydro-17-phenyl-18,19,20-trinor-prostaglandin F_2α)-induced relaxation of the rabbit submental vein was studied. Prostaglandin E₂ caused maximum relaxation of endothelin-1 precontracted vessels (EC₅₀: 1.8×10⁻⁸ M). Much of the relaxation could be abolished by denuding the endothelium with the nitric oxide synthase inhibitor,

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-NAME (N^G-Nitro-

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-arginine methylester). CGRP-(8–37) (calcitonin gene-related peptide fragment (8–37)), a calcitonin gene-related peptide receptor antagonist, exhibited a partial blocking effect, whereas the tachykinin NK₁ receptor blocker, GR 82334 ([

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-Pro⁹[Spiro-γ-Lactam]Leu¹⁰,Trp¹¹]physalaemin (1–11)), markedly attenuated the response. Both prostaglandin F_2α and the relatively selective FP receptor agonist, latanoprost acid, caused relaxation of the veins to about 50% of the precontracted state in the presence of GR 32191B ([1R-[1α(Z),2β,3β,5α]]-(+)-7-[5-([1,1′-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid), a thromboxane receptor antagonist (EC₅₀: for prostaglandin F_2α 7.9×10⁻⁹ M, and for latanoprost acid 4.9×10⁻⁹ M).

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-NAME, as well as denuding the endothelium, completely abolished the effect. In addition, most or at least a large part of the relaxation was also blocked by CGRP-(8–37) as well as GR 82334. These results indicate that the FP receptor-mediated relaxation of veins is based on release of nitric oxide in addition to involvement of calcitonin gene-related peptide and substance P, or some other tachykinin, probably released from perivascular sensory nerves. The more pronounced relaxation induced by prostaglandin E₂ could be due to vasodilator EP receptors in the smooth muscle layer of the veins.     

Melanin in the trabecular meshwork is associated with age, POAG but not Latanoprost treatment. A masked morphometric study

We wished to conduct a light and electron microscopic investigation of pigmentation within the trabecular meshwork of normals and primary open angle glaucoma (POAG) patients. In particular we wished to get a precise determination of whether there was a relationship between pigmentation and age. In addition we wanted to know if there was a difference between normals and POAGs and whether trabecular meshwork hyperpigmentation was associated with topical latanoprost medication. A total of 25 sham trabeculectomies conducted on post mortem donor eyes provided the age-matched normals and there were 62 trabeculectomy specimens from POAG patients. These were masked and the meshwork subjected to qualitative and quantitative morphological investigation. Light and electron microscopy confirmed that most of the trabecular meshwork melanin was phagocytosed and within meshwork cells. The granules were measured and found to be of the large iris epithelial type. Light microscopic morphometric analysis showed that the number of meshwork cell profiles that contained melanin increased both in normals and POAGs with age. However there was nearly three times more pigmented meshwork cells in the POAGs than the normals. The POAGs were divided into three groups of (1) minimal or no medication prior to surgery, (2) maximal medical therapy and (3) maximum medical therapy including latanoprost (12 specimens). All groups were significantly greater that the normals but of the three it was the maximal medical therapy group (without latanoprost) that had the highest pigmentation. We concluded that pigmentation of the meshwork is age-related and it is elevated in POAG by mechanisms unknown. The melanin accumulation seems to be partly due to the disease process, partly as a consequence of chronic antiglaucoma medication but interestingly not due to latanoprost even in patients where there is iris darkening (four specimens).     

拉坦前列素对体外培养的猪毛囊生长的影响

目的探讨拉坦前列素对体外培养的猪毛囊生物学特性的影响。方法采用猪毛囊体外培养模型,记录体外培养的猪毛囊生长速度和毛球部形态学改变,评价拉坦前列素对毛发生长的作用。结果与阴性对照组比较,拉坦前列素质量浓度达到0.8ng/mL时即能使培养的猪毛囊生长速度加快(P<0.05),并持续生长达8d,且毛囊毛球部仍然呈现生长期样形态,而对照组则表现为退行期/休止期样外观。结论拉坦前列素对体外培养的猪毛囊生长具有明显的促进作用。能够延长毛囊的生长期。     

多佐胺和噻吗洛尔联用与拉坦前列腺素比较治疗开角型青光眼的系统评价

目的系统评价多佐胺和噻吗洛尔联合用药与拉坦前列腺素比较治疗开角型青光眼的有效性和安全性。方法电子检索MEDLINE（1966～2008）、EMbase（1974～2008）、Cochrane Library（2007年2期）、CBM（1978～2008）、CNKI（1979～2008）和VIP（1989～2008）,并手工检索相关领域杂志,纳入多佐胺和噻吗洛尔联用与拉坦前列腺素比较治疗开角型青光眼的随机对照试验,并按Cochrane系统评价方法选择试验、评价质量和提取有效数据,用RevMan5．0版软件进行Meta分析。结果共纳入6个随机对照试验,包括361例患者,361只眼。Meta分析结果显示：用药后两组眼压降低率差异有统计学意义[WMD=-0．49,95％CI（-1.06,0．07）,P=0．09],眼部不良反应发生率差异无统计学意义[WMD=1．43,95％CI（0．49,4．21）,P=0．51];全身不良反应中头痛的发生率差异也无统计学意义[WMD=0．40,95％CI（0．13,1．26）,P=0．12]。结论与拉坦前列腺素比较,多佐胺和噻吗洛尔联用可提高眼压降低率,但由于本系统评价纳入研究质量及例数有限,上述结论尚需开展多中心、大样本、随机、双盲对照试验一步验证。     

拉坦前列腺素与曲伏前列腺素治疗原发性开角型青光眼和高眼压症有效性和安全性的Meta分析

目的系统评价拉坦前列腺素滴眼液(latanoprost)与曲伏前列腺素滴眼液(travoprost)降眼压的有效性和安全性。方法计算机检索MEDLINE、EMbase、OVID、CNKI,收集有关拉坦前列腺素与曲伏前列腺素治疗原发性开角型青光眼和高眼压症的随机对照试验(RCT)。由两名评价员按照纳入与排除标准独立进行文献筛选、资料提取和质量评价,而后采用RevMan5.0软件进行Meta分析。结果共纳入13个RCT,合计1?433例患者。Meta分析结果显示:①拉坦前列腺素滴眼液与曲伏前列腺素滴眼液降眼压效果,在2周时差异有统计学意义[WMD=-1.47,95%CI(-2.62,-0.33)],而在1个月[WMD=-0.50,95%CI(-1.52,0.52)]和6个月[WMD=-0.12,95%CI(-0.85,0.61)]后两组降眼压差异无统计学意义。②随访结束时,曲伏前列腺素组结膜充血发生率高于拉坦前列腺素组,其差异有统计学意义[OR=0.47,95%CI(0.35,0.63)],但两组眼部疼痛[OR=0.55,95%CI(0.27,1.12)]和皮肤或虹膜失色素[OR=1.25,95%CI(0.53,2.92)]不良反应发生率差异无统计学意义。结论治疗原发性开角型青光眼和高眼压症,拉坦前列腺素与曲伏前列腺素两种滴眼液降眼压效果相似,但曲伏前列腺素组结膜充血不良反应发生率较拉坦前列腺素高。但由于纳入研究的方法学质量中等,致使本系统评价结果论证强度不高,因此需要开展更多高质量大规模的临床随机对照研究,以便更客观、全面、正确地评价其疗效和安全性。     

贝美前列素和曲伏前列素治疗开角型青光眼和高眼压症的疗效对照研究

【目的】评价贝美前列素和曲伏前列素替代拉坦前列素治疗原发性开角型青光眼和高眼压症的临床效果和安全性。【方法】采用前瞻性、随机、单盲、平行对照临床试验,选择使用拉坦前列素不能达到目标眼压的原发性开角型青光眼和高眼压症患者并随机分两组,分别滴用贝美前列素或曲伏前列素,均为每晚1次,每次1滴。测量替换用药前、1个月和3个月时的眼压,观察不良反应。【结果】两组平均基线日间眼压无统计学差异。替换治疗后1个月和3个月的平均日间眼压,贝美前列素组较曲伏前列素组有显著性下降。总体上,在替换治疗1个月和3个月时,22%贝美前列素组患者和12.1%曲伏前列素组患者平均日间眼压降幅达到15%以上,两组差异有统计学意义(P<0.05)。在3个月时平均日间眼压下降幅度贝美前列素组为2.1 mmHg(11.0%),曲伏前列素组为1.4 mmHg(7.4%),两组差异有统计学意义(P<0.05)。贝美前列素组3例(8.8%)和曲伏前列素组2例(5.7%)出现了与治疗相关的不良反应。与治疗有关的结膜充血患者发生率,贝美前列素组为3.1%,曲伏前列素组为1.5%,两组间无统计学差异(P>0.05)。无严重不良反应和全身不良反应发生。【结论】经拉坦前列素治疗不能达到目标眼压的患者,更换贝美前列素或曲伏前列素后,短时间内的日间眼压下降前者比后者更明显,替换用药后结膜充血发生率二者均较低。     

Bimatoprost: Mechanism of Ocular Surface Hyperemia Associated with Topical Therapy

Bimatoprost is a safe and well‐tolerated intraocular pressure (IOP) lowering drug that was approved in the United States in 2001 for the treatment of glaucoma and ocular hypertension. It is highly efficacious and produces greater mean reductions in IOP than other currently available antiglaucoma drugs. Conjunctival hyperemia is a common side effect of bimatoprost, but the hyperemia is typically mild and transient. No association has been found between signs of inflammation and the presence of hyperemia in bimatoprost‐treated patients. Preclinical studies have elucidated the pharmacological mechanism of bimatoprost‐related hyperemia and have examined the possible involvement of inflammation. Bimatoprost, as well as the free acid of latanoprost, elicited endothelium‐de‐pendent vasorelaxation in the rabbit jugular vein preparation, a quantitative in vitro model for ocular surface hyperemia (OSH). The vasorelaxant responses to either bimatoprost or latanoprost free acid were significantly inhibited by L‐NAME, a nitric oxide synthase inhibitor. Similarly, the in vivo OSH responses to topically applied bimatoprost or latanoprost in dog eyes were significantly inhibited by L‐NAME. As predicted, prostaglandin E₂ (PGE₂)‐induced conjunctival hyperemia was not inhibited by L‐NAME, since PGE₂ has a direct relaxant effect on the vascular smooth muscle. In‐life observations and histopatho‐logical assessment of ocular surface tissues following bimatoprost treatment were performed for multiple‐dose one month, 6 month, or 12 month safety studies in rabbits, dogs, and non‐human primates. Results of these studies showed no evidence of bimatoprost‐re‐lated inflammation in the ocular surface tissues. In summary, OSH related to bimatoprost treatment in laboratory animals occurs by endothelial‐derived nitric oxide‐mediated vasodilatation and is not associated with inflammation. These studies suggest that conjunctival hyperemia, a side effect of bimatoprost treatment, results from non‐inflammatory, pharmacologically based vasodilatation.     

Sustained delivery of latanoprost by thermosensitive chitosan–gelatin-based hydrogel for controlling ocular hypertension

Glaucoma is an irreversible ocular disease that may lead to progressive visual field loss and eventually to blindness with inadequately controlled intraocular pressure (IOP). Latanoprost is one of the most potent ocular hypotensive compounds, the current first-line therapy in glaucoma. However, the daily instillation required for efficacy and undesirable side-effects are major causes of treatment adherence failure and persistence in glaucoma therapy. In the present study, we developed an injectable thermosensitive chitosan/gelatin/glycerol phosphate (C/G/GP) hydrogel as a sustained-release system of latanoprost for glaucoma treatment. The latanoprost-loaded C/G/GP hydrogel can gel within 1 min at 37  °C. The results show a sustained release of latanoprost from C/G/GP hydrogel in vitro and in vivo. The latanoprost-loaded C/G/GP hydrogel showed a good in vitro and in vivo biocompatibility. A rabbit model of glaucoma was established by intravitreal injection of triamcinolone acetonide. After a single subconjunctival injection of latanoprost-loaded C/G/GP hydrogel, IOP was significantly decreased within 8 days and then remained at a normal level. The results of the study suggest that latanoprost-loaded C/G/GP hydrogel may have a potential application in glaucoma therapy.     

The efficacy of a monocular drug trial in normal-tension glaucoma

Purpose

To evaluate the efficacy of a monocular drug trial in eyes with normal-tension glaucoma (NTG).

Methods

This prospective study enrolled 74 patients with NTG. The monocular drug trial was started using latanoprost 0.005% for one week. If the intraocular pressure (IOP) reduction was greater than 15%, the same medication was administered to both eyes for one month. The unadjusted change and adjusted change (the change in the treated eye minus the change in the contralateral eye) in IOP were evaluated, and the predictors of IOP response were analyzed by multivariate linear regression.

Results

Among the initial 74 patients, 31 (41.9%) were included; others were excluded because they did not meet the requisite conditions. The most significant predictors of IOP response in the initial eye and subsequent eye were the baseline IOPs in both eyes (β = 0.907, 0.771, respectively). The adjusted change in IOP of the initial eye had greater association (β = 0.589) with the IOP after monocular trial in the initial eye than that of unadjusted IOP change (β = 0.279). The adjusted change in IOP also had greater predictability (β = 0.348) for IOP after monocular trial in the subsequent eye than that of the unadjusted IOP change (β = 0.090).

Conclusions

Although the monocular trial in NTG patients had limited efficacy due to its stringent conditions, it was useful for evaluating the IOP response in the initial eye and for predicting the IOP response in the subsequent eye.