Intraocular penetration and systemic absorption after topical application of dexamethasone disodium phosphate

Weijtens, Olga; Schoemaker, Rik C.; Romijn, Fred P.H.T.M.; Cohen, Adam F.; Lentjes, Eef G.W.M.; Meurs, Jan C. van

doi:10.1016/s0161-6420(02)01176-4

Cited by 134 publications

(108 citation statements)

References 11 publications

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“…23 Since 8 days pi, the time point pi of maximal observed loss of innervation, coincides with a highly inflammatory milieu in the infected cornea, 12,14 we hypothesized the mechanism triggering regression of corneal nerves is immune system mediated. To test this hypothesis, we evaluated the effects of DEX, a clinically prescribed, anti-inflammatory reagent, 25,26 on the corneal nerve network after HSV-1 infection. C57BL6 mice were ocularly infected or scarified and left uninfected as controls.…”

Section: Dex Prevents Corneal Nerve Regression and Sensation Loss Aftmentioning

confidence: 99%

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

Chucair-Elliott

Jinkins

Carr

et al. 2016

The American Journal of Pathology

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Herpes simplex virus type 1 (HSV-1) is a leading cause of neurotrophic keratitis characterized by decreased corneal sensation because of damage to the corneal sensory fibers. We and others have reported regression of corneal nerves during acute HSV-1 infection. To determine whether denervation is caused directly by the virus or indirectly by the elicited immune response, mice were infected with HSV-1 and topically treated with dexamethasone (DEX) or control eye drops. Corneal sensitivity was measured using a Cochet-Bonnet esthesiometer and nerve network structure via immunohistochemistry. Corneas were assessed for viral content by plaque assay, leukocyte influx by flow cytometry, and content of chemokines and inflammatory cytokines by suspension array. DEX significantly preserved corneal nerve structure and sensitivity on infection. DEX reduced myeloid and T-cell populations in the cornea and did not affect viral contents at 4 and 8 days post infection. The elevated protein contents of chemokines and inflammatory cytokines on infection were greatly suppressed by DEX. Subconjunctival delivery of neutralizing antibody against IL-6 to infected mice resulted in partial preservation of corneal nerve structure and sensitivity. Our study supports a role for the immune response, but not local virus replication in the development of HSV-1einduced neurotrophic keratitis. IL-6 is one of the factors produced by the elicited inflammatory response to HSV-1 infection contributing to nerve regression.

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Section: Dex Prevents Corneal Nerve Regression and Sensation Loss Aftmentioning

confidence: 99%

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

Chucair-Elliott

Jinkins

Carr

et al. 2016

The American Journal of Pathology

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“…To assess the possible direct role of glucocorticoids in the up-regulation of CXCR4 in treated patients, we incubated the synthetic glucocorticoid dexamethasone with in vitro-cultured CD4 ϩ T cells across a wide range of concentrations (Fig. 3a), including those estimated to be present in AqH from glucocorticoid-treated patients (30). Dexamethasone showed potent induction of CXCR4 at pharmacologically relevant concentrations.…”

Section: Regulation Of Cxcr4 Expression By Glucocorticoidsmentioning

confidence: 99%

Topical Glucocorticoid Therapy Directly Induces Up-Regulation of Functional CXCR4 on Primed T Lymphocytes in the Aqueous Humor of Patients with Uveitis

Curnow

Wloka

Faint

et al. 2004

The Journal of Immunology

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Overexpression of the constitutive chemokine receptor CXCR4 has been shown to contribute to the accumulation of leukocytes at sites of chronic inflammation. Glucocorticoids are widely used to treat inflammatory disorders such as uveitis to considerable effect, yet paradoxically have been reported to increase CXCR4 expression in vitro. We show here that ocular lymphocytes isolated from patients with uveitis who had been treated with topical glucocorticoids expressed highly elevated levels of CXCR4. The up-regulation of CXCR4 could be reproduced in vitro by culture of CD4+ T cells with aqueous humor (AqH), indicating a role for the ocular microenvironment rather than preferential recruitment of CXCR4+ cells. Untreated uveitis and noninflammatory AqH up-regulated CXCR4 to a limited extent; this was dependent on TGF-β2. However, the highest levels of CXCR4 both in vivo and in vitro were found in the glucocorticoid-treated patients. Glucocorticoids appeared to be directly responsible for the induction of CXCR4 in treated patients, as the glucocorticoid receptor antagonist RU38486 inhibited the in vitro up-regulation by AqH from these patients. Dexamethasone selectively up-regulated CXCR4 in vitro, but not any of a wide range of other chemokine receptors. CXCL12, the ligand for CXCR4, was present in AqH under noninflammatory conditions, but the levels were low in untreated uveitis and undetectable in treated uveitis AqH. The importance of these results for the treatment of HIV patients with glucocorticoids is discussed as well as a role for glucocorticoid-induced CXCR4 up-regulation and CXCL12 down-regulation in controlling the migration of lymphocyte populations, resulting in resolution of inflammation.

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“…21 However, lipophilic molecules can be absorbed significantly by the organism even in topical administration, reaching the systemic circulation in considerable concentration. 22 The administration of a classical b 1 -selective antagonist such as atenolol would not solve the problem due to its more hydrophilic characteristic (Figure 1), which impairs its penetration through the eye. In this case, a lipophilic b 1 -selective antagonist (such as betaxolol) would avoid the respiratory impairment and achieve adequate concentrations inside the eye to threat glaucoma.…”

Section: Resultsmentioning

confidence: 99%

The Importance of Medicinal Chemistry Knowledge in the Clinical Pharmacist’s Education

Fernandes

2018

American Journal of Pharmaceutical Education

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Objective. To show why medicinal chemistry must be a key component of the education of pharmacy students, as well as in the pharmacist's practice. Findings. Five case reports were selected by their clinically relevant elements of medicinal chemistry and were explained using structure-activity relationship data of the drugs involved in the case easily obtained from primary literature and in medicinal chemistry textbooks. Summary. This paper demonstrates how critical clinical decisions can be addressed using medicinal chemistry knowledge. While such knowledge may not explain all clinical decisions, medicinal chemistry concepts are essential for the education of pharmacy students to explain drug action in general and clinical decisions.

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Intraocular penetration and systemic absorption after topical application of dexamethasone disodium phosphate

Cited by 134 publications

References 11 publications

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

Topical Glucocorticoid Therapy Directly Induces Up-Regulation of Functional CXCR4 on Primed T Lymphocytes in the Aqueous Humor of Patients with Uveitis

The Importance of Medicinal Chemistry Knowledge in the Clinical Pharmacist’s Education

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