Dorzolamide hydrochloride

A topically active, carbonic anhydrase inhibitor for the treatment of glaucoma

Michael F. Sugrue, Alon Harris, Ingrid Adamsons

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Dorzolamide hydrochloride is a water-soluble potent inhibitor of human carbonic anhydrase (CA) isoenzymes II and IV. In contrast to acetazolamide and methazolamide, it is a very weak inhibitor of human CA isoenzyme I. Dorzolamide has been observed to be a very good ocular penetrator in rabbits following topical dosing. Dorzolamide, alone and in combination with timolol, was very effective in lowering the intraocular pressure (IOP) of ocular hypertensive animals. This effect of the drug was due to a local action within the eye and was the result of reduced aqueous humor inflow. Topically applied dorzolamide was well tolerated in long-term ocular irritation studies in several animal species and no microscopic changes in ocular tissues were observed. Dorzolamide is metabolized in the liver by N-deethylation and N- deethyldorzolamide is an inhibitor of CA isoenzymes I, II and IV. Multiple dosing with 2% dorzolamide resulted in the accumulation of parent drug and metabolite in human red blood cells. However, the red blood cell content of CA was not saturated and approximately 20% of total CA activity in the red blood cell was retained. Furthermore, plasma levels of dorzolamide and N- deethyldorzolamide were lower than the detection limit of the assay (5 ng/ml). These findings are consistent with the inability to detect biochemical changes indicative of the extraocular inhibition of CA in both plasma and urine of humans following the long-term administration of dorzolamide. Experiments have been undertaken in both healthy volunteers and normal-tension glaucoma patients to evaluate the effect of topically applied 2% dorzolamide on retinal blood flow velocity. Scanning laser angiography was the technique employed. For the normal subjects, 2% dorzolamide hydrochloride ophthalmic solution was administered acutely after baseline readings were obtained. Two hours later, a second group of readings was made. Dorzolamide treatment decreased retinal arteriovenous passage time by 19%, while placebo treatment had no effect. Both macular capillary transit velocity and optic nerve head capillary transit velocity were also significantly accelerated by the drug. No drug-induced changes were observed in blood velocity in four retrobulbar vessels (nasal and temporal posterior ciliary, central retinal and ophthalmic arteries), as assessed by color Doppler imaging. Treatment with dorzolamide significantly lowered IOP from 15.7 mmHg to 13.7 mmHg. A pilot study was undertaken in normal-tension glaucoma patients who had IOP values of <21 mmHg, glaucomatous optic disc appearance and/or visual field loss. Dorzolamide or placebo was administered t.i.d. for 4 weeks. Glaucoma patients demonstrated a significant decrease of 14% in retinal arteriovenous passage time and their IOP was significantly reduced from 15.8 mmHg to 13.7 mmHg following dosing with the drug. Dorzolamide hydrochloride ophthalmic solution has been extensively evaluated in clinical studies and has been found to be highly effective both as monotherapy and as adjunctive therapy to β-blockers. When used as adjunctive therapy, 2.0% dorzolamide b.i.d. has demonstrated a similar IOP-lowering effect to that of 2.0% pilocarpine q.i.d. and approximately 1 mmHg less of an effect than 250 mg acetazolamide p.o. q.i.d. Adjunctive therapy with dorzolamide was greatly preferred by patients over adjunctive therapy with pilocarpine, and was better tolerated than adjunctive therapy with acetazolamide. No significant change in corneal endothelial cell count of corneal thickness was seen after 1 year of treatment, thus demonstrating the corneal safety of dorzolamide. Finally, the safety profile of dorzolamide observed in clinical trials has been supported by market experience in over 1 million patients worldwide, confirming the dorzolamide is generally well tolerated.

Original languageEnglish
Pages (from-to)283-298
Number of pages16
JournalDrugs of Today
Volume33
Issue number5
StatePublished - 1997

Fingerprint

dorzolamide
Carbonic Anhydrase Inhibitors
Glaucoma
Therapeutics
Intraocular Pressure
Acetazolamide
Carbonic Anhydrases
Carbonic Anhydrase IV
Carbonic Anhydrase I
Low Tension Glaucoma
Isoenzymes
Pilocarpine
Pharmaceutical Preparations
Ophthalmic Solutions
Erythrocytes
Optic Disk

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology (medical)
  • Pharmacology

Cite this

Dorzolamide hydrochloride : A topically active, carbonic anhydrase inhibitor for the treatment of glaucoma. / Sugrue, Michael F.; Harris, Alon; Adamsons, Ingrid.

In: Drugs of Today, Vol. 33, No. 5, 1997, p. 283-298.

Research output: Contribution to journalArticle

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abstract = "Dorzolamide hydrochloride is a water-soluble potent inhibitor of human carbonic anhydrase (CA) isoenzymes II and IV. In contrast to acetazolamide and methazolamide, it is a very weak inhibitor of human CA isoenzyme I. Dorzolamide has been observed to be a very good ocular penetrator in rabbits following topical dosing. Dorzolamide, alone and in combination with timolol, was very effective in lowering the intraocular pressure (IOP) of ocular hypertensive animals. This effect of the drug was due to a local action within the eye and was the result of reduced aqueous humor inflow. Topically applied dorzolamide was well tolerated in long-term ocular irritation studies in several animal species and no microscopic changes in ocular tissues were observed. Dorzolamide is metabolized in the liver by N-deethylation and N- deethyldorzolamide is an inhibitor of CA isoenzymes I, II and IV. Multiple dosing with 2{\%} dorzolamide resulted in the accumulation of parent drug and metabolite in human red blood cells. However, the red blood cell content of CA was not saturated and approximately 20{\%} of total CA activity in the red blood cell was retained. Furthermore, plasma levels of dorzolamide and N- deethyldorzolamide were lower than the detection limit of the assay (5 ng/ml). These findings are consistent with the inability to detect biochemical changes indicative of the extraocular inhibition of CA in both plasma and urine of humans following the long-term administration of dorzolamide. Experiments have been undertaken in both healthy volunteers and normal-tension glaucoma patients to evaluate the effect of topically applied 2{\%} dorzolamide on retinal blood flow velocity. Scanning laser angiography was the technique employed. For the normal subjects, 2{\%} dorzolamide hydrochloride ophthalmic solution was administered acutely after baseline readings were obtained. Two hours later, a second group of readings was made. Dorzolamide treatment decreased retinal arteriovenous passage time by 19{\%}, while placebo treatment had no effect. Both macular capillary transit velocity and optic nerve head capillary transit velocity were also significantly accelerated by the drug. No drug-induced changes were observed in blood velocity in four retrobulbar vessels (nasal and temporal posterior ciliary, central retinal and ophthalmic arteries), as assessed by color Doppler imaging. Treatment with dorzolamide significantly lowered IOP from 15.7 mmHg to 13.7 mmHg. A pilot study was undertaken in normal-tension glaucoma patients who had IOP values of <21 mmHg, glaucomatous optic disc appearance and/or visual field loss. Dorzolamide or placebo was administered t.i.d. for 4 weeks. Glaucoma patients demonstrated a significant decrease of 14{\%} in retinal arteriovenous passage time and their IOP was significantly reduced from 15.8 mmHg to 13.7 mmHg following dosing with the drug. Dorzolamide hydrochloride ophthalmic solution has been extensively evaluated in clinical studies and has been found to be highly effective both as monotherapy and as adjunctive therapy to β-blockers. When used as adjunctive therapy, 2.0{\%} dorzolamide b.i.d. has demonstrated a similar IOP-lowering effect to that of 2.0{\%} pilocarpine q.i.d. and approximately 1 mmHg less of an effect than 250 mg acetazolamide p.o. q.i.d. Adjunctive therapy with dorzolamide was greatly preferred by patients over adjunctive therapy with pilocarpine, and was better tolerated than adjunctive therapy with acetazolamide. No significant change in corneal endothelial cell count of corneal thickness was seen after 1 year of treatment, thus demonstrating the corneal safety of dorzolamide. Finally, the safety profile of dorzolamide observed in clinical trials has been supported by market experience in over 1 million patients worldwide, confirming the dorzolamide is generally well tolerated.",
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N2 - Dorzolamide hydrochloride is a water-soluble potent inhibitor of human carbonic anhydrase (CA) isoenzymes II and IV. In contrast to acetazolamide and methazolamide, it is a very weak inhibitor of human CA isoenzyme I. Dorzolamide has been observed to be a very good ocular penetrator in rabbits following topical dosing. Dorzolamide, alone and in combination with timolol, was very effective in lowering the intraocular pressure (IOP) of ocular hypertensive animals. This effect of the drug was due to a local action within the eye and was the result of reduced aqueous humor inflow. Topically applied dorzolamide was well tolerated in long-term ocular irritation studies in several animal species and no microscopic changes in ocular tissues were observed. Dorzolamide is metabolized in the liver by N-deethylation and N- deethyldorzolamide is an inhibitor of CA isoenzymes I, II and IV. Multiple dosing with 2% dorzolamide resulted in the accumulation of parent drug and metabolite in human red blood cells. However, the red blood cell content of CA was not saturated and approximately 20% of total CA activity in the red blood cell was retained. Furthermore, plasma levels of dorzolamide and N- deethyldorzolamide were lower than the detection limit of the assay (5 ng/ml). These findings are consistent with the inability to detect biochemical changes indicative of the extraocular inhibition of CA in both plasma and urine of humans following the long-term administration of dorzolamide. Experiments have been undertaken in both healthy volunteers and normal-tension glaucoma patients to evaluate the effect of topically applied 2% dorzolamide on retinal blood flow velocity. Scanning laser angiography was the technique employed. For the normal subjects, 2% dorzolamide hydrochloride ophthalmic solution was administered acutely after baseline readings were obtained. Two hours later, a second group of readings was made. Dorzolamide treatment decreased retinal arteriovenous passage time by 19%, while placebo treatment had no effect. Both macular capillary transit velocity and optic nerve head capillary transit velocity were also significantly accelerated by the drug. No drug-induced changes were observed in blood velocity in four retrobulbar vessels (nasal and temporal posterior ciliary, central retinal and ophthalmic arteries), as assessed by color Doppler imaging. Treatment with dorzolamide significantly lowered IOP from 15.7 mmHg to 13.7 mmHg. A pilot study was undertaken in normal-tension glaucoma patients who had IOP values of <21 mmHg, glaucomatous optic disc appearance and/or visual field loss. Dorzolamide or placebo was administered t.i.d. for 4 weeks. Glaucoma patients demonstrated a significant decrease of 14% in retinal arteriovenous passage time and their IOP was significantly reduced from 15.8 mmHg to 13.7 mmHg following dosing with the drug. Dorzolamide hydrochloride ophthalmic solution has been extensively evaluated in clinical studies and has been found to be highly effective both as monotherapy and as adjunctive therapy to β-blockers. When used as adjunctive therapy, 2.0% dorzolamide b.i.d. has demonstrated a similar IOP-lowering effect to that of 2.0% pilocarpine q.i.d. and approximately 1 mmHg less of an effect than 250 mg acetazolamide p.o. q.i.d. Adjunctive therapy with dorzolamide was greatly preferred by patients over adjunctive therapy with pilocarpine, and was better tolerated than adjunctive therapy with acetazolamide. No significant change in corneal endothelial cell count of corneal thickness was seen after 1 year of treatment, thus demonstrating the corneal safety of dorzolamide. Finally, the safety profile of dorzolamide observed in clinical trials has been supported by market experience in over 1 million patients worldwide, confirming the dorzolamide is generally well tolerated.

AB - Dorzolamide hydrochloride is a water-soluble potent inhibitor of human carbonic anhydrase (CA) isoenzymes II and IV. In contrast to acetazolamide and methazolamide, it is a very weak inhibitor of human CA isoenzyme I. Dorzolamide has been observed to be a very good ocular penetrator in rabbits following topical dosing. Dorzolamide, alone and in combination with timolol, was very effective in lowering the intraocular pressure (IOP) of ocular hypertensive animals. This effect of the drug was due to a local action within the eye and was the result of reduced aqueous humor inflow. Topically applied dorzolamide was well tolerated in long-term ocular irritation studies in several animal species and no microscopic changes in ocular tissues were observed. Dorzolamide is metabolized in the liver by N-deethylation and N- deethyldorzolamide is an inhibitor of CA isoenzymes I, II and IV. Multiple dosing with 2% dorzolamide resulted in the accumulation of parent drug and metabolite in human red blood cells. However, the red blood cell content of CA was not saturated and approximately 20% of total CA activity in the red blood cell was retained. Furthermore, plasma levels of dorzolamide and N- deethyldorzolamide were lower than the detection limit of the assay (5 ng/ml). These findings are consistent with the inability to detect biochemical changes indicative of the extraocular inhibition of CA in both plasma and urine of humans following the long-term administration of dorzolamide. Experiments have been undertaken in both healthy volunteers and normal-tension glaucoma patients to evaluate the effect of topically applied 2% dorzolamide on retinal blood flow velocity. Scanning laser angiography was the technique employed. For the normal subjects, 2% dorzolamide hydrochloride ophthalmic solution was administered acutely after baseline readings were obtained. Two hours later, a second group of readings was made. Dorzolamide treatment decreased retinal arteriovenous passage time by 19%, while placebo treatment had no effect. Both macular capillary transit velocity and optic nerve head capillary transit velocity were also significantly accelerated by the drug. No drug-induced changes were observed in blood velocity in four retrobulbar vessels (nasal and temporal posterior ciliary, central retinal and ophthalmic arteries), as assessed by color Doppler imaging. Treatment with dorzolamide significantly lowered IOP from 15.7 mmHg to 13.7 mmHg. A pilot study was undertaken in normal-tension glaucoma patients who had IOP values of <21 mmHg, glaucomatous optic disc appearance and/or visual field loss. Dorzolamide or placebo was administered t.i.d. for 4 weeks. Glaucoma patients demonstrated a significant decrease of 14% in retinal arteriovenous passage time and their IOP was significantly reduced from 15.8 mmHg to 13.7 mmHg following dosing with the drug. Dorzolamide hydrochloride ophthalmic solution has been extensively evaluated in clinical studies and has been found to be highly effective both as monotherapy and as adjunctive therapy to β-blockers. When used as adjunctive therapy, 2.0% dorzolamide b.i.d. has demonstrated a similar IOP-lowering effect to that of 2.0% pilocarpine q.i.d. and approximately 1 mmHg less of an effect than 250 mg acetazolamide p.o. q.i.d. Adjunctive therapy with dorzolamide was greatly preferred by patients over adjunctive therapy with pilocarpine, and was better tolerated than adjunctive therapy with acetazolamide. No significant change in corneal endothelial cell count of corneal thickness was seen after 1 year of treatment, thus demonstrating the corneal safety of dorzolamide. Finally, the safety profile of dorzolamide observed in clinical trials has been supported by market experience in over 1 million patients worldwide, confirming the dorzolamide is generally well tolerated.

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