The potential effect of topical aminophylline on acute glaucoma model

 

Mohammed J Manna¹, Murtadha S Jabur², Haider Raheem Mohammad³, Haidar A Abdulamir⁴*

¹College of Dentistry,  Mustansiriyah University, Baghdad, Iraq.

²College of Pharmacy,  National University for Science and Technology, Nasiriyah, Iraq.

³College of Pharmacy,  Mustansiriyah University, Baghdad, Iraq.

⁴College of Pharmacy,  Almaaqal University, Basrah, Iraq.

 

ABSTRACT:

Objectives: to study the oculo- hypotensive effect of non-selective phosphodiestrase inhibitor aminophylline. Methods: The study was conducted on fifteen albino rabbits (2.5–2.8 Kg) and model of acute ocular hypertension was obtained by 5% glucose water administration at 15ml/kg through the marginal vein of the rabbit’s ear. Aminophylline was dissolved in vehicle of phosphate buffer saline and diluted to desired concentration as 0.5%. Phosphate buffer saline solution also served as control. The left eye of rabbit was received one drop of aminophylline (0.5%) on the other hand the right eye treated by the vehicle and considered as control parameter. The pressure measurement was recorded at 15, 30, 45, 60, 90, 120, 135, 150 and 165 min after drug instillation. Results: After 30 minutes of topical 0.5% aminophylline administration the normal tension of the eye remain unchanged. However topical 0.5% aminophylline eye drop significantly (p < 0.05) successes in the decrease of the acute elevation of ocular pressure due to 5% glucose infusion. Moreover, in this study aminophylline pretreatment has the ability to facilitating the returns of the IOP to normal levels Conclusions: Topical administration of aminophylline (0.5%) significantly prevent acute rise in the ocular pressure induced by 5% glucose administration. The IOP lowering effect of aminophylline can be considered as potential antiglaucoma drug.

 

 

 

INTRODUCTION:

One of the most important risk factors for open-angle glaucoma is raised intraocular pressure and can be caused by primary or secondary causes¹. Early treatment of ocular hypertension potentially allow for the prevention of devastating blindness caused by untreated glaucoma². It is no surprise that the mechanism of action of all current drug of glaucoma are through reducing ocular pressure and maintaining it at levels that prevent alteration and deterioration of the visual field and optic nerve³. In addition, intraocular pressure is the primary important modifiable risk factor that prevents the progression of glaucoma dramatically if this pressure is decreased from baseline by 30–50%⁴.

 

Aminophylline is the ethylenediamine complex of theophylline⁵. Aminophylline, historically used as a bronchodilator to treat asthma and COPD⁶. Aminophylline competitively inhibits phosphodiestrase (PDE) type III and IV; the enzyme responsible for degradation of cyclic Adenosine mono phosphate (AMP), and mediate the bronchodilator effect in smooth muscle cells⁷. On the other hand aminophylline binds and blocks the adenosine receptor that result in bronchoconstriction⁶. However, the anti-inflammatory effect may be induced by activation of histone deacetylase to inhibit transcription of inflammatory genes⁸.

 

Nevertheless, immunological Nitric oxide synthase (iNOS) is inducible in pathological conditions will generates large quantity of nitric oxide for long term, where nitric oxide is converted into potentially cytotoxic peroxynitrite free radical that may cause degeneration of both optic nerve and posterior retina, which finally may lead to raise ocular tension and glaucoma^9,10.

 

Other studies on the other hand on anterior segments of eye have depicted an increase in nitric oxide generation after increased of the ocular pressure, accompanied by increased of iNOS gene expression¹¹.

 

Studies have been depicted that cytotoxicity of eye associated with high level of nitric oxide are caused by overproduction of peroxynitrite, (ONOO⁻), a powerful oxidant that can induce cell damage or even death¹² by cell membranes lipid peroxidation¹³, sulfhydryl groups oxidation¹⁴ and amino acid functional groups oxidation or nitration, such as tyrosine¹⁵. Formation of nitrotyrosine is the major reaction with proteins¹⁶. Researches have been provided evidences of an oxidative damage of DNA in patient with glaucoma¹⁷.

 

Studies showed that iNOS overexpression in vivo has been implicated in the progression of glaucoma could implicated in cell damage, through nitration process of protein by a highly reactive peroxynitrite. This condition can be mandatory link in the sequence of events leading to the oxidative damage seen in severe acute glaucoma^17,18. Therefore, the goal of this study was to investigate the potential role of aminophylline as inhibitors of iNOS activity to treat or prevent this condition.

 

At present there is no drug in the market that utilizes this property of these compounds in the treatment or prevention of glaucoma. Aminophylline is investigated in this work for its protective effect on intraocular tension in an acute experimental glaucoma.

 

MATERIALS AND METHODS:

A 15 New Zealand adult albino rabbits (2.5–2.8 Kg) are adapted to the laboratory environment at least seven days prior to experiment. They were housed individually in animal cages in ventilated rooms, under good hygienic conditions. Rabbits were allowed to drink water ad libitum and fed with green vegetables and leafy alfalfa.

 

Aminophylline, pure powder was a gift sample from the national center for drug control and researches. Aminophylline was dissolved in saline phosphate buffer and diluted to required strength of 0.5%. Phosphate buffer solution was prepared from chemicals obtained from British Drug House (BDH) company, and was used as vehicle. Intraocular pressure was recorded by using schiotz tonometer after 45 seconds of administrating one drop of propracaine eye drop; schiotz indentation tonometer was adjusted by manometric method of calibration. At least three reading were recorded for each IOP measurement and their mean was calculated before drug instillation. Basal ocular pressure was measured for both eyes in all rabbits. One drop of Aminophylline (0.5%) was administered as eye drop in the left eye while the right eye served as a control and received the vehicle.

 

After 30 minutes of administration of investigated drug and vehicle the intraocular pressure was obtained in both eyes. On the other hand induction of ocular hypertension in rabbits by 5% glucose administration of 15ml/kg through the surface marginal ear vein of rabbit¹⁹.

 

The intraocular pressure was then measured every 15 min for 165 minutes. Experiments were scheduled for the same time each day of experimentation.

 

Statistical analysis:

The results were analyzed and managed using SPSS version 13 (SPSS, Inc, Chicago, IL, USA). The means, standard errors, standard deviations, and 95% confidence intervals were used as descriptive statistics. Student t-test was used for comparison between means of treated and control groups. All statistical tests were two-tailed with p value of < 0.05 deemed statistically significant.

 

RESULTS:

Figure depicts the baseline reading of intraocular pressure (IOP) of both topical 0.5% aminophylline and control treated eyes. After 30 minutes of aminophylline administration normal tension of the eye remain essentially unchanged.

 

Figure 1: The effect of aminophylline 0.5% on intraocular pressure in acute ocular tension. Each point represents the mean of fifteen observations. Significance of difference from control (P value < 0.05).

*: Baseline reading IOP at zero time.

**: 2^nd reading after applying the tested medications at 30 minutes time followed by further readings to observe the effect of tested medications on the induced increased IOP. Also this point considered the time of induction of acute glaucoma

However, topical 0.5% aminophylline pretreatment significantly (p < 0.05) successes in the decrease of the acute elevation of intraocular pressure induced by the infusion of 5% glucose when compared with the control eye. Moreover, in this study aminophylline pretreatment has the ability to fastening the returns of the intraocular pressure to normal levels as shown the below figure.

 

DISCUSSION:

This study has been concerning to evaluate and investigate the potential ocular hypotensive effect of aminophylline in experimentally induced acute model of ocular hypertension that was induced by injection of 5% glucose water at 15ml/Kg through the marginal ear vein of animal. This technique is one of the fastest, easiest and more dependable procedure to screen ocular hypotensive agents¹⁹. Induction model has been obtained by administration of 5% glucose water infusion that leads to decreased in the osmolarity of blood, which in turn leads to entrapped of water into the eyes, causing acute raise of intra ocular pressure^20,21.

 

Although nitric oxide ( NO) in the anterior segment of the eyes is act in the regulation the dynamics of ophthalmic aqueous humor and there is substantial evidences that small quantities of nitric oxide could be useful to support both metabolites and blood circulation of eyes^21,22 via nitric oxide – dependent mechanisms that may improve aqueous humor drainage^22,23. On the other hand Nitric oxide donors have been shown to markedly reduce ocular hypertension^23,24 however, a sustained increased in the NO level may result in direct eye toxicity and mediate neuronal degeneration^24,25 and so agents that lower the level of nitric oxide may provide neuroprotection of retinal ganglion cells^25,26.

 

Nevertheless, adenosine is a potent modulator of vascular smooth muscle via the release of nitric oxide which elicits vasodilation^26,27. In this study topical aminophylline administration had no effect on normal tension of the eye. However, it prevented the acute elevation of ocular pressure due to administration of 5% glucose infusion. The IOP lowering effect achieved by aminophylline in this study could be attributed to aminophylline act by inhibition of adenosine receptors on ophthalmic tissue^27,28. Moreover there is substantial evidence that aminophylline act through inhibiting the L-arginine-dependent production of nitric oxide²⁸ which subsequently markedly reduce nitric oxide and the free radical peroxynitrate²⁸ that significantly protect against ophthalmic nerve degeneration and reduction of ocular tension²⁹.

 

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Accepted on 29.08.2021           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(1):197-200.