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PubMed1993

Selective suppression by bunazosin of alpha-adrenergic agonist evoked elevation of intraocular pressure in sympathectomized rabbit eyes.

PURPOSE: To determine whether there is alpha 1-adrenergic receptor heterogeneity associated with the regulation of intraocular pressure (IOP) and mydriasis in rabbits, the authors tested the hypothesis by characterizing the ability of the selective alpha 1-adrenergic antagonist, bunazosin, to block the ocular hypertensive and mydriatic responses to alpha 1-adrenoceptor stimulation by either norepinephrine (NE) or phenylephrine (PE). METHODS: The effects of topical application of bunazosin on IOP and pupillary diameter were measured in unilateral superior cervical ganglionectomized (SCGX) rabbits after exposure to either NE or PE. RESULTS: Bunazosin (0.1%) alone only lowered the IOP in the normal eye and did not elicit a pupillary response on either side. NE (0.01-1.0%) by itself caused a concentration-dependent rise in IOP on both sides, but mydriasis did not occur on the normal side. In SCGX eyes, the sensitivity of the IOP response to NE increased tenfold over that measured on the normal side. Unlike on the normal side, concentration-dependent mydriatic responses occurred with 0.1 and 1% NE. After pretreatment with bunazosin (0.1%), neither NE (0.1%) nor PE (0.1%) evoked a rise in IOP. However, the mydriatic response to either one of these agonists in the SCGX eyes was less affected. By contrast, pretreatment with the alpha 2-adrenergic antagonist, 0.5% yohimbine, did not change the IOP increase elicited by 0.1% NE. CONCLUSIONS: These results suggest that the alpha 1-adrenergic receptors that regulate IOP and pupillary diameter are different from one another in the rabbit.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Modulation by antidepressant drugs of CNS postsynaptic alpha 2-adrenoceptors mediating mydriasis in the rat.

The modulation of central postsynaptic alpha 2-adrenoceptors mediating mydriasis in the pentobarbitone-anaesthetized rat was studied after the acute and short/long-term administration of antidepressant treatments (drugs, electroshock). The acute administration of cyclic antidepressant drugs (2.5 mg/kg, i.v.) resulted in different mydriatic effects (amitriptyline greater than protriptyline approximately imipramine greater than clomipramine greater than nortriptyline greater than desipramine approximately maprotiline) which were attenuated (17-55%) by idazoxan (1 mg/kg, i.v., 5 min) and reserpine (5 mg/kg, s.c., 18 h) indicating that, besides the well-known anticholinergic properties of some of these drugs, their mydriatic effects are due in part to activation of alpha 2-adrenoceptors (through endogenous noradrenaline). In contrast, the long-term (7-21 days) but not the short-term (1-4 days) administration of cyclic antidepressant drugs (2.5-10 mg/kg, i.p.), MAO inhibitors (1 mg/kg, i.p.), lithium (20 mg/kg, i.p.) and electroshock (150 mA, 63 Hz, 8 ms during 300 ms) resulted in dose- and time-dependent reductions of the dose-pupillary response curve for clonidine (ED50 increased 1.2-2.0-fold; Emax decreased by 9-29%) which indicated desensitization of postsynaptic alpha 2-adrenoceptors. In line with these findings, treatment for 7 days with clonidine (0.1-1 mg/kg, i.p.) or idazoxan (3-10 mg/kg, i.p.) led to an opposite modulation (down- and up-regulation) of the dose-pupillary response curve for clonidine. The main results demonstrate that cyclic antidepressant drugs, through indirect mechanisms which involve endogenous noradrenaline, can modulate the sensitivity of brain postsynaptic alpha 2-adrenoceptors mediating mydriasis in the rat.

Anesthesia↗
PubMed1993

Evaluation of the effect of thymoxamine solution 0.5% on mydriasis induced by ibopamine solution 1%.

The effects of thymoxamine 0.5% solution and of a placebo solution (mannitol) on the mydriasis induced by ibopamine 1% solution were evaluated in 8 healthy volunteers and 12 patients with eye diseases. One drop of ibopamine was instilled into each eye and 30 min later 1 drop of thymoxamine was instilled into one eye and 1 drop of placebo into the contralateral eye. Pupillary diameter was measured before and 30 min after the instillation of ibopamine, immediately before the treatment with thymoxamine and placebo and 30, 60 and 90 min after the instillation of thymoxamine or of placebo. Within 30 min of treatment, ibopamine had produced a statistically and clinically significant mydriatic effect. In eyes treated with thymoxamine, prompt reversal of mydriasis was observed, the baseline diameter being observed within 60 min. No difference in the time-course of the mydriatic effect was detected between healthy subjects and patients. The pupillary response to thymoxamine was not influenced by the colour of the iris. The tolerability of ibopamine and of thymoxamine was good. No local or systemic adverse events were seen or reported.

Adult↗
PubMed1981

Interaction of desipramine and amitriptyline with adrenergic mechanisms in the human iris in vivo.

Mydriatic responses of the pupil were evoked by locally instilled noradrenaline and methoxamine in eight healthy volunteers. The effects of three single oral doses (25 mg, 50 mg and 100 mg) of amitriptyline and desipramine were compared on the mydriatic responses. Both antidepressants potentiated the mydriasis evoked by noradrenaline; desipramine appeared to be approximately four times more potent than amitriptyline. Both antidepressants antagonised the mydriasis evoked by noradrenaline; desipramine appeared to be approximately four times more potent than amitriptyline. Both antidepressants antagonised the mydriasis evoked by methoxamine, amitriptyline being approximately twice as potent as desipramine. It is suggested that the potentiation of the response to noradrenaline may reflect the blockade of the uptake of noradrenaline into adrenergic nerve terminals, whereas the antagonism of the response to methoxamine may reflect the blockade of postsynaptic alpha-adrenoceptors by the antidepressants. It is argued that the interaction of the antidepressants with adrenergic mechanisms could explain why amitriptyline, a potent anticholinergic agent, causes no significant change in resting pupil diameter, while desipramine, a relatively weaker anticholinergic agent, produces a significant mydriasis.

Adult↗
PubMed2005

Pharmacokinetic and pharmacodynamic evaluations of the zwitterionic metabolite of a new series of N-substituted soft anticholinergics.

PURPOSE: This study was conducted to evaluate the zwitterionic common metabolite of a novel series of N-substituted soft analogs of glycopyrrolate both as racemates and as 2R isomers. METHODS: Activities were assessed using both in vitro (receptor binding assay, guinea pig ileum pA2 assay) and in vivo techniques (rabbit mydriatic response, rat cardiac effects). Pharmacokinetic characterizations in rats were also performed. RESULTS: The metabolite was highly water-soluble and very stable in buffer solutions as well as in rat biological media. Following i.v. administration in rats, it was very rapidly eliminated, mainly through renal excretion with a half-life of about 10 min. Receptor binding and guinea pig ileum assays indicated this metabolite as more than 1 order of magnitude less active than its parent soft drugs or glycopyrrolate. Moderate M3/M2 muscarinic receptor subtype selectivity was observed, further reducing the likelihood of cardiac side effects. The metabolite showed to some extent mydriatic effect and protective effect against carbachol-induced bradycardia, but of much shorter durations than glycopyrrolate; it had, however, no effect on resting heart rate. CONCLUSIONS: N-Substituted zwitterionic metabolites retain some, but only considerably reduced activity of their parent quaternary ammonium ester soft anticholinergic drugs, and they are very rapidly eliminated from the systemic circulation. They are suitable for their assigned role within the framework of inactive metabolite-based soft anticholinergic design.

Administration, Topical↗
PubMed2006

Phenylephrine and pilocarpine eye drop test for dementia with Lewy bodies and Alzheimer's disease.

Pupillary response test using dilute phenylephrine, a sympathetic agonist, and dilute pilocarpine, a cholinergic agonist, were performed in 24 patients with dementia with Lewy bodies (DLB), 40 patients with Alzheimer's disease (AD), and 23 normal elderly subjects. The mydriatic response to 0.5% phenylephrine was significantly greater in the DLB group than in the AD and control groups. The mydriatic change correlated inversely with the reduction in cardiac 123I-metaiodobenzylguanidine uptake. In contrast, miotic response to 0.0625% pilocarpine was significantly greater in the DLB and AD groups than in the control group. The pupil assay using combined phenylephrine and pilocarpine eye drop test may be useful in the detection of patients with DLB and AD and in distinguishing between them.

3-Iodobenzylguanidine↗
PubMed2006

A combination solution for routine pupillary dilation.

BACKGROUND: This study investigated the ability of a combination drop containing reduced concentrations of tropicamide and phenylephrine to produce pupillary dilation adequate for routine fundoscopy. METHODS: One eye of each subject (N = 28; age range, 21 to 40 years; median, 23 years) was dilated with 1 drop of a solution containing 0.5% tropicamide and 2.5% phenylephrine (0.5T/2.5P). The other eye was dilated with 1 drop of either of 2 mixtures: 0.5% tropicamide and 1.25% phenylephrine (0.5T/1.25P, N = 15; median age, 23 years), or 0.25% tropicamide and 1.25% phenylephrine (0.25T/1.25P, N = 13; median age, 23 years). A topical anesthetic was administered before instilling the mydriatic agents. Pupil diameter was measured from a flash photograph taken every 15 minutes for 3 hours. There was no significant difference in pupil diameter between eyes dilated with the 0.5T/1.25P test solution and the 0.5T/2.5P control solution for the first 75 minutes after instillation (P = 0.41). All pupils reached their maximum diameter 60 minutes after drop instillation; where no significant difference was observed between the 3 mydriatic solutions (P = 0.81). All pupils were at least 7 mm in diameter 30 minutes after drop instillation, and this size was maintained for at least another 75 minutes for all solutions. CONCLUSIONS: Combination preparations of reduced concentrations of tropicamide and phenylephrine can produce clinically adequate mydriasis.

Adult↗
PubMed1990

Hydroxyamphetamine mydriasis in normal subjects.

Hydroxyamphetamine eyedrops are used to help localize the lesion in Horner's syndrome. Because normal variability in the response to the eyedrops may influence the interpretation of test results in patients with Horner's syndrome, we studied both the interocular variability of the drug's mydriatic effect within each normal subject and the variation between individuals. We used photographs to document the variability among 26 normal subjects. Hydroxyamphetamine hydrobromide 1% eyedrops (Paredrine) were placed in both eyes of normal subjects in the same way that patients with Horner's syndrome are tested. The drug produced a mean increase in pupil size of 1.96 mm (+/- 0.61 S.D.) in the 52 eyes tested. In normal subjects, the mydriatic effect of hydroxyamphetamine was symmetric in each pair of eyes. The mean interocular asymmetry of mydriasis as measured by the difference in dilation (right eye dilation minus left eye dilation) was -0.087 mm (+/- 0.29 S.D.). Thus, the variability of hydroxyamphetamine mydriasis from one eye to the other in a single subject was much lower than the variability between subjects.

Adult↗
PubMed1982

Inhibitors of surgically induced miosis.

Miosis induced by surgical trauma is a frequent problem during extracapsular cataract surgery. In experimental surgery on rabbits, the inhibitory effect on pupillary constriction of cyclo-oxygenase inhibitors, local anesthetics, capsaicin (presumed substance P depletor), sympathomimetic agents, and anticholinergic agents were studied. In eyes predilated with tropicamide, iris massage caused marked pupillary constriction. Randomized pretreatment with the following agents significantly inhibited miosis: flurbiprofen, P less than 0.005; topical anesthetics (benoxinate, P less than 0.001, cocaine, P less than 0.05, proparacaine, P less than 0.005); and retrobulbar capsaicin, P less than 0.005. No significant inhibition was shown with topical indomethacin aqueous solution (P less than 0.15), topical tetracaine (P less than 0.15), or retrobulbar lidocaine (P less than 0.15). No single agent or combination of agents blocked the total miotic response; however, a combination of flurbiprofen, benoxinate, and capsaicin blocked more than two third of the miosis. Phenylephrine, a sympathomimetic (active) mydriatic agent, was more effective than anticholinergic (passive) mydriatic agents in obtaining maximal pupillary size after surgical iris massage.

Anesthetics, Local↗
PubMed1995

A comparison of pressure patching versus no patching for corneal abrasions due to trauma or foreign body removal. Corneal Abrasion Patching Study Group.

PURPOSE: To evaluate the effectiveness of pressure patching in the treatment of noninfected, noncontact lens-related traumatic corneal abrasions and abrasions secondary to removal of corneal foreign bodies. METHODS: Two hundred twenty-three patients with noninfected, noncontact lens-related traumatic or foreign body removal-related corneal abrasions were followed daily after receiving topical antibiotics and mydriatics and after being randomized to receive either a pressure patch or no patch. RESULTS: Twenty-two patients were excluded from the study. For data analysis, the remaining patients were split into two sections: those with traumatic corneal abrasions (120 patients) and those with corneal abrasions secondary to removal of corneal foreign bodies (81 patients). Patients with traumatic corneal abrasions healed significantly faster, had less pain, and had fewer reports of blurred vision" when they were not wearing a patch. The amount of photophobia, tearing, and foreign body sensation were similar between the patch and no-patch groups. Similarly, for corneal abrasions due to removal of foreign bodies, patients healed significantly faster and had less pain when they were not wearing a patch. There was no difference in the amount of photophobia, tearing, foreign body sensation, or blurred vision. Finally, there was better compliance in the no-patch group. CONCLUSIONS: Noninfected, noncontact lens-related traumatic corneal abrasions as well as abrasions secondary to foreign body removal can be treated with antibiotic ointment and mydriatics alone without the need for a pressure patch.

Adult↗
PubMed2002

Topical ketorolac tromethamine 0.5% versus diclofenac sodium 0.1% to inhibit miosis during cataract surgery.

PURPOSE: To compare the effect of topical ketorolac tromethamine 0.5% solution and topical diclofenac sodium 0.1% solution on the inhibition of surgically induced miosis. SETTING: Tertiary care teaching hospital in South India. METHODS: Fifty-one patients were prospectively randomized to receive ketorolac 0.5% or diclofenac 0.1% at 3 intervals preoperatively. Patients with diabetes mellitus, pseudoexfoliation, or local pupil abnormalities were excluded from the study. Mydriatics comprising homatropine 1% plus phenylephrine 10% were instilled in all patients 1 hour before the peribulbar block at 5 intervals. Horizontal pupil diameters were obtained at the beginning of surgery, after capsulotomy, after intraocular lens (IOL) implantation, and at the end of surgery. RESULTS: The mean horizontal pupil diameter was 7.40 mm at the start of surgery in both groups. The ketorolac group showed a consistent trend toward larger pupil diameters at subsequent surgical intervals. Changes from baseline also indicated more significant inhibition of miosis in the ketorolac group. CONCLUSIONS: Topical ketorolac was a more effective inhibitor of miosis than topical diclofenac during extracapsular cataract extraction and IOL implantation. It also provided a more stable mydriatic effect throughout surgery.

Administration, Topical↗
PubMed1993

Soft drugs--XIV. Synthesis and anticholinergic activity of soft phenylsuccinic analogs of methatropine.

Three soft drug analogs and a metabolite of methatropine based on phenylsuccinic structural moiety were synthesized and tested for activity. In an in vivo assay, the soft drugs were found to be two orders of magnitude less potent than methatropine while the carboxylate metabolite was found to be one order of magnitude less potent than the soft drugs. A structural isomer of compound 4a was found to be less potent. All the soft drugs tested elicited shorter durations of mydriatic action in rabbit eyes compared to atropine. The untreated eye was dilated in the atropine treated animals while no dilation occurred in the soft drug treated animals indicating facile systemic metabolism of the soft drugs to inactive moieties, possibly the carboxylate metabolite. In in vitro stability studies, the soft drugs have been found to be more hydrolytically labile than atropine. The shorter duration of mydriatic action of compound 4a coupled with increased hydrolytic lability make this a candidate for further study.

Animals↗
PubMed2003

Design, pharmacokinetic, and pharmacodynamic evaluation of a new class of soft anticholinergics.

PURPOSE: To design and evaluate a new class of soft anticholinergics with subtype selectivity. METHODS: A new class of soft anticholinergics was designed based on the "inactive metabolite" approach. Four compounds were synthesized. The potency and soft nature of the compounds were evaluated by receptor binding, cardiac, and mydriatic studies. Stability and pharmacokinetic studies were also performed on these newly synthesized soft anticholinergics. RESULTS: Receptor binding studies of the soft anticholinergics on cloned muscarinic receptors indicated pKi values in the range of 7.5 to 8.9. Two compounds, 9a and 13a, of the series showed muscarinic subtype receptor selectivity (M3/M2). In mydriatic studies, 13a and 13b showed shorter duration of action in the treated eyes than tropicamide. In the control eyes, significant dilation of pupils was found only in rabbits treated with atropine and tropicamide, indicating that the soft anticholinergics lack systemic effects because of their facile hydrolytic deactivation. Consistent with their soft nature, this new class of soft anticholinergics displayed much shorter cardiovascular effects in the carbachol-induced bradycardia (10 to 15 min) in rats than atropine (> 60 min). Stability and pharmacokinetic studies suggested that the new soft anticholinergics were rapidly eliminated from plasma (systemic circulation) after i.v. administration. CONCLUSIONS: A new class of anticholinergics was designed and synthesized, and the PK/PD evaluation confirmed they were potent "soft" anticholinergics; two of them showed muscarinic receptor subtype selectivity (M3/M2).

Administration, Topical↗
PubMed1998

Comparison of the cardiovascular effects of 2.5% phenylephrine and 10% phenylephrine during ophthalmic surgery.

PURPOSE: The recommended concentration of topical phenylephrine for mydriasis is still a matter of debate. Our purpose was to compare the cardiovascular effects of 10% and 2.5% topical aqueous phenylephrine. METHODS: We carried out a double-masked randomised study on 54 consecutive patients undergoing routine local anaesthetic cataract extraction, comparing the effects on blood pressure and heart rate of either 2.5% or 10% topical aqueous phenylephrine in combination with 1% topical aqueous tropicamide in those with no history of cardiovascular disease. RESULTS: No difference was found in the rise in blood pressure produced by 2.5% and 10% topical aqueous phenylephrine. We also found no sustained changes in blood pressure or heart rate after instillation of either 2.5% or 10% topical aqueous phenylephrine. CONCLUSION: We recommend the routine use of 2.5% topical aqueous phenylephrine as a mydriatic agent during cataract surgery and acknowledge the role of 10% topical aqueous phenylephrine as an effective mydriatic agent in cases where 2.5% phenylephrine may not be so effective, such as in subjects with darkly pigmented irides.

Aged↗
PubMed2002

Ophthalmic vehicles containing polymer-solubilized tropicamide: "in vitro/in vivo" evaluation.

Commercial 1.0% aqueous tropicamide (TR) eyedrops are buffered to pH 4.4-5.0 to produce sufficiently stable solutions of the weakly basic, poorly soluble drug. These acidic solutions, however, are irritants and may induce copious lachrimation, thus reducing the drug bioavailability. The aim of the present study was to evaluate some solubilizing agents for the preparation of 1.0% TR ophthalmic solutions adjusted at physiologically compatible pH, potentially showing increased eye tolerance, activity, and stability when compared with standard commercial eyedrops. The tested solubilizers were two non-ionic surfactants-Tyloxapol (TY) and Cremophor EL (CR) and one polymer, Pluronic P85 (PL). Four stable 1% TR formulations, containing 3% TY, 7.5% CR, 15% PL, or 5% CR + 10% PL were submitted to mydriatic activity tests in rabbits. They improved to a small but statistically significant extent the AUC for mydriatic effect of TR in the test animals when compared with commercial 1.0% TR eyedrops.

Animals↗
PubMed2003

Studies of alpha-adrenoceptor antagonists on sympathetic mydriasis in rabbits.

This study was undertaken to identify the alpha-adrenergic receptor type responsible for sympathetically evoked mydriasis in pentobarbital-anesthetized rabbits. Frequency-response curves of pupillary dilation were generated by stimulation of the preganglionic cervical sympathetic nerve (1-64 Hz). Evoked mydriatic responses were inhibited by systemic administration of nonselective alpha-adrenergic antagonists, phentolamine (0.3-10 mg/kg) and phenoxybenzamine (0.03-0.3 mg/kg), as well as the selective alpha(1)-adrenergic antagonist, prazosin (0.1-1 mg/kg). The alpha(2)-adrenergic antagonist, RS 79948 (0.3 mg/kg, i.v.) was without inhibitory effect, but potentiated the mydriatic response. In addition, the selective alpha(1A)-adrenoceptor antagonist, 5-methylurapidil (0.1-1 mg/kg, i.v.), antagonized the elicited mydriasis in a dose-dependent fashion. Unlike previous observations that prazosin does not block the adrenoceptor in rabbit iris dilator muscle, our results suggest that prazosin is effective in inhibiting neuronally elicited mydriasis in this species, and that alpha(1A)-adrenoceptors appear to mediate the response.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1981

Dose-response effects of tropicamide HCl.

Using double-masking procedures, the mydriatic and cycloplegic effects of 0.25, 0.5, 0.75, and 1.0% tropicamide were studied. All doses produced clinically useful mydriasis of at least 6-mm pupils. Using testing conditions of both normal (35 ft-c) and bright (150 ft-c) illumination, no mydriatic dose-response differences for the four concentrations were found. Cycloplegic effects were dose related. A single drop of either 0.75 or 1.0% tropicamide reduced the amplitude of accommodation to about 1.5 D, which is adequate for a cycloplegic refraction.

Adult↗
PubMed1997

Effect of proparacaine on tropicamide-induced mydriasis.

PURPOSE: The use of a topical anesthetic before the instillation of a mydriatic is recommended in order to enhance both the rate and magnitude of pupillary dilation. However, there is a paucity of data supporting the prior use of topical anesthetics with tropicamide, the most commonly used mydriatic agent in optometric practice. Therefore, we conducted a study to determine the clinical effect of proparacaine on tropicamide-induced pupillary dilation. METHODS: We investigated the effects of prior instillation of 0.5% proparacaine (Ophthetic) on pupillary dilation with 0.5% tropicamide (Mydriacyl) using a double-blind, placebo-controlled protocol on two groups of young adult subjects. Thirty subjects, aged between 18 and 30 years, were divided into 2 groups of 15, based on whether they had light- or dark-colored irides. The pupils of both eyes of each subject were dilated with tropicamide, but only one eye, chosen at random, received proparacaine (experimental condition), whereas the other was administered a saline placebo (control condition). Pupil diameter was measured using a ruler and magnifying loupe. RESULTS: Subjects with light-colored irides had a greater average pupil dilation than subjects with dark-colored irides. There was a small, statistically significant difference in pupil diameter between the control and experimental conditions, but only for subjects with light-colored irides. The rate of pupillary dilation to peak pupil diameter and the rate of decrease in pupil diameter after peak pupil diameter was reached did not differ between experimental conditions or subject groups. CONCLUSIONS: Although prior instillation of topical proparacaine produced a statistically significant difference in pupil diameter for subjects with light-colored irides, the result was not clinically significant. Therefore, we do not recommend the use of a topical anesthetic before tropicamide-induced mydriasis for young adult patients.

Administration, Topical↗