The Kinetics of Timolol in the Rabbit Lens: Implications for Ocular Drug Delivery

This study examines the uptake and distribution of timolol in the rabbit lens following topical instillation using a heuristic approach. The implications of anisotropic drug diffusion through the lens are presented here and discussed in the context of actual in vivo data. The dynamics of timolol in the lens involve an initial, rapid uptake of the drug by the capsule and epithelium followed by slower, anisotropic diffusion through the cortex body. Kinetically, the capsule and epithelium can be treated as a separate compartment which is distinct from the cortex and which serves to provide a concentration gradient for subsequent diffusion of timolol into the dense interior structures of the lens. Model simulations support the hypothesis that the preferred route of penetration of timolol into the vitreous humor via the lens is the diffusion of drug around the capsule/epithelium and peripheral cortical layers. It is also shown that due to the high and increasing diffusional resistance toward the center of the lens, as well as the diminishing drug concentrations in the capsule and epithelium, steady-state levels in the lens may be extremely difficult to achieve in some therapeutic situations. This phenomenon could have a significant impact on the success or failure of a drug treatment involving the lens and ocular tissues.     

噻吗心安对离体培养心肌细胞的影响

本文观察噻吗心安(5×10~(-6) M～5×10~(-5)M)对培养心肌细胞搏动强度(dv/dt)有明显抑制作用,而对搏动频率无明显影响。噻吗心安也可明显抑制异丙肾上腺素增加dv/dt及搏动频率的作用;拮抗异丙肾上腺素(5×10~(-5)M)增加cAMP含量及腺苷环化酶活性的作用。本文还观察到噻吗心安对培养心肌细胞的缺氧缺糖性损伤具保护作用。上述结果在细胞分子水平上进一步证明了噻吗心安通过阻断β受体而发挥其药理作用。     

Prevention of IOP-rise following Nd-YAG laser capsulotomy with pre-operative timolol eye-drops and 1 tablet acetazolamide 250 mg systematically

Short-term observation following Nd-YAG laser capsulotomy indicates that serious elevation of intra-ocular pressure may occur, unrelated to the amount of energy used.In this study the IOP in 3 groups of 10 pseudophakic patients undergoing Nd-YAG laser posterior capsulotomy was measured before capsulotomy and 2 and 4 hours afterwards, using the fellow-eye as control. The first group received no medication, the second received timolol 1/2% eyedrops preoperatively, the third group a combination of timolol 1/2% and 1 tablet of acetazolamide 250 mg systemically. Pretreatment with timolol 0.5% minimizes IOP-rise but does not give complete protection.The combination of timolol 0.5% with 1 tablet of acetazolamide 250 mg proves to be a safe procedure for the prevention of IOP-rise after YAG laser capsulotomy.To prevent other complications it is advisable to make a small capsulotomy of 2–3 mm diameter using as little energy as possible. Also a defocussing system in the laser is a great advantage. Indomethacin drops during a period of 6 weeks after Nd-YAG laser capsulotomy should prevent cystoid macular edema.     

Effects of timolol on visual-field mean retinal sensitivity in normal subjects

This single-blind, randomized study investigated the effects of unilateral instillation of 0.5% maleate timolol twice a day for 7 days on visual-field parameters of both eyes. Twelve normal, young subjects (30.6±4.2 years) participated in this study. Using program Gl of the Octopus 500 automated perimeter, the visual fields were measured one week and one day before therapy and a third time one week after beginning therapy. The paired T-test was used for statistical analysis, where a P-value0.05 indicated significance. Whereas nothing statistically significant was found in the treated eyes, the contralateral, untreated eyes showed a statistically significant decrease of mean sensitivity between the first visual fields and the third ones (P< 0.01) This diminution of mean sensitivity in the untreated contralateral eyes may be due to statistically significant lowering of blood pressure (P<0.01) and slowing of cardiac frequency, which were not compensated by a local decrease of intraocular pressure. If confirmed, these findings could be of clinical importance in the management of glaucoma patients, since some authors have, in some cases, recommended a unilateral therapy.     

Ocular hypotensive effect of sublingual administration of timolol

Purpose: A randomized clinical trial to assess ocular hypotensive effect of sublingual administration of timolol was performed. Patients and methods: Seventeen (9 male, 8 female; age range 45 to 68 years) with bilateral ocular hypertension were selected for the study. Each patient was evaluated with regard to IOP, arterial blood pressure and heart rate before and after each of the following experimental treatment: unilateral ocular administration of 20 l of 0.5% timolol solution; sublingual administration of 20 l of 0.5% timolol solution; unilateral ocular administration of 20 l of saline solution (placebo); sublingual administration of 20 l of saline solution (placebo). The sequence of the treatments and the eye topically treated were randomly chosen. At least four weeks wash-out elapsed between each experimental treatment. Results: Our results showed that sublingual administration of timolol was able to induce a bilateral significant reduction of the IOP. This reduction was not statistically different from that obtained in the eye treated with timolol. A significantly greater reduction of the IOP was obtained by sublingual timolol than in the contralateral eye after unilateral topical administration of timolol solution. No significant modification of arterial blood pressure and heart rate were evidenced after the treatment. Conclusions: Sublingual administration seems to be a new interesting way for reducing the IOP. Long term studies are required in order to test efficacy and safety of this new treatment.     

LASIK术后不同时间应用噻吗洛尔对高度近视屈光回退的影响

目的：观察LASIK术后不同时间应用噻吗洛尔对高度近视患者屈光回退的影响。

方法：前瞻性研究。选取2015-08/2016-08收入我院的高度近视患者90例180眼为研究对象,随机分为对照组和观察组,各45例90眼,两组患者术后均常规使用抗生素滴眼液7d,对照组患者于术后第8d开始使用噻吗洛尔滴眼液,观察组患者于术后第1d开始使用噻吗洛尔滴眼液。分别于术前、术后7d,1、3、6mo检测并比较两组患者裸眼视力、等效球镜度、眼压、角膜表面曲率、角膜基质厚度。

结果：术后不同时间点两组患者裸眼视力、等效球镜度均有差异(P<0.05),且术后6mo,观察组患者裸眼视力、等效球镜度均优于对照组(0.03±0.01 vs 0.08±0.01; 0.15±0.33D vs -0.17±0.36D; 均P<0.05)。术后不同时间点两组患者角膜基质厚度和角膜表面曲均无组间差异性(P>0.05)。术后7d,1、3mo观察组患者眼压均明显低于对照组(均P<0.05),术后6mo两组患者眼压趋于稳定。

结论：LASIK术后早期应用噻吗洛尔能有效降低眼压,并保持相对较长时间眼压稳定,阻止角膜膨隆,进而起到预防屈光回退的效果。     

Treatment of rapidly proliferating haemangiomas in newborns with propranolol and review of the literature

Aim: Infantile haemangiomas (IH) are neoplastic proliferations of endothelial cells which occur with an incidence of 10–12%. IH rapidly growing and found in cosmetically sensitive areas or complicated with ulcerations are of special concern of parents.

Methods: A review of medical charts was performed for newborns treated with propranolol because of IH between 2012 and 2013. There were two boys and two girls, referred to our department at the age of 2–3 weeks. Children were commenced on propranolol 0.5?mg/kg daily and closely monitored. The dosage was increased up to a maximum of 2?mg/kg/d and was maintained until the lesion had involuted or showed good result.

Results: The minimal dosage required to achieve involution was 1.5–2.0?mg/kg/d. No rebound growth or complications were observed. Three patients showed excellent response with resolution of the lesion. Fourth patient showed good result with >50% reduction of IH.

Conclusions: Propranolol at 1.5–2.0?mg/kg/d is effective and safe for treating IH in our series of newborn patients. Treatment should be maintained until the lesion is involuted or shows good cosmetic result. Still there is need for larger scale studies confirming the safety and efficacy of propranolol in treatment of haemangiomas in newborns.     

Predictors for visual field progression and the effects of treatment with dorzolamide 2% or brinzolamide 1% each added to timolol 0.5% in primary open‐angle glaucoma

Purpose: This study aims to identify progression factors in patients with primary open‐angle glaucoma (POAG), including the effects of treatment with dorzolamide 2% or brinzolamide 1%, each added to timolol 0.5%. Methods: A sample of 161 POAG patients were prospectively randomized to receive either dorzolamide 2% (DT) or brinzolamide 1% (BT) b.i.d., each added to timolol 0.5%, during a 60‐month, evaluator‐masked study. Progression was determined by perimetric criteria. Factors associated with visual field progression were estimated using a conditional Cox hazard model with patient intraclass correlation and were expressed as hazard ratios (HRs) with 95% confidence intervals (95% CIs). Results: Predictive baseline factors were lower diastolic blood pressure (DBP), lower mean arterial pressure (MAP), antihypertensive treatment, lower end‐diastolic velocity (EDV) in the ophthalmic artery (OA) and short posterior ciliary artery (SPCA), and a higher resistivity index (RI) in the OA and SPCA. Progression risk decreased by approximately 30% and 20% with each centimetre per second increase of EDV in the OA and SPCA, respectively, from baseline to the last follow‐up visit. Each RI decrease (or increase) of 0.01 unit in the OA or SPCA was associated with an approximate 20% decrease (or increase) in risk for progression. In a multivariate analysis, progression risk was significantly lower in eyes treated with DT (HR = 0.65, 95% CI 0.41–0.90) compared with those treated with BT. Conclusions: Progression increased with lower DBP, lower MAP, antihypertensive medication, lower EDV in the OA and SPCA, and higher RI in the OA and SPCA. The risk for progression in patients treated with DT was half that in patients treated with BT.     

Influence of betaxolol and timolol on the venous tone in glaucoma patients

The aim of this study was the assessment of physiological venous reflexes in 40 glaucoma patients treated with topically applied timolol maleate 0.50% and betaxolol HCL 0.50%. They were divided into two groups of twenty each; one group being given timolol and the other betaxolol. The assessment of the venous tone was performed by testing venous reflexes. We found no statistically significant difference between timolol and betaxolol; however, when the influence of circulating catecholamines and the other vasoactive substances was excluded by suprasphygmatic insufflation of a pediatric cuff, a significant difference was found in the Valsalva's maneuver (125.5 ± 8.1 vs 85.0 ± 34.3 venoconstrictive units VCUs, p = 0.03).The IOP was significantly decreased in both treatment group, although the pressure reduction effect was more pronounced in the timolol group.Our study suggests that timolol and betaxolol have a slightly different mode of action on the venous side of circulation under topical medications. It is possible that the use of betaxolol topically may reducea systemic venoconstriction.     

Bimatoprost: a member of a new class of agents,the prostamides,for glaucoma management

Bimatoprost, a synthetic analogue of endogenous prostamides, is in development as a topical ocular hypotensive agent for the treatment of glaucoma and ocular hypertension. Prostamides are a newly discovered class of compounds that have been shown to have potent ocular hypotensive activity in the laboratory. Bimatoprost mimics the endogenous prostamides by lowering intraocular pressure (IOP). Bimatoprost provides outstanding control of IOP throughout the day, and a high percentage of patients receiving bimatoprost achieve the low target pressures important for clinical success. In controlled clinical trials, bimatoprost 0.03% given once daily has displayed efficacy superior to timolol 0.5% given twice daily, the current standard for therapy. Analysis of pooled six month data from two large Phase III trials demonstrated that mean IOP was consistently 2 - 3 mmHg lower with bimatoprost q.d. than with timolol b.i.d. Bimatoprost 0.03% q.d. has also been shown to provide significantly better diurnal IOP control than latanoprost 0.005% q.d., probably the most efficacious topical medication currently available. Patients receiving bimatoprost q.d. were more likely than timolol or latanoprost patients to achieve low target pressures. In all clinical evaluations, bimatoprost q.d. has been demonstrated to be safe and well-tolerated. Bimatoprost will likely be available for clinical use in 2001 and it has great potential to be superior to all other medications in IOP-lowering efficacy. It is anticipated that bimatoprost will have an important role in therapy for glaucoma and ocular hypertension.