The beta-adrenergic blocking agents and the treatment of glaucoma

The autonomic nervous system is divided into the parasympathetic and sympathetic systems, with three types of adrenergic receptors: alpha (smooth muscle contraction), beta₁ (cardiac acceleration and fatty acid mobilization) and beta₂ (smooth muscle relaxation). Substances affecting the function of the adrenergic system are the agonists or stimulators, which mimic the effects of endogenous norepinephrine or epinephrine, and antagonists or blockers, which block the receptors and prevent stimulation by the agonists. Autonomic stimulation in the eye mediates various changes which apparently affect outflow facility and rate of formation of aqueous humor. Alteration of either or both of these factors by autonomic agonists or antagonists may have a direct or an indirect effect on intraocular pressure. Beta-adrenergic blocking substances have been used to treat a variety of diseases. Some of the effects of these drugs are attributable to properties other than beta blockade, such as intrinsic sympathomimetic activity and local anaesthetic activity. Side effects of this class of drugs require caution in cases of congestive heart failure and in asthmatics. Autonomic agents used in the treatment of ocular hypertension and glaucoma include pilocarpine, a cholinergic agonist, epinephrine, an adrenergic agonist, and various beta adrenergic blockers or antagonists including propranolol, atenolol and timolol. The physico-chemical properties and pharmacokinetics of timolol are reviewed. Data showing a significant reduction in intraocular pressure as a result of ocular instillation of timolol are presented. Reduction of the rate of aqueous formation appears to be the mechanism of action. A low incidence of non-serious side effects is reported.     

国产噻吗心安对原发性开角性青光眼疗效观察

用国产噻吗心安0.25%眼药水治疗原发性青光眼。用一滴眼药水后观察24小时内眼压变化并与1%匹罗卡品比较;以及每日两次,每次一滴,连续用药六个月,观察眼压控制情况及副作用。证明其疗效满意,优于匹罗卡品,大多数病人眼压可以控制在正常范围内,无重大不良反应。并证实其降眼压作用的机制,系减少房水生成。     

Studies on the adrenergic systems of the eye at the Wilmer Institute

The study of the ocular adrenergic systems at the Wilmer Institute over the last 40 years began with the examination of the formation and outflow of aqueous humor by Jonas Friedenwald and his co-workers in the early 1940's. At that time, researchers were attempting to understand the mechanisms of fluid dynamics in the eye, with the idea of altering these mechanisms to alleviate glaucoma only a distant goal. In the late 1950's, Langham and others reported on the effect of superior cervical ganglionectomy on intraocular pressure, following this work with a succession of papers on the relationship between alpha and beta adrenergic substances and aqueous humor dynamics. Sears, in collaboration with Bárány, described the effects of alpha and beta adrenergic substances on outflow resistance. Eakins, in 1963, suggested a mechanism of action for isoproterenol in the lowering of intraocular pressure. Work on timolol at Wilmer began with a report from Radius, Diamond, Pollack and Langham covering experimental studies with rabbits and clinical studies of the drug's ocular hypotensive effects on glaucoma patients. Richter and others also studied a small number of patients on maximal therapy and found further intraocular pressure reduction with added timolol.     

Latanoprost versus timolol gel-forming solution once daily in primary open-angle glaucoma or ocular hypertension

BACKGROUND: To compare the efficacy and safety of latanoprost and timolol gel-forming solution (GFS). METHODS: This was a randomized, crossover, investigator-masked, active-control study of patients with primary open-angle glaucoma and ocular hypertension. Patients received either once-daily 0.5% timolol GFS (n=40) or once-daily 0.005% latanoprost (n=35) for 8 weeks (period 1). Patients were then crossed over to the other medication and treated for another 8 weeks (period 2). Intraocular pressure (IOP) was determined every 2 hours from 8:00 to 20:00 at baseline and weeks 8 and 16. Safety was assessed by visual acuity, slit-lamp biomicroscopy, and adverse event reports. RESULTS: During period 1, reduction in mean (SD) diurnal IOP was significantly greater in latanoprost-treated patients (-6.9 [3.0] mm Hg) than in timolol GFS-treated patients (-5.5 [2.4] mm Hg), p=0.034. There was also a significant reduction in IOP from baseline after switching from timolol GFS to latanoprost (p<0.001), not observed when patients were switched from latanoprost to timolol GFS. After results from each drug's treatment periods were combined between treatment arms, latanoprost reduced IOP more (-6.9 [2.9] mm Hg) than did timolol GFS (-6.2 [2.7] mm Hg), p=0.018. Hyperemia was the most common adverse event in both treatment groups, with 5 incidences in timolol GFS-treated patients, and 10 in latanoprost. INTERPRETATION: Latanoprost is more effective than timolol GFS in reducing IOP, and patients switched from timolol GFS to latanoprost have a further significant reduction in IOP.     

Prospective,open‐label,rater‐blinded and self‐controlled pilot study of the treatment of proliferating superficial infantile hemangiomas with 0.5% topical timolol cream versus 595‐nm pulsed dye laser

Topical timolol and 595‐nm pulsed dye laser (PDL) are both widely used in the treatment of superficial infantile hemangiomas (IH). However, to date, there is no reliable study comparing the therapeutic outcomes between the two treatment options. We designed the present study to evaluate and compare the efficacy and safety of timolol cream and PDL in the treatment of superficial proliferating IH. Twenty‐one patients with superficial IH were included in the study. Each lesion was divided into two regions; one part was treated with 0.5% topical timolol cream four times daily, and the other part was treated monthly with PDL. Both treatments were continued for 2–6 months. Five independent and blinded assessors were asked to judge the results in both the topical timolol‐treated and PDL‐treated parts by comparing photographs taken before and after treatment. Both treatments resulted in significant clinical improvements after 3.39 sessions in the 2‐month follow up. The average visual evaluation showed that PDL had significantly better results than topical timolol (6.55 ± 2.26 to 4.98 ± 2.92, P < 0.01). No patients experienced permanent side‐effects during the treatment. Our short‐term study revealed that PDL had better results compared with topical timolol cream application in the treatment of superficial proliferating IH. Further studies with longer follow‐up time and larger sample size are required to validate our findings.     

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.     

Effects of timolol on Ca2+ handling and viability in human prostate cancer cells

Timolol is a medication used widely to treat glaucoma. Regarding Ca²⁺ signaling, timolol was shown to modulate Ca²⁺-related physiology in various cell types, however, the effect of timolol on Ca²⁺ homeostasis and cell viability has not been explored in human prostate cancer cells. The aim of this study was to explore the effect of timolol on intracellular Ca²⁺ concentrations ([Ca²⁺]_i) and viability in PC3 human prostate cancer cells. Timolol at concentrations of 100–1000?μM induced [Ca²⁺]_i rises. The Ca²⁺ signal in Ca²⁺-containing medium was reduced by removal of extracellular Ca²⁺ by approximately 75%. Timolol (1000?μM) induced Mn²⁺ influx suggesting of Ca²⁺ entry. Timolol-induced Ca²⁺ entry was partially inhibited by three inhibitors of store-operated Ca²⁺ channels: nifedipine, econoazole and SKF96365, and by a protein kinase C (PKC) activator (phorbol 12-myristate 13 acetate [PMA]) or an inhibitor (GF109203X). In Ca²⁺-free medium, treatment with the endoplasmic reticulum Ca²⁺ pump inhibitor thapsigargin abolished timolol-evoked [Ca²⁺]_i rises. Conversely, treatment with timolol abolished thapsigargin-evoked [Ca²⁺]_i rises. Inhibition of phospholipase C (PLC) with U73122 abolished timolol-induced [Ca²⁺]_i rises. Timolol at concentrations between 200 and 600?μM killed cells in a concentration-dependent fashion. Chelation of cytosolic Ca²⁺ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM (BAPTA/AM) did not reverse cytotoxicity of timolol. Together, in PC3 cells, timolol induced [Ca²⁺]_i rises by evoking Ca²⁺release from the endoplasmic reticulum in a PLC-dependent manner, and Ca²⁺ influx via PKC-regulated store-operated Ca²⁺ entry. Timolol also caused cell death that was not linked to preceding [Ca²⁺]_i rises.