Mydriatic Effect Research Articles

Tolerance to the mydriatic effect of buprenorphine, butorphanol, nalbuphine, and cyclorphan, and cross-tolerance to morphine in mice

An increase in the use of opioid derivatives in the treatment of pain syndrome in clinical practice, and especially in the treatment of cancer, has added impetus to the search for an agent which does not induce tolerance and cross-tolerance to other opiodis. The mydriatic effect of opioids in mice, the correlation between analgesia and mydriasis, and tolerance to the analgesic effect of morphine in mice were evaluated previously. In the present work, tolerance to the mydriatic effect of four agonist-antagonists and cross-tolerance to morphine were examined. Measurement of the pupillary diameter was performed using a binocular operating microscope. Tolerance and cross-tolerance to morphine were developed following a chronic use of buprenorphine, nalbuphine, and cyclorphan. After chronic injection of butorphanol, no tolerance or cross-tolerance to morphine was observed.

Tolerance to the mydriatic effect of buprenorphine, butorphanol, nalbuphine, and cyclorphan, and cross-tolerance to morphine in mice

Tolerance to the mydriatic effect of buprenorphine, butorphanol, nalbuphine, and cyclorphan, and cross-tolerance to morphine in mice

Pholedrine for determining the site of Horner syndrome

Pharmacologic testing by indirect acting sympathomimetics like hydroxyamphetamine may determine the site of the lesion in Horner's syndrome. Pholedrine is chemically similar to hydroxyamphetamine. Therefore we examined if it shows the same effects in normal subjects and in patients with Horner's syndrome. Pupil diameter was measured by means of standardized photography before and after single and with different intervals repeated administration of pholedrine eye drops in normal subjects. In 18 patients with Horner's syndrome and known hydroxyamphetamine test results, a pholedrine test was carried out analogous to the hydroxyamphetamine test. Pholedrine dilates the normal pupil by 2.2 mm (mean). It acts at the longest 8-10 hours with maximal effect between 20 and 90 minutes. After this period its effect decreases rapidly. It acts independently from age and from baseline pupil diameter. Given repeatedly the second administration reaches the same mydriatic effect as the first only if the interval between both applications is 72 hours or more. This is because it needs some time to refill the noradrenaline stores in the sympathetic neuron innervating the dilator muscle of the pupil. In Horner's syndrome pholedrine dilates the involved pupil only minimally in case of a postganglionic lesion, and in case of a preganglionic lesion it dilates the pupil even slightly more than the normal fellow pupil. It shows the same effect as hydroxyamphetamine. There are only few side effects. Pholedrine is a substitute for hydroxyamphetamine to localize the site of the lesion in patients with Horner's syndrome.

Mydriatic and antinociceptive effects of intrathecal dexmedetomidine in conscious rats.

A comparison was made of the dose-effect relationship of intrathecally applied dexmedetomidine as concerns its mydriatic and antinociceptive effects in rats. Pupil diameter was measured with a photographic method without anesthesia. Antinociception was measured by means of the tail-withdrawal test. The intrathecal (i.t.) administration of dexmedetomidine led to dose-dependent antinociception (P < 0.05) and mydriasis (P < 0.001). Both effects reached their maximum 10 min after drug application. The tail-withdrawal latency was prolonged by 9 micrograms dexmedetomidine. Mydriasis appeared on administration of a 1 microgram dose and its degree was proportional to the dexmedetomidine dosage up to 12 micrograms. A significant correlation was not found between pupil diameter and tail-withdrawal latency in the same rat after any dexmedetomidine dose. Based on the present experiments, we conclude that the mydriatic effect of i.t. dexmedetomidine appears at a lower dose than its antinociceptive effect. Our results suggest that the assessment of pupillary response is a sensitive method for estimation of the supraspinal effect of i.t. administered alpha 2-adrenoceptor agonists.

Comparative use of various mydriatic drugs in kestrels (Falco tinnunculus)

Summary The mydriatic effect of 3 curare-like neuromuscular blocking agents was tested in European kestrels (Falco tinnunculus) after topical application. Alcuronium chloride (5 mg/ml) was found to be effective at a dose of 1 drop (20 drops = 1 ml) administered twice at a 15-minute interval. Mydriasis was achieved at t = 26 ± 11 minutes, maximal effect was reached at t = 60 ± 39 minutes, and sufficient mydriasis ended at t = 364 ± 134 minutes. Nevertheless, side effects, including temporary full paralysis in 1 bird, indicated that this drug should not be used. Pancuronium bromide (2 mg/ml) had an inconsistent effect on each bird at a dose of 2 drops administered twice at 15-minute intervals, and total mydriasis was not reached in 5 of 8 birds. Mydriasis was achieved at t = 34 ± 11 minutes, maximal effect was reduced and reached at t = 43 ± 13 minutes, and sufficient mydriasis ended at t = 90 ± 39 minutes. Vecuronium bromide (4 mg/ml) was administered at a dose of 2 drops, 3 times, at 15-minute intervals. Mydriasis was achieved at t = 23 ± 8 minutes, maximal effect was reached at t = 65 ± 12 minutes, and sufficient mydriasis ended at t = 253 ± 65 minutes. Side effects were not detected. Vecuronium bromide should be used in raptorial birds whenever retinal examination requires fundoscopy.

Plasma concentrations and ocular effects of cyclopentolate after ocular application of three formulations.

1. Eight volunteers received in randomized order two 30 microliters drops of either 1% w/v cyclopentolate hydrochloride or a corresponding amount of cyclopentolate polygalacturonate in saline or in acetate buffer in one eye. Cyclopentolate concentrations in plasma were measured by a radioreceptor assay. 2. Peak plasma drug concentrations of about 3 ng ml-1 occurred within 30 min after all formulations. Occasionally, a second concentration peak in plasma, probably reflecting drug absorption from the gastrointestinal tract, was seen after 2 h. The mean elimination half-life of cyclopentolate was 111 min when all subjects and formulations were considered together. There were no statistically significant differences between the formulations with respect to the time-course of plasma drug concentration. 3. The maximal mydriatic effect was reached within about 15 min and was maintained for several hours, often being 1/3 of its peak value after 30 h. Similarly, an intense cycloplegic response was achieved within a few minutes, the peak changes in the near-point of vision being 9 to 10 dioptres. The cycloplegic response was more intense after one of the polygalacturonate complexes, especially at later time points.

Ocular Pharmacokinetics and Pharmacodynamics in Rabbits of Ibopamine, a New Mydriatic Agent

Ibopamine is an original dopamine analogue. The drug, instilled in the conjunctival sac, induces mydriasis and is well-tolerated. In the present study, we have investigated the pharmacokinetic and pharmacodynamic characteristics of ibopamine alter ocular application.Ibopamine produces a dose-dependent mydriasis endowed with very interesting characteristics: rapid onset, marked pupil dilation and rapid return to normal pupillary diameter. Ibopamine is well absorbed through the cornea, it is rapidly hydrolysed by esterases to epinine and the mydriatic effect is correlated with the concentration of epinine in the aqueous humor.The results of the experiments with the α1-antagonists bunazosin and thymoxamine, and with reserpine, suggest that the mydriatic effect of ibopamine is obtained by direct stimulation of the α1-adrenergic receptors; pretreatment with bunazosin almost completely inhibits the mydriatic activity of ibopamine: the mydriasis is also antagonized by thymoxamine. Pretreatment with reserpine has no effect on the extent of the mydriasis induced by ibopamine.

Effect of apraclonidine hydrochloride on the attack of Posner-Schlossman syndrome.

The intraocular pressure (IOP) of glaucomatocyclitic crisis with the attack fell 50.3%, from 37.8 +/- 8.2 mmHg to 18.8 +/- 4.8 mmHg, 4 hours after instillation of 1% apraclonidine. Glaucomatocyclitic crisis showed a more significant hypotensive response to 1% apraclonidine than primary open-angle glaucoma (24.8%, from 43. 1 +/- 8.1 mmHg to 32.4 +/- 7.5 mmHg after 4 hours). The intraocular pressure decrease percentage was similar regardless of the initial level of intraocular pressure. Clinically significant changes in mean systolic and diastolic blood pressures, were not observed, however, a mild decrease in the pulse rate was noted. And the local mydriatic effect on the pupillary diameter was significant. Apraclonidine, 1% might be newly indicated to control the IOP rise of glaucomatocyclitic crisis. Further studies on the possible mechanism of the prostaglandin mediated hypotensive effect of 1% apraclonidine are suggested.

Action of opioid agonist-antagonist drugs on the pupil and nociceptive responses in mice.

Opioid derivatives with mixed agonist-antagonist activities are becoming increasingly more popular in analgesia. We tested the mydriatic and analgesic activity of morphine in mice in comparison with similar effects of three agonist-antagonist agents: buprenorphine, butorphanol and nalbuphine. We also examined the antagonistic action of these three drugs by evaluating the analgesia and mydriasis in animals pretreated with morphine. The analgesic effect was assayed using the hot plate method while the pupillary responses were measured with a binocular operating microscope. Morphine produced dose-dependent mydriasis and analgesia in mice. The morphine-type agent buprenorphine and two nalorphine-type agonist-antagonists, butorphanol and nalbuphine, caused agonistic mydriatic and analgesic effects, usually less effective then morphine. Buprenorphine proved to have higher agonist activity than butorphanol and nalbuphine. The difference between butorphanol and nalbuphine was not statistically significant. A correlation between the mydriatic and the analgesic activity, known to exist among opioid derivatives with agonist activity only, was also demonstrated in the three investigated agonist-antagonist agents. Morphine-induced mydriasis and analgesia were reversed by all three agonist-antagonist drugs, but buprenorphine is a significantly weak antagonist in comparison with butorphanol and nalbuphine. An antagonistic property (antimydriatic and antianalgesic effects after pretreatment with morphine) of both nalorphine-type investigated drugs was not statistically significant, except for the antianalgesic effect of nalbuphine in doses 1 and 3 mg.kg(-1), which was higher in comparison with butorphanol.

Insulin potentiates receptor mediated tyrosine kinase activity, and glucose transport in bovine lens

The intraocular pressure (IOP) and pupillary effects of dipivalyl esters of epinephrine and α-methylepinephrine were compared after topical application in conscious rabbits. Both dipivalyl-α-methylepinephrine (DPαmeE) and dipivalylepinephrine (DPE) produced a dose-dependent pupillary dilation (PD) and decrease in IOP. The onset of PD was approximately 30 min for both agents and reached maximal plateau within 1 and 2 hr for DPE and DPαmeE, respectively. Duration of mydriatic effect was also dose-related, although more prolonged with DPαmeE. This probably reflects differences in rate of inactivation of these compounds. The onset of IOP lowering effect of DPαmeE was more rapid (35–45 min) when compared with DPE (1·5-2 hr) which may be due to the initial ocular hypertensive response seen with DPE. The initial rise in IOP was prevented by transection of three rectus muscles. DPαmeE produced initial ocular hypertension only at the highest doses. The decrease of IOP lasted more than 6 hr for both drugs, returning to normal by 24 hr. No pupillary or IOP effects were seen in the contralateral eye.Denervation supersensitivity to both the pupillary and IOP responses to DPαmeE was seen after superior cervical ganglionectomy. These findings are consistent with the hypothesis that the pupillary and IOP responses to DPαmeE do not require intact adrenergic innervation to the eye, and that these effects are mediated by activation of postjunctional α-adrenoceptors. It is concluded that DPαmeE is a potent adrenergic ocular hypotensive agent. In comparison to DPE, DPαmeE has a more rapid onset, longer duration of action, less pupillary effect, and produces ocular hypotension with less initial ocular hypertension.

Sympathetic Denervation of the Iris Dilator in Noninsulin- Dependent Diabetes

Twenty-three subjects with noninsulin-dependent diabetes mellitus (NIDDM) and 23 age- and sex-matched controls were tested for sympathetic denervation of the iris dilator by comparing the mydriatic effect of the combination of 1% phenylephrine and 1% tropicamide with that of 1% tropicamide alone. Most of the diabetic subjects had no clinical signs of severe diabetic complications. Nine diabetics and two controls showed sympathetic denervation, defined as a 1 mm or greater dilation due the addition of 1% phenylephrine. One of those two controls had a recent history of vascular headache. The diabetics with pupillary neuropathy had higher glycosylated hemoglobin percentages and a history of higher fasting blood sugars (FBS's) than the diabetics with normal pupils. Our results show that pupillary neuropathy can develop in persons with diabetes, often before the other complications of diabetes become manifest.

Phenylephrine Prodrug: Report of Clinical Trials

The authors evaluated the mydriatic effect of phenylephrine oxazolidine prodrug, a lipophilic sympathomimetic that undergoes hydrolysis to phenylephrine as it passes through the cornea and aqueous humor. Double-masked clinical trials were performed randomizing 66 healthy subjects to receive either the silicone vehicle as a placebo, 10% viscous phenylephrine hydrochloride (HCI), or prodrug in 0.25%, 0.50%, or 1.0% concentrations. A mean horizontal pupillary diameter of 8.8 mm was achieved in 30 minutes in those receiving 1 prodrug versus 6.5 mm obtained at 30 minutes with 10% viscous phenylephrine HCI. Statistically, this difference was highly significant at P ≤ 0.0001. There were minimal systemic or ocular adverse effects from any preparation.

Ocular effects of dipivalyl esters of epinephrine and α-methylepinephrine

The intraocular pressure (IOP) and pupillary effects of dipivalyl esters of epinephrine and α-methylepinephrine were compared after topical application in conscious rabbits. Both dipivalyl-α-methylepinephrine (DPαmeE) and dipivalylepinephrine (DPE) produced a dose-dependent pupillary dilation (PD) and decrease in IOP. The onset of PD was approximately 30 min for both agents and reached maximal plateau within 1 and 2 hr for DPE and DPαmeE, respectively. Duration of mydriatic effect was also dose-related, although more prolonged with DPαmeE. This probably reflects differences in rate of inactivation of these compounds. The onset of IOP lowering effect of DPαmeE was more rapid (35–45 min) when compared with DPE (1·5-2 hr) which may be due to the initial ocular hypertensive response seen with DPE. The initial rise in IOP was prevented by transection of three rectus muscles. DPαmeE produced initial ocular hypertension only at the highest doses. The decrease of IOP lasted more than 6 hr for both drugs, returning to normal by 24 hr. No pupillary or IOP effects were seen in the contralateral eye. Denervation supersensitivity to both the pupillary and IOP responses to DPαmeE was seen after superior cervical ganglionectomy. These findings are consistent with the hypothesis that the pupillary and IOP responses to DPαmeE do not require intact adrenergic innervation to the eye, and that these effects are mediated by activation of postjunctional α-adrenoceptors. It is concluded that DPαmeE is a potent adrenergic ocular hypotensive agent. In comparison to DPE, DPαmeE has a more rapid onset, longer duration of action, less pupillary effect, and produces ocular hypotension with less initial ocular hypertension.

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.

Modulation by antidepressant drugs of CNS postsynaptic ?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.

Biological Effects of Very Long Term Antidepressant Treatment

In a preliminary study the mydriatic effect of tyramine was reduced in patients who had been taking tricyclic antidepressants for periods of up to 15 years. These findings, together with the withdrawal effects seen in these patients, show that the drugs were still pharmacologically active, even after many years of use. However, the lack of drug effect upon melatonin suggests that net noradrenergic neurotransmission may have been unaltered.

A Subchronic Toxicity Study of Two Ihhaled Aerosolized Atropine Sulfate Formulations in Rats and Dogs

The potential subchronic (21 days) toxicity of inhaled metered aerosol formulations (solution and suspension) of atropine sulfate was investigated in rats and dogs. The doses administered to rats were 0.78 and 2.5 mg/kg/day (solution) or 1.4 and 3.2 mg/kg/day (suspension). In the dog, the daily doses achieved were 0.5 and 1.3 mg/kg/day, regardless of formulation. In both species, sham control animals inhaled air only and vehicle control animals inhaled either placebo solution or placebo suspension. There was no mortality or other evidence of a toxic effect of atropine sulfate. The expected mydriatic effect of atropine sulfate was seen in both species and, similarly, the pupillary light reflex was impaired in rats and dogs receiving either formulation of atropine sulfate at both dose levels. Reduced salivation was also noted and ophthalmologic examinations in both species were unremarkable. In dogs, atropine sulfate (high-dose) caused tachycardia but there was no evidence of an adverse effect on the electrocardiogram or on systolic blood pressure. In both species, atropine sulfate did not alter body weight, food consumption or clinical pathology parameters. Necropsy observations and histopathological findings revealed no effect of atropine sulfate in either species although, in the rat, adrenal gland hypertrophy in both sexes followed inhalation of the suspension at both dose levels. With this possible exception, nothing but the expected pharmacological effects of atropine sulfate were seen in either rats or dogs.

Influence of thymoxamine eye‐drops on the mydriatic effect of tropicamide and phenylephrine alone and in combination

In a preliminary experiment in 12 healthy volunteers, one drop of thymoxamine 0.5% instilled into the conjunctival sac completely reversed the mydriasis produced by phenylephrine 2.5%, 5% and 10% after 20 minutes. In a second study in eight volunteers, thymoxamine 0.5% completely prevented the mydriasis produced by phenylephrine 2.5% and produced a miosis. It also completely reversed the mydriasis produced by tropicamide 0.5%. The mydriatic effect of tropicamide 0.5% plus phenylephrine 2.5%, however, was not completely reversed by thymoxamine 0.5% over a period of 180 minutes. Phenylephrine, tropicamide and thymoxamine are freely available for use by registered optometrists.

Medetomidine — a novel α2-adrenoceptor agonist: A review of its pharmacodynamic effects

1.1. The pharmacodynamic effects of medetomidine, a novel α2-adrenoceptor agonist, are reviewed.2.2. In receptor binding experiments, and in isolated organ preparations medetomidine shows high specificity and selectivity to α2-adrenoceptors. Its α2α2 selectivity ratio is 1620 compared to 220 of clonidine. It is a highly potent full agonist at α2-adrenoceptors, a fact that also distinguishes it from clonidine.3.3. Medetomidine induces a dose-dependent decrease in the central release and turnover of norepinephrine (NE) measured as changes in metabolite concentrations or using pharmacological intervention techniques.4.4. The selectivity, specificity and potency of medetomidine is further supported by various in vivo experiments showing dose-dependent hypotensive, bradycardic, sedative, anxiolytic mydriatic, hypothermic and analgesic effects.5.5. The pharmacological, neurochemical and behavioral effects of medetomidine can be inhibited by prior, simultaneous or subsequent administration of selective and specific α2-antagonists.6.6. In humans medetomidine is well-tolerated and pharmacodynamic effects including e.g. dose-dependent decrease of vigilance, blood pressure, heart rate, salivary secretion and plasma NE are compatible with an agonistic action at α2-adrenoceptors.

A Pupillographic Evaluation of a Phenylephrine HC1 5% - Tropicamide 0.8% Combination Mydriatic

A continuously recording high-resolution pupillometer was used to measure changes in pupil size and pupil reactivity to temporally modulated light, following topical application of a phenylephrine HCl 5%-tropicamide 0.8% combination mydriatic (Phenyltrope). A controlled light stimulus induced pupillary changes in the left eye while changes in the consensual pupillary responses were measured in the mydriatic-treated right eye. The effects on pupil light reactivity of a single drop of the combination mydriatic were also compared to those caused by one drop of tropicamide 1% alone. Phenyltrope was introduced onto the ophthalmic market ostensibly offering faster mydriasis because of its combined effect of both the parasympathetic and sympathetic innervation to the pupil. In the present study, we looked for any differences in the pupil reaction times and amplitudes as a function of time after drug administration, iris coloration and type of mydriatic instilled. Our results show that while the combination is a fast acting mydriatic providing a large and stable pupillary dilation in subjects with either blue or brown irides, it does not differ appreciably in efficacy from the mydriatic effect of tropicamide 1% alone in healthy subjects between 20 to 36 years of age. Applications of our findings to the clinical environment are presented.