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Biomedical subjects

L A Wheeler

Publications and source records attributed to L A Wheeler.

At least 19 recordsLinked to original sources
PubMed2004

Bimatoprost: a novel antiglaucoma agent.

The aim of glaucoma therapy is to preserve vision by reducing intraocular pressure (IOP). Following recent National Eye Institute sponsored studies, it is becoming increasingly apparent that every mmHg of extra IOP lowering counts. Bimatoprost is the newest and most effective addition to the physician's armamentarium of ocular hypotensive drugs. Direct clinical comparisons have demonstrated that it is more efficacious than the prostaglandin (PG) FP receptor agonist prodrugs, latanoprost and travoprost, as well as a beta-adrenoceptor antagonist, timolol, alone or in fixed combination with the carbonic anhydrase inhibitor, dorzolamide. Moreover, patients that are refractory to latanoprost therapy may be successfully treated with bimatoprost. Such evidence provides support, at the clinical level, for the contention that bimatoprost is pharmacologically distinct from PG FP receptor agonist prodrugs. Bimatoprost is a structural analog of PGF2alpha-ethanolamide (prostamide F2alpha), which is formed from the endocannabinoid anandamide by a biosynthetic pathway involving cyclooxygenase-2 (COX-2). Their pharmacology is remarkably similar, such that bimatoprost may be regarded as a prostamide mimetic. The target receptor for bimatoprost and the prostamides appears unique and unrelated to PG- and endocannabinoid-sensitive receptors. Extensive ocular distribution/metabolism studies in non-human primates demonstrate that bimatoprost is not a prodrug, it remains essentially intact. Its profound ocular hypotensive effects may, therefore, be attributed to its prostamide-mimetic properties.

Amides↗
PubMed2003

Pharmacological characterization of a novel antiglaucoma agent, Bimatoprost (AGN 192024).

Replacement of the carboxylic acid group of prostaglandin (PG) F(2alpha) with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF(2alpha) analog, where the carboxylic acid is replaced by a neutral ethylamide substituent. Bimatoprost potently contracted the feline lung parenchymal preparation (EC(50) value of 35-55 nM) but exhibited no meaningful activity in a variety of PG-sensitive tissue and cell preparations. Its activity seemed unrelated to FP receptor stimulation according to the following evidence. 1) Bimatoprost exhibited no meaningful activity in tissues and cells containing functional FP receptors. 2) Bimatoprost activity in the cat lung parenchyma is not species-specific because its potent activity in this preparation could not be reproduced in cells stably expressing the feline FP receptor. 3) Radioligand binding studies using feline and human recombinant FP receptors exhibited minimal competition versus [(3)H]17-phenyl PGF(2a) for Bimatoprost. 4) Bimatoprost pretreatment did not attenuate PGF(2alpha)-induced Ca(2+) signals in Swiss 3T3 cells. 5) Regional differences were apparent for Bimatoprost but not FP agonist effects in the cat lung. Bimatoprost reduced intraocular pressure in ocular normotensive and hypertensive monkeys over a 0.001 to 0.1% dose range. A single-dose and multiple-dose ocular distribution/metabolism studies using [(3)H]Bimatoprost (0.1%) were performed. Within the globe, bimatoprost concentrations were 10- to 100-fold higher in anterior segment tissues compared with the aqueous humor. Bimatoprost was overwhelmingly the predominant molecular species identified at all time points in ocular tissues, indicating that the intact molecule reduces intraocular pressure.

Amides↗
PubMed2001

Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma.

Our group recently demonstrated that autoimmune T cells directed against central nervous system-associated myelin antigens protect neurons from secondary degeneration. We further showed that the synthetic peptide copolymer 1 (Cop-1), known to suppress experimental autoimmune encephalomyelitis, can be safely substituted for the natural myelin antigen in both passive and active immunization for neuroprotection of the injured optic nerve. Here we attempted to determine whether similar immunizations are protective from retinal ganglion cell loss resulting from a direct biochemical insult caused, for example, by glutamate (a major mediator of degeneration in acute and chronic optic nerve insults) and in a rat model of ocular hypertension. Passive immunization with T cells reactive to myelin basic protein or active immunization with myelin oligodendrocyte glycoprotein-derived peptide, although neuroprotective after optic nerve injury, was ineffective against glutamate toxicity in mice and rats. In contrast, the number of surviving retinal ganglion cells per square millimeter in glutamate-injected retinas was significantly larger in mice immunized 10 days previously with Cop-1 emulsified in complete Freund's adjuvant than in mice injected with PBS in the same adjuvant (2,133 +/- 270 and 1,329 +/- 121, respectively, mean +/- SEM; P < 0.02). A similar pattern was observed when mice were immunized on the day of glutamate injection (1,777 +/- 101 compared with 1,414 +/- 36; P < 0.05), but not when they were immunized 48 h later. These findings suggest that protection from glutamate toxicity requires reinforcement of the immune system by antigens that are different from those associated with myelin. The use of Cop-1 apparently circumvents this antigen specificity barrier. In the rat ocular hypertension model, which simulates glaucoma, immunization with Cop-1 significantly reduced the retinal ganglion cell loss from 27.8% +/- 6.8% to 4.3% +/- 1.6%, without affecting the intraocular pressure. This study may point the way to a therapy for glaucoma, a neurodegenerative disease of the optic nerve often associated with increased intraocular pressure, as well as for acute and chronic degenerative disorders in which glutamate is a prominent participant.

Adjuvants, Immunologic↗
PubMed2001

Role of alpha-2 adrenergic receptors in neuroprotection and glaucoma.

The loss of retinal ganglion cells (RGCs) in glaucoma occurs progressively over many years. A neuroprotective drug should enhance survival of RGCs in the presence of chronic stress/injury. Four criteria are proposed for assessing the likely therapeutic utility in human glaucoma of drugs that have demonstrated neuroprotective activity in animal models: 1) A specific receptor target must be in the retina/optic nerve; 2) Activation of the target must trigger pathways that enhance a neuron's resistance to stress/injury and/or suppresses toxic insults; 3) The drug must reach the retina/vitreous at pharmacologic doses; and 4) The neuroprotective activity should be demonstrated in clinical trials. Data are presented that illustrate how the specific and potent alpha-2 agonist, brimonidine, meets these criteria. The alpha-2A receptor was localized in the inner rat retina by immunohistochemistry. Brimonidine reduced the rate of RGC loss in the calibrated rat optic nerve injury model even when dosed 12 and 24 hours before injury, consistent with a long-term enhancement of RGC resistance to stress. Brimonidine was also neuroprotective in the lasered chronic hypertensive rat model, reducing RGC loss over three weeks from 33% to 15%. A clinical trial has been initiated to determine brimonidine's neuroprotective activity in patients with non-arteritic ischemic optic neuropathy.

Adrenergic alpha-Agonists↗
PubMed2001

The pharmacology of bimatoprost (Lumigan).

Bimatoprost (Lumigan) is a pharmacologically unique and highly efficacious ocular hypotensive agent. It appears to mimic the activity of a newly discovered family of fatty acid amides, termed prostamides. One biosynthetic route to the prostamides involves anandamide as the precursor. Bimatoprost pharmacology has been extensively characterized by binding and functional studies at more than 100 drug targets, which comprise a diverse variety of receptors, ion channels, and transporters. Bimatoprost exhibited no meaningful activity at receptors known to include antiglaucoma drug targets as follows: adenosine (A(1-3)), adrenergic (alpha(1), alpha(2), beta(1), beta(2)), cannabinoid (CB(1), CB(2)), dopamine (D(1-5)), muscarinic (M(1-5)), prostanoid (DP, EP(1-4), FP, IP, TP), and serotonin (5HT(1-7)). Bimatoprost does, however, exhibit potent inherent pharmacological activity in the feline iris sphincter preparation, which is prostamide-sensitive. Bimatoprost also resembles the prostamides in that it is a potent and highly efficacious ocular hypotensive agent. A single dose of bimatoprost markedly reduces intraocular pressure in dogs and laser-induced ocular hypertensive monkeys. Decreases in intraocular pressure are well maintained for at least 24 hr post-dose. Human studies have demonstrated that systemic exposure to bimatoprost is low and that accumulation does not occur. The sclera is the preferred route of accession to the eye. The high scleral permeability coefficient Papp is a likely contributing factor to the rapid onset and long-acting ocular hypotensive profile of bimatoprost.

Amides↗
PubMed2001

Differential effects of alpha-adrenoceptor agonists on human retinal microvessel diameter.

The effects of locally administered brimonidine, clonidine, and p-aminoclonidine on microvessel caliber were compared in human retinal tissues grafted into the hamster cheek pouch. Clonidine and p-aminoclonidine, but not brimonidine, potently constricted human retinal microvessels over a broad concentration range. All three agonists elicited significant vasoconstriction in naive hamster cheek pouch microvasculature. The alpha2-adrenoceptor antagonist, rauwolscine, inhibited p-aminoclonidine-induced constriction in naive hamster cheek pouch microvessels, but not p-aminoclonidine-induced effects in retinal grafts. Selective alpha1-adrenoceptor agonists evoked vasoconstriction in retinal grafts only at relatively high concentrations. These differential effects on the retinal microvasculature could not be readily explained solely on the basis of alpha1- or alpha2-adrenoceptor involvement. Clonidine, p-aminoclonidine and brimonidine are also imidazoline derivatives that interact with putative non-adrenergic imidazoline-sensitive binding sites, the so-called I1-imidazoline binding site subtype implicated by some investigators in mediation of peripheral vasoconstriction. As with p-aminoclonidine, the potent vasoconstriction in human retinal microvasculature elicited by moxonidine, an alpha-adrenergic agonist that has also been reported to exhibit selectivity for putative I1-imidazoline binding sites, was not inhibited by the selective alpha-adrenoceptor antagonist, rauwolscine, nor by idazoxan, an antagonist characterized as having substantial activity at putative I2-imidazoline binding sites. These data suggest the possible involvement of an unconventional non-adrenergic imidazoline-sensitive pathway in regulation of microvascular responses in the inner retina, and that drug activity mediated via such an imidazoline-sensitive component could potentially evoke deleterious effects in the retinal microvasculature.

Adrenergic alpha-Agonists↗
PubMed2001

alpha(2)-Adrenoceptor agonists inhibit vitreal glutamate and aspartate accumulation and preserve retinal function after transient ischemia.

Recent studies have suggested that alpha(2)-adrenergic agonists prevent neuronal cell death in a number of animal models, although the mechanism of alpha(2)-neuroprotection remains unclear. In a retinal ischemia model, the alpha(2)-specific agonist brimonidine (1 mg/kg i.p.) preserves approximately 80% of the electroretinogram (ERG) b-wave. The protective effect of brimonidine is completely blocked by coadministration of the alpha(2)- antagonist rauwolscine. Brimonidine treatment preserves the ERG b-wave if animals are treated 1 or 3 h before ischemia, but has no effect if it is injected during ischemia. The 3-h pretreatment effect is blocked by i.v. injection of rauwolscine 2 h later (1 h before ischemia). A comparison of vitreous humor glutamate levels between untreated and brimonidine-treated eyes shows that 1) after ischemia, glutamate levels rise 2- to 3-fold in the untreated animals, and 2) glutamate levels in the brimonidine-treated animals are comparable to the nonischemic controls. Hence, the mechanism for brimonidine-mediated protection in the retinal ischemia model requires activation of the alpha(2)-adrenergic receptors immediately before and during ischemia. These data suggest that activation of the alpha(2)-adrenergic receptor may reduce ischemic retinal injury by preventing the accumulation of extracellular glutamate and aspartate.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2001

Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension.

PURPOSE: To examine the neuroprotective effect of the alpha(2)-adrenergic agonist brimonidine in a chronic ocular hypertension model. METHODS: Intraocular pressure (IOP) was elevated by laser photocoagulation of episcleral and limbal veins. Retinal ganglion cell loss was evaluated in wholemounted retinas. Brimonidine or timolol was administered, either at the time of or 10 days after IOP elevation and continued for 3 weeks. Drug-related immunohistochemical changes in glial fibrillary acidic protein (GFAP) were also determined after 3 weeks. RESULTS: Laser treatment caused a twofold IOP increase over baseline that was maintained for 2 months. A time-dependent loss of ganglion cells occurred with elevated IOP. Systemic administration of brimonidine or timolol caused little decrease in IOP. After 3 weeks of elevated IOP, ganglion cell loss in control rats was 33% +/- 3%. Brimonidine reduced the progressive loss of ganglion cells to 26% +/- 1% and 15% +/- 2% at doses of 0.5 and 1 mg/kg. d, respectively. Timolol had no effect. Ten days of high IOP resulted in 22% +/- 4% ganglion cell loss. Brimonidine administration initiated 10 days after IOP elevation prevented any further loss of ganglion cells. In vehicle- or timolol-treated rats, ganglion cell loss continued to 33%. The increase in immunoreactivity of GFAP in ocular hypertensive retinas was attenuated by brimonidine. CONCLUSIONS: Systemic application of brimonidine or timolol had little effect on IOP. Brimonidine, but not timolol, showed significant protection of retinal ganglion cells when applied at the time of IOP elevation and prevented further cell loss when applied after IOP was elevated. This indicates that brimonidine has a neuroprotective activity unrelated to its effect on ocular hypotension.

Adrenergic alpha-Agonists↗
PubMed2000

Replacement of the carboxylic acid group of prostaglandin f(2alpha) with a hydroxyl or methoxy substituent provides biologically unique compounds.

Replacement of the carboxylic acid group of PGF(2alpha) with the non-acidic substituents hydroxyl (-OH) or methoxy (-OCH(3)) resulted in an unexpected activity profile. Although PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) exhibited potent contractile effects similar to 17-phenyl PGF(2alpha) in the cat lung parenchymal preparation, they were approximately 1000 times less potent than 17-phenyl PGF(2alpha) in stimulating recombinant feline and human FP receptors. In human dermal fibroblasts and Swiss 3T3 cells PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) produced no Ca(2+) signal until a 1 microM concentration was exceeded. Pretreatment of Swiss 3T3 cells with either 1 microM PGF(2alpha) 1-OH or PGF(2alpha) 1-OCH(3) did not attenuate Ca(2+) signal responses produced by PGF(2alpha) or fluprostenol. In the rat uterus, PGF(2alpha) 1-OH was about two orders of magnitude less potent than 17-phenyl PGF(2alpha) whereas PGF(2alpha) 1-OCH(3) produced only a minimal effect. Radioligand binding studies on cat lung parenchymal plasma membrane preparations suggested that the cat lung parenchyma does not contain a homogeneous population of receptors that equally respond to PGF(2alpha)1-OH, PGF(2alpha)1-OCH(3), and classical FP receptor agonists. Studies on smooth muscle preparations and cells containing DP, EP(1), EP(2), EP(3), EP(4), IP, and TP receptors indicated that the activity of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) could not be ascribed to interaction with these receptors. The potent effects of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) on the cat lung parenchyma are difficult to describe in terms of interaction with the FP or any other known prostanoid receptor.

3T3 Cells↗
PubMed2000

RGC death in mice after optic nerve crush injury: oxidative stress and neuroprotection.

PURPOSE: To establish a method for morphometric analysis of retrogradely labeled retinal ganglion cells (RGCs) of the mouse retina, to be used for the study of molecular aspects of RGC survival and neuroprotection in this model; to evaluate the effect of overexpression of Cu-Zn-superoxide dismutase (CuZnSOD) on RGC survival after severe crush injury to the optic nerve, and to assess the effect of the alpha2-adrenoreceptor agonist brimonidine, recently shown to be neuroprotective, on RGC survival. METHODS: A severe crush injury was inflicted unilaterally in the orbital portion of the optic nerves of wild-type and transgenic (Tg-SOD) mice expressing three to four times more human CuZnSOD than the wild type. In each mouse all RGCs were labeled 72 hours before crush injury by stereotactic injection of the neurotracer dye FluoroGold (Fluorochrome, Denver, CO) into the superior colliculus. Survival of RGCs was then assessed morphometrically, with and without systemic injection of brimonidine. RESULTS: Two weeks after crush injury, the number of surviving RGCs was significantly lower in the Tg-SOD mice (596.6 +/- 71.9 cells/mm(2)) than in the wild-type control mice (863. 5 +/- 68 cells/mm(2)). There was no difference between the numbers of surviving RGCs in the uninjured retinas of the two strains (3708 +/- 231.3 cells/mm(2) and 3904 +/- 120 cells/mm(2), respectively). Systemic injections of brimonidine significantly reduced cell death in the Tg-SOD mice, but not in the wild type. CONCLUSIONS: Overexpression of CuZnSOD accelerates RGC death after optic nerve injury in mice. Activation of the alpha2-adrenoreceptor pathway by brimonidine enhances survival of RGCs in an in vivo transgenic model of excessive oxidative stress.

Adrenergic alpha-Agonists↗
PubMed1999

Pseudomesotheliomatous carcinoma involving pleura and peritoneum: A clinicopathologic and immunohistochemical study of three cases.

Pseudomesotheliomatous carcinoma is a rare variant of peripheral adenocarcinoma of the lung that can manifest clinical, radiologic, and pathologic features similar to malignant mesothelioma. We present three patients with pseudomesotheliomatous carcinoma of the lung. In one patient the carcinoma extended beyond the thorax and extensively involved the peritoneum, mesentery, omentum, and intestines. All patients experienced weight loss and chest pain. All were white men aged 63, 65, and 67 years. Two were smokers and had shortness of breath, cough, and pleural effusion. One had a history of asbestos exposure. No patient developed dyspnea or hemoptysis. One was successfully treated for prostatic carcinoma 18 months earlier. Radiographically, all tumors were pleura-based. Grossly, the tumors spread extensively over pleural (and in one case peritoneal) surfaces and mimicked malignant mesothelioma. Histologically, all tumors were poorly differentiated and necrotic; two tumors exhibited spindle-cell components and desmoplasia. Mucin production was detectable in none, 10%, and 50% of tumor cells. The percentages of tumor cells immunoreactive for Ber-EP4 were 70%, 100%, and 80%; for Leu MI 0%, 90%, and 50%; for epithelial membrane antigen 80%, 80%, and 100%; for B 72.3%, 0%, 90%, and 20%; for polyclonal carcinoembryonic antigen 0%, 10%, and 10%; and for monoclonal 5%, 0%, and 0%. Of these, Ber-EP4 and B 72.3 rendered the most reliable diagnostic results. The clinical, radiologic, and gross and routine histologic findings were similar to those of a malignant mesothelioma; the final diagnosis could be made based mainly on immunocytochemical results. We have reviewed the English and German literature regarding 65 such tumors and present our experience with three additional cases. We emphasize the application of immunocytochemical studies on pleura-based poorly or undifferentiated malignant tumors of unknown origin.

Aged↗
PubMed1999

Amputation prevention by vascular surgery and podiatry collaboration in high-risk diabetic and nondiabetic patients. The Operation Desert Foot experience.

OBJECTIVE: To describe a unique multidisciplinary outpatient intervention for patients at high risk for lower-extremity amputation. RESEARCH DESIGN AND METHODS: Patients with foot ulcers and considered to be high risk for lower-extremity amputation were referred to the High Risk Foot Clinic of Operation Desert Foot at the Carl T. Hayden Veterans Affairs' Medical Center in Phoenix, Arizona, where patients received simultaneous vascular surgery and podiatric triage and treatment. Some 124 patients, consisting of 90 diabetic patients and 34 nondiabetic patients, were initially seen between 1 October 1991 and 30 September 1992 and followed for subsequent rate of lower-extremity amputation. RESULTS: In a mean follow-up period of 55 months (range 3-77), only 18 of 124 patients (15%) required amputation at the level of the thigh or leg. Of the 18 amputees, 17 (94%) had type 2 diabetes. The rate of avoiding limb loss was 86.5% after 3 years and 83% after 5 years or more. Furthermore, of the 15 amputees surviving longer than 2 months, only one (7%) had to undergo amputation of the contralateral limb over the following 12-65 months (mean 35 months). Compared with nondiabetic patients, patients with diabetes had a 7.68 odds ratio for amputation (95% CI 5.63-9.74) (P < 0.01). CONCLUSIONS: A specialized clinic for prevention of lower-extremity amputation is described. Initial and contralateral amputation rates appear to be far lower in this population than in previously published reports for similar populations. Relative to patients without diabetes, patients with diabetes were more than seven times as likely to have a lower-extremity amputation. These data suggest that aggressive collaboration of vascular surgery and podiatry can be effective in preventing lower-extremity amputation in the high-risk population.

Adult↗
PubMed1999

Alpha2-adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration.

PURPOSE: The neurodegenerative progression of glaucoma is considered to be related not only to primary risk factors such as the elevation of intraocular pressure, but also to mediators of secondary neuronal degeneration. In the present study, the neuroprotective activity of the alpha2-adrenoreceptor agonists brimonidine, AGN 191103, and clonidine were examined in an animal model that simulates secondary neuronal degeneration of the optic nerve in a way thought to be independent of elevation of intraocular pressure. The beta-blocker timolol, currently used clinically to decrease intraocular pressure, was also examined for neuroprotective activity at dosages corresponding to the effective antihypertensive dosage. METHODS: A single dose of each of the tested compounds was administered intraperitoneally immediately after partial crush injury of the rat optic nerve. Secondary degeneration was measured by determining injury-induced deficits with and without the drug. This was achieved electrophysiologically by measurement of compound action potential amplitude, and morphometrically by counting the retrogradely labeled retinal ganglion cells, representing viable optic nerve axons, in wholemounted retinas. RESULTS: All three alpha2-adrenoreceptor agonists, but not timolol, exhibited neuroprotective effects. Treatment immediately after injury with each of these agonists resulted in a dose-dependent attenuation of the injury-induced decrease in compound action potential amplitude. Moreover, after treatment with 100 microg/kg brimonidine administered intraperitoneally, the loss of retinal ganglion cells 2 weeks after injury was three times lower than in saline-treated animals. CONCLUSIONS: In addition to their known effect of lowering intraocular pressure, alpha2-adrenoreceptor agonists, unlike timolol, exert a neuroprotective effect. Use of the rat optic nerve model of partial crush injury can serve as a method of screening compounds that are potentially capable of alleviating the progression of secondary neuronal degeneration.

Action Potentials↗
PubMed1997

Synthesis and evaluation of 2-(arylamino)imidazoles as alpha 2-adrenergic agonists.

A series of 2-(arylamino)imidazoles was synthesized and evaluated for activity at alpha 1- and alpha 2-adrenoceptors. This class of agents has been shown to have potent and selective agonist activity at the alpha 2-adrenoceptors. The most potent member of this class, 2-[(5-methyl-1,4-benzodioxan-6yl)amino]imidazole, proved efficacious for the reduction of intraocular pressure upon topical administration and for the reduction of blood pressure upon intravenous administration. During the course of our studies, we developed a new reagent that allowed rapid assembly of the target compounds. This reagent, N-(2,2-diethoxyethyl)carbodiimide, was convenient to prepare and was stable under low-temperature storage conditions.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1996

Synthesis and evaluation of 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a potent, peripherally acting alpha 2 adrenoceptor agonist.

We have synthesized 2-[(5-methylbenz-1-ox-4-azin-6-yl)imidazoline, 3, a potent, peripherally acting alpha 2 adrenoceptor agonist. The agent is conveniently prepared in five steps from 2-amino-m-cresol. The agent has demonstrated good selectivity for alpha 2 adrenoceptors in binding and functional studies. When applied topically to eyes, the agent is efficacious for the reduction of intraocular pressure. The agent does not penetrate the blood-brain barrier and, as a consequence, does not lower blood pressure or induce sedation when administered topically or intravenously. We have determined the pKa and log P in water versus both octanol and dodecane of 3 and a set of related agents. The best physical parameter to explain its lack of central nervous system penetration appears to be log P measured in octanol versus water.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1996

In-vivo activity and enzymatic hydrolysis of novel prostaglandin F2 alpha prodrugs in ocular tissues.

Enzymatic hydrolysis and in-vivo ocular studies were performed on a novel series of prostaglandin F2 alpha (PGF2 alpha) pivaloyl ester prodrugs to assess their therapeutic potential. These novel PGF2 prodrugs were esterified at the 9-, 11-, and 15-OH positions. Their enzymatic hydrolysis rates were compared to PGF2 alpha 1-isopropyl ester in dog, monkey, and human ocular tissues. Intraocular pressure (IOP) studies were performed in monkeys and dogs, and ocular surface hyperemia was monitored in dogs. PGF2 alpha 9-monopivaloyl ester was not enzymatically hydrolysed in dog and human ocular tissues. PGF2 alpha 11- and 15-monopivaloyl esters and PGF2 alpha 11,15-dipivaloyl ester were converted to PGF2 alpha by all ocular tissues at a substantially slower rate than PGF2 alpha l-isopropyl ester. Despite their slow enzymatic hydrolysis rates, the ocular hypotensive activity of PGF2 alpha mono and dipivaloyl esters, where positions 11- and 15- were functionalized, closely approached the activity achieved with PGF2 alpha l-isopropyl ester. The degree of ocular surface hyperemia associated with PGF2 alpha 11-pivaloyl ester and PGF2 alpha 11,15-dipivaloyl ester was less than that associated with equivalent doses of PGF2 alpha l-isopropyl ester. It appears that rapid enzymatic hydrolysis rates are not necessary to obtain efficacious ocular hypotensive PGF2 alpha ester prodrugs. Slow enzymatic hydrolysis rates may assist in reducing the degree of ocular surface hyperemia. A further contributory factor in this regard could be the approximately ten-fold favorable difference in enzymatic hydrolysis rates between iris-ciliary body and conjunctival tissue for these novel pivaloyl esters of PGF2 alpha. These factors appear to translate into an improved therapeutic index for separating ocular hypotensive and ocular surface hyperemic effects.

Animals↗