Dipivalyl Epinephrine Research Articles

The use of cyclodextrins in ophthalmic formulations of dipivefrin

Dipivefrine (dipivalyl epinephrine, DPE) is a dipivalic acid ester prodrug of epinephrine. The present study evaluates the possible use of hydroxypropyl- β-cyclodextrin (HP- β-CD) or sulfobutyl ether β-cyclodextrin ((SBE) 7m- β-CD) in ophthalmic formulations of DPE in order to increase the aqueous stability of DPE. The solubility of DPE was determined by phase-solubility method at pH 7.4 while the stability of DPE was investigated as a function of temperature (37–70°C) and CD concentrations at pH 5.0 and 7.4. The effect of HP- β-CD and (SBE) 7m- β-CD on the aqueous phase to organic phase transfer kinetics was studied with an aqueous buffer/ n-octanol system, while the effect of (SBE) 7m- β-CD on (in vitro) corneal uptake of DPE was studied with isolated rabbit corneas in order to predict the ophthalmic bioavailability of DPE in the presence of CD. The negatively charged (SBE) 7m- β-CD formed significantly stronger inclusion complexes with the positively charged DPE (p K a=9.01) and enhanced the aqueous stability of DPE significantly more compared to the neutral cyclodextrin HP- β-CD. At room temperature and at pH values of 5.0 and 7.4, 9.2 mM (SBE) 7m- β-CD increased the aqueous stability of DPE about 20- and 100-fold, respectively, while 9.2 mM HP- β-CD increased the stability about four to five times. The phase-transfer and in vitro corneal uptake studies suggested that the complexation of DPE with both CDs may decrease the ophthalmic availability of DPE.

Prodrugs: Topical and Ocular Drug Delivery

Prodrugs are reversible chemical derivatives that are hydrolyzed to release the active drug in an absorbing tissue or organ. This approach represents only a small, but significant, part of drug delivery and there is only one commercial product, Propine (Allergan Pharmaceuticals, Irvine, Calif; dipivalyl epinephrine) that uses this concept in the eye. Nevertheless, prodrugs have considerable potential to improve drug stability and/or membrane permeability and, as such, can dramatically increase the fraction of dose absorbed, the rate and extent of metabolism, and the fraction of dose reaching the biophase from the pool of drug in the surrounding fluid or tissue. These advantages are often offset by higher manufacturing and development costs and greater difficulty in securing US Food and Drug Administration approval. This short text, consisting of seven chapters, deals primarily with percutaneous absorption; five of seven chapters are devoted to prodrugs and the skin, one chapter deals with prediction

Contact allergy to ophthalmic dipivalyl epinephrine hydrochloride: demonstration by patch testing

A patient presented with a 3-month history of conjunctivitis and periocular eczema. He had a 3-year history of glaucoma and was being treated with 3 different locally applied eyedrops (Timoptic (timolol maleate) ophthalmic solution 0.25%, Pilocar (pilocarpine) ophthalmic solution 1%, and Propine (dipivalyl epinephrine hydrochloride) ophthalmic solution 0.1%). Patch testing with all 3 undiluted eyedrop solutions revealed a reaction only to Propine eyedrops. Patch testing to the individual components of Propine eyedrops revealed an allergic reaction to 0.5% dipivalyl epinephrine hydrochloride that was apparent on the 2nd patch test reading. After discontinuing the Propine eyedrops, the conjunctivitis as well as the periocular dermatitis resolved, proving that the positive patch tests were relevant to both. It was reported that re-exposure to dipivalyl epinephrine hydrochloride by intra-ocular challenge was necessary to diagnose this allergy. This is the first demonstration of dipivalyl epinephrine hydrochloride allergy by patch testing. Since the 1st patch test reading (2 days) was weak, 2nd patch test (4 days) readings may be important in diagnosing this allergy by patch testing.

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.

Effects of Topically Applied 2% Epinephrine and 0.1% Dipivalyl Epinephrine on the Adrenergic Nerves as Revealed by Histofluorescence

Commercially available epinephrine (EPI) 2% and dipivalyl epinephrine (DPE) 0.1% ophthalmic solutions were instilled twice daily in the eyes of rats over a 12-week period and compared to placebo-vehicle-treated controls. Fluorescence photomicrographs of stretch preparations from the dilator muscle of the rat irises showed a weaker fluorescence in the eyes treated with EPI and DPE as compared with controls treated with a placebo vehicle. This study provides further evidence that EPI and DPE treatment can result in a chemical sympathectomy as has been described following topical application of 6-hydroxydopamine.

Soluble forms of isobutylmethylxanthine enhance the ocular hypotension induced by catecholamines

Isobutylmethylxanthine (IBMX) suspended in 0.5% hydroxypropyl methylcellulose has been shown to enhance the reduction in intraocular pressure (IOP) induced by epinephrine and norepinephrine in rabbits and beagles. In the present study, the effects of two soluble forms of IBMX, i.e. the ethylenediamine salt (IBMX-ED) and IBMX bound to cyclodextrin in saline (IBMX-CD), were studied in rabbits. When used alone, 1% IBMX-ED did not affect the IOP, but the hypotensive response to 0.1% epinephrine was enhanced dose-dependently by combination of the catecholamine with IBMX-ED. Although 1% IBMX-CD applied alone also failed to influence the IOP, the hypotensive response to epinephrine, dipivalyl epinephrine and norepinephrine was enhanced by combination of these substances with IBMX-CD. Soluble IBMX-ED as well as soluble IBMX-CD and the IBMX suspension enhanced, to a similar extent and in a dose-dependent manner, the IOP reduction induced by catecholamines. IBMX-CD, which has a neutral pH, may be a suitable form of IBMX for future long-term experiments.

New Developments in the Drug Treatment of Glaucoma

This article reviews standard treatment modalities for patients with glaucoma and describes 3 classes of drugs which are undergoing development: apraclonidine (aplonidine, ALO 2145), an alpha 2-adrenergic agonist which has been released for clinical use; topical carbonic anhydrase inhibitors, a modification of the systemic carbonic anhydrase inhibitors currently in use; and prostaglandins (PGs), a new class of drugs with topical ocular hypotensive activity. Standard treatment modalities include parasympathomimetic agents such as pilocarpine, carbachol, and phospholine iodide, which lower intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork. A newer form of pilocarpine as a gel produces a longer action. Adrenergic agonist medications, such as epinephrine (adrenaline) and its prodrug dipivefrine (dipivalyl epinephrine), function by increasing uveoscleral outflow and trabecular outflow facility. A decrease in aqueous formation by the ciliary processes is thought to be the mechanism of action of beta-adrenoceptor antagonists, but the physiological basis for this action has not been clearly demonstrated. A newer beta-blocker, betaxolol, has relatively selective beta 1-blocking activity. Carbonic anhydrase inhibitors are nonbacteriostatic sulphonamide derivatives which decrease aqueous formation by the ciliary body. Almost 50% of patients taking these medications are unable to tolerate them because of their adverse effects, and there is thus much interest in the development of a topical carbonic anhydrase inhibitor with the potential for fewer adverse effects. MK 507 is the most recent and most potent compound in the series of topically active carbonic anhydrase inhibitors. Apraclonidine hydrochloride is a derivative of clonidine hydrochloride, an alpha 2-adrenergic agonist. Clonidine has previously been shown to lower IOP significantly, but has the potential to produce marked lowering of both systolic and diastolic blood pressures. Its major ocular effect appears to be a decrease in aqueous production. The structural modification to apraclonidine decreases corneal absorption and the drug's ability to cross the blood-brain barrier, minimising the risk of centrally mediated cardiovascular side effects. Apraclonidine may also influence secondary avenues of aqueous outflow, such as uveoscleral outflow, and may also affect conjunctival and episcleral vascular flow. It produces a mean decrease in IOP of 25% for as long as 12 hours. Adverse effects include blanching of the conjunctiva, minimal mydriasis and eyelid retraction. This drug has been approved in the US for use in prevention of elevated IOP after argon laser trabeculoplasty and iridotomy, and has potential uses in preventing an IOP rise after YAG laser posterior capsulotomy and cataract surgery in patients already on other antiglaucomatous medications.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Central vein thrombosis and topical dipivalyl epinephrine

A report is given on an 83-year-old female who acquired central vein thrombosis in her seeing eye one day after having started topical medication with dipivalyl epinephrine for advanced glaucoma discovered in the other eye. From present knowledge about the effects of adrenergic eye drops on ocular blood circulation, it is difficult to suggest an association between the two events, which may be coincidental only.

Evaluation of ocular hypersensitivity to dipivalyl epinephrine by component eye-drop testing

Dipivalyl epinephrine (dipivefrin) is a prodrug of epinephrine used for topical glaucoma therapy. Local side effects have been noted in approximately 20% of patients treated and include conjunctival hyperemia, foreign body sensation, and follicular conjunctivitis. We studied five patients with adverse local reactions to dipivefrin (Propine) eye drops. Propine contains the following: dipivefrin, 0.1%; mannitol, 1.89%; sodium metabisulfite, 0.075%; disodium edetate, 0.0127%; and benzalkonium chloride, 0.004%. Since the reactions could conceivably have been caused by an ingredient other than dipivefrin, we first patch tested the patients with the maximum recommended concentration of each ingredient. All patch tests were negative. Sterile ophthalmic solutions of each individual component at the concentrations used in the commercial product were then prepared. In a double-blinded study, the patients applied two drops of each preparation, twice daily for 1 week, with a 1-week, drug-free period between trials. Dipivefrin alone reproduced each patient's initial Propine-induced conjunctivitis; symptoms occurred unilaterally in one patient and bilaterally in the other four patients. This study indicates that testing with single component eye drops can identify the provocative component in ocular drug hypersensitivity and that these reactions can be unilateral.

Corneal Endothelial Changes Caused by Ophthalmic Drugs

Morphological changes were examined in the corneal endothelium of rabbits after administration of several drugs widely used in ophthalmology. After administration of epinephrine and dipivalyl epinephrine eye drops, swelling of corneal endothelial cells developed; however, these changes were reversible. No pathological changes were observed in the corneal endothelial layer following the administration of timolol, betamethasone, and gentamicin eye drops. Morphological changes were observed in the corneal endothelial layer after the subconjunctival injection of timolol, betamethasone, and gentamicin.

The role of esterase activity in the ocular disposition of dipivalyl epinephrine in rabbits

Dipivalyl epinephrine (DPE), a clinically useful prodrug of epinephrine in the treatment of glaucoma, relies on hydrolysis by ocular esterases for expression of its pharmacological activity. This study demonstrated that in rabbits, variations in esterase activity with age and iris pigmentation did not alter the fraction of DPE absorbed by the eye and its adnexa at 10 min post-instillation of 0.1% DPE solutions. Specifically, about 10% of the instilled dose was absorbed into the eyes of albino and pigmented rabbits, 6 and 12 weeks of age. Nonetheless, the concentration of epinephrine, derived from hydrolysis of DPE in the aqueous humor and selected ocular tissues correlated with age- and pigmentation-related variations in esterase activity, and was between 2.5 and 5 times higher than the concentrations achieved following the topical instillation of 0.1% epinephrine solutions. The results also indicated that absorption and the subsequent hydrolysis of DPE in the conjunctiva accounted for 60–75% of the instilled DPE recovered in the eye and its adnexa.

Experience with dipivalyl epinephrine. Its effectiveness, alone or in combination, and its side effects.

Dipivalyl epinephrine was as effective as adrenaline as an eyedrop for glaucoma. It was responsible for fewer side effects, through side effects did occur. It had an additive effect when used with timolol maleate and, in 12 of 14 patients on long-term medication with both drugs, a rise of pressure of 3 mmHg or more occurred when dipivalyl epinephrine was stopped. As sole therapy dipivalyl epinephrine was effective in chronic simple open-angle glaucoma, ocular hypertension and pseudoexfoliative glaucoma, and may be useful on its own in the latter two conditions. In low-tension glaucoma it seemed the best therapy when combined with timolol. Headache and ocular pain were uncommon but prominent side effects.

Toxicity of Dipivalyl Epinephrine

Fourteen patients with open-angle glaucoma applied one drop 0.1% dipivalyl epinephrine topically twice daily for three years. Four of the 14 patients developed severe blepharoconjunctivitis after 17 to 26 months of exposure to this epinephrine prodrug. Two of the four patients with dipivalyl epinephrine intolerance had a history of epinephrine intolerance. Three other patients had asymptomatic conjunctival hyperemia after 30 months of dipivalyl epinephrine exposure. No patients had conjunctival pigment deposits or cardiovascular side effects. The exfoliative cytology of two patients was characterized by karyomegaly of the conjunctival epithelial cells.

Is phenylephrine pivalate a prodrug?

Phenylephrine pivalate has been assumed to be a prodrug devoid of important intrinsic activity because of its structural similarity to dipivefrin (dipivaly epinephrine). However, unlike dipivefrin, the pharmacologic activity of phenylephrine pivalate was not prevented by prior administration of echothiophate iodide. Rabbits pretreated bilaterally with 0.25% echothiophate for two and seven days had similar mydriasis, both in quantity and duration, after receiving 10% phenylephrine hydrochloride to one eye and 1% phenylephrine pivalate to the other eye. This as consistent with the hypothesis that the phenylephrine pivalate molecule has important alpha-adrenergic activity regardless of whether it is converted to phenylephrine.

Epinephrine as the initial therapy in selected cases of ocular hypertension

The authors believe that the epinephrines should be employed as the initial therapy in both primary open angle glaucoma and, when treated, ocular hypertension. Unlike pilocarpine, epinephrine does not produce miosis and accommodative spasm. Because of longer experience with epinephrine than with costly timolol, its longterm effectiveness and side effects are better known. Although the side effects of epinephrine are usually not serious, they may be intolerable to the patient. However, allergic blepharoconjunctivitis may be ameliorated by concomitant hydroxymesterone therapy. The availability of dipivalyl epinephrine (DPE) may decidedly shift the balance of the treatment of ocular hypertension, when indicated, to an epinephrine compound.

2. Epinephrine

Epinephrine is reported to reduce intraocular pressure by decreasing aqueous formation and increasing outflow facility. Because epinephrine is devoid of accommodative and miotic effects, is administered twice a day, and is accompanied by relatively minor complications, it can be used as the initial therapy for primary open angle glaucoma, as an additive to current therapy, and as part of maximal medical therapy for glaucoma. Epinephrine is contraindicated for angle-closure glaucoma and should be used with caution in patients with narrow angles. Although there is a potential for serious systemic side effects, most of the recognized side effects are not serious and are reversible with drug discontinuation. The development of dipivalyl epinephrine (DPE) as a molecule with greater ocular penetration promises to maintain this drug's therapeutic effect with a reduction in external and extraocular side effects.

External Ocular Toxicity of Dipivalyl Epinephrine

Of 26 patients enrolled in a study designed to assess the usefulness of dipivalyl epinephrine 0.1%, administered topically at 12-hour intervals, for lowering intraocular pressure in patients with glaucoma and ocular hypertension, six patients (23.1%) developed adverse external ocular side effects severe enough to require that the drug be discontinued. Four of these six patients had a history of previous intolerance to epinephrine. The other two had successfully used epinephrine HCl 2% for more than two years before being treated with dipivalyl epinephrine and developed an adverse reaction after taking the drug 18 and 22 months, respectively. One patient with a history of epinephrine intolerance has successfully used dipivalyl epinephrine for 26 months to date. Our observations suggest that duration of exposure is an important factor in the development of sensitization to topically applied dipivalyl epinephrine.

Clinical Comparison of Dipivalyl Epinephrine and Epinephrine in the Treatment of Glaucoma

Dipivalyl epinephrine, 0.1%, though slightly less effective in decreasing intraocular pressure, showed significantly fewer side effects than epinephrine hydrochloride, 2%. Seventeen patients with symmetrically increased intraocular pressures who completed a six-month double-masked crossover study showed a significant decrease in intraocular pressure averaging 23.7% for dipivalyl epinephrine over the entire study and 27.4% for epinephrine. In the first treatment period, dipivalyl epinephrine was slightly less effective than epinephrine. In the second treatment period, dipivalyl epinephrine was statistically less effective than epinephrine. Two of the original 25 patients were dropped from the study because of epinephrine allergy or intolerance, one had uncontrolled pressures with either drug, and five failed to maintain adequate follow-up. Complaints of side effects such as burning and irritation occurred much more frequently in eyes receiving epinephrine (24%) than dipivalyl epinephrine (3%). Mild mydriasis occurred with each drug, averaging +0.65 mm with dipivalyl epinephrine and +0.55 mm Hg with epinephrine. No effect on blood pressure or pulse rate was found for the two drugs.

Lack of Hydrophilic Lens Discoloration in Patients Using Dipivalyl Epinephrine For Glaucoma

Five glaucoma patients used topical dipivalyl epinephrine for periods of up to 84 weeks without discoloration of their soft contact lenses. Thus, patients who need both soft contact lenses and antiglaucoma therapy with topical epinephrine may use the dipivalyl analogue without lens spoilage.