Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

4. Treatment

As with any atopic condition, avoidance of allergens is important. Often this is difficult for VKC patients, because of the possible large number of antigens to which they react. Seasonal removal of affected children from their home to a reduced allergen climate is usually not practical for most families. Hyposensitization in VKC has limitations. It is not feasible to desensitize these children to all of the allergens to which they are responsive. Moreover, some suggest that while skin and lung are responsive to hyposensitization, the conjunctiva is not (Bielory, 2000).

For the patient with a significant seasonal exacerbation, a short-term, high dose pulse regimen of topical steroids is necessary. Usually, dexamethasone 0.1% or prednisolone phosphate 1% 8 times daily for 1 week brings excellent relief of symptoms. This should be tapered rapidly to as little as is needed to maintain patient comfort. As in any chronic ocular inflammatory disease, the risks of prolonged use of corticosteroids are cataract and glaucoma. Therefore, any limited use of steroids should include additional measures to sustain a decreased state of inflammation. Cromolyn sodium has repeatedly been shown to be effective in VKC (El Hennawi, 1980; Foster and Duncan, 1980; Tabbara and Arafat, 1977). At the time of an exacerbation, the patient should be given a steroid pulse dose as outlined earlier and begin taking cromolyn

or a dual acting drug such as olopatadine, ketotifen, azelastine, or epinastine concurrently to begin mast cell stablization and antihistamine treatment. Other drugs that have undergone clinical trials for VKC are variously available and listed in Table 11.2.

Oral medications that have a variable role include steroids, antihistamines, and nonsteroidal anti-inflammatory agent. For the care of severe, bilateral, vision-threatening disease, oral steroids may be used, but using this treatment for VKC alone is unusual. Maximizing the use of non-sedating antihistamines is often helpful. Oral leukotriene inhibitors taken for asthma also reduced symptoms of VKC (Lambiase et al., 2003). Oralaspirinhasbeeneffective,oftenrequiring a dose as high as 2400mg daily (Chaudhary, 1990; Anwar, 2003; Sankarkumar et al., 1992; Srinivas, 1989; Lemrini et al., 1989; Meyer et al., 1987; Abelson et al., 1983).

Topical cyclosporin A (CSA) may show promise in the treatment of VKC. The release of interleukin-2 is diminished with CSA, thus reducing the expansion of certain T-cell clones. Several studies have demonstrated the effectiveness of CSA in VKC (Tomida et al., 2002; Pucci et al., 2002; Gupta and Sahu, 2001; Avunduk et al., 2001; Mendicute et al., 1997; Secchi et al., 1990; Holland et al., 1993; BenEzra et al., 1986). Akpek et al. (2000) has shown that low dose topical mitomycin C can effectively treat VKC that is refractory to steroid treatment.

The corneal shield ulcer is a visionthreatening complication of VKC. Treatment may include antibiotic-steroid ointment and occlusive therapy. If a plaque forms in the ulcer bed, a superficial keratectomy is sometimes beneficial in promoting epithelial healing (Jones, 1961; Cameron, 1995). Recently, phototherapeutic keratectomy (Autrata et al., 2002) and keratectomy with amniotic membrane graft placement have been shown effective (Sridhar et al., 2001; Rouher et al., 2004).

Climatotherapy may be beneficial. This may involve simple measures, such as cool compresses over the closed lids. Maintenance of an air-conditioned environment or relocation to a cool, dry climate is most helpful during seasonal exacerbations. The economic and geographic restrictions of these measures are obvious.

Surgical procedures may have a role, alone or in combination with medical treatment. Cryoablation of upper tarsal cobblestones is reported to render short-term

improvement. However, scar formation from this may lead to lid and tear film abnormalities. Surgical removal of the upper tarsal papilla, in combination with forniceal conjunctival advancement or buccal mucosal grafting, may result in obliteration of the fornix (Beigelman, 1950; Nishiwaki-Dantas et al., 2000). Injection of shortor long-acting steroids into the tarsal papilla has been shown effective at reducing their size (Saini et al., 1999; Sethi et al., 2002; Holsclaw et al., 1996). Excision of papillary changes, combined with injection of steroids, and topical treatment post-operatively with cromolyn sodium and CSA, was found effective in treatment of recalcitrant disease (Fujishima et al., 2000). Excision of papilla and intra-operative treatment with mitomyocin C proved better than excision alone (Tanaka et al., 2004).

The therapy of the future will be directed toward immunomodulation of the cellmediated response and diminishing mast cell and local leukocyte numbers.

C. Atopic Keratoconjunctivitis

AKC is a bilateral, chronic inflammation of the conjunctiva and lids associated with atopic dermatitis. Hogan, in 1953, was the first to describe the findings of chronic conjunctivitis and keratitis in patients with atopic dermatitis. Three to 9% of the population has atopic dermatitis (Nnoruka, 2004; Garrity and Liesegang, 1984; Rich and Hanifin, 1985). From 15 to 67.5% of patients with atopic dermatitis have ocular involvement, usually AKC (Garrity and Liesegang, 1984; Rich and Hanifin, 1985; Dogru et al., 1999).

The onset of disease is usually in the second through fifth decade. Series of patients report the onset of symptoms between the ages of 7 and 76 (Tuft et al., 1991; Foster and Calonge, 1990; Power et al., 1998). The male/female ratio is reported as

2.4:1 (Tuft et al., 1991) and fewer than 1:1 (Foster and Calonge, 1990). No racial or geographic predilection is reported.

1. Clinical parameters

Itching is the major symptom of AKC. This may be more pronounced in certain seasons or it may be perennial. Other symptoms, in decreasing order of frequency, include watering, mucous discharge, redness, blurring of vision, photophobia, and pain. Exacerbation of symptoms most frequently occurs in the presence of animals (Tuft et al., 1991).

Signs of AKC include skin, lid margin, conjunctival, corneal, and lens changes (Table 11.3). The periocular skin often shows a scaling, flaking dermatitis with a reddened base (Figure 11.6). The lids may become

lichenified and woody, developing cicatricial ectropion and lagophthalmos. Lateral canthal ulceration, cracking, and madarosis may also be present. This may be the principal manifestation in a minority of cases. The lid margins may show loss of cilia, meibomianitis, keratinization, and punctal ectropion. The conjunctiva of the tarsal surfaces has a papillary reaction, follicles, and possibly a pale white edema (Figure 11.7). In contrast to VKC, the papillary hypertrophy of AKC is more prominent in the inferior conjunctival fornix. Subepithelial fibrosis is present in many, fornix foreshortening in some, and symblepharon in a few. The bulbar conjunctiva may have few findings besides erythema and chemosis. A perilimbal, gelatinous hyperplasia may occur (Figure 11.8). Horner–Trantas dots have been reported to occur in AKC (Friedlaender, 1979).

Significant vision loss in this disease usually results from pathologic conditions of the cornea. Punctate epithelial keratopathy is the most common corneal finding. Persistent epithelial defects, scarring, microbial ulceration, and neovascularization are the main corneal causes for decreased vision (Table 11.3). Penetrating keratoplasty typically results in similar surface problems, but has been shown to improve vision in some (Ghoraishi et al., 1995). Herpetic keratitis is reported to occur in 14 to 17.8% of patients. Keratoconus occurs in 6.7 to 16.2% of patients (Tuft et al., 1991; Foster and Calonge, 1990).

Anterior uveitis and iris abnormalities are not reported. The prevalence of cataract associated with AKC is difficult to determine, since steroids are so frequently used in the treatment of the disease. The lens

opacity typically associated with AKC, however, is an anterior or posterior subcapsular cataract. This cataract often has the configuration of a Maltese cross. Retinal detachment, with or without previous cataract surgery, is the principal posterior manifestation of AKC reported (Hurlbut and Damonkos, 1961; Klemens, 1966; Yoneda et al., 1995).

2. Pathophysiology

AKC is thought to consist of both Type I and Type IV hypersensitivity mechanisms. Evidence of the pathologic process comes from histologic and immunohistochemical analysis of conjunctival biopsy specimens, and from tear fluid analysis for mediators and cells.

Mast cells and eosinophils are found in the conjunctival epithelium of AKC patients, but not in normal individuals. Mast cells in the epithelium of AKC patients contain predominantly tryptase as the neutral protease (Baddeley et al., 1995). Goblet cell density and squamous metaplasia are then examined by impression cytology (Dogru et al., 1998). The epithelium may become involuted, allowing pseudotubule structures to form (Foster and Calonge, 1990). Antibodies to HLA-DR stain diffusely throughout the

epithelium (Foster et al., 1991). This suggests an upregulation of antigen presentation. There is an increase in the CD4/CD8 ratio in AKC over normal conjunctival epithelium (Foster et al., 1991). This increase of CD4 or helper T-cells probably serves to amplify the immune response that is occurring.

The substantia propria in AKC has an increased number of mast cells compared to normal. Eosinophils, never found in normal structures, are present in the substantia propria in AKC. These eosinophils are found to have increased numbers of activation markers on their surface (Hingorani et al., 1998a). A large number of mononuclear cells are present in the substantia propria. Fibroblast number is increased, and there is an increased amount of collagen compared to normal individuals. In addition, the substantia propria demonstrates increased CD4/CD8, B-cells, HLA-DR staining, and Langerhans’ cells (Foster et al., 1991). The T-cell receptor on lymphocytes in the substantia propria is predominantly of the α or β subtype (Foster et al., 1991). The T-cell population of the substantia propria includes CD4 and memory cells (Metz et al., 1996). Th2 cytokines predominate in allergic disease, yet lymphocytes with Th1 cytokines have been found in the

substantia propria of AKC patients (Metz et al., 1997).

Tears of AKC patients contain increased levels of IgE, eosinophil cationic protein, T-helper cells, activated B-cells, eotaxin, eosinophil neurotoxin, soluble IL-2 receptor, IL- 4, IL-5, and osteopontin, as well as decreased Schirmers values (56% less than 5mm) (Dogru et al., 1999; Metz et al., 1997; Montan and van Hage-Hamsten, 1996; Avunduk et al., 1998b, 1997; Leonardi et al., 2000a; Uchio et al., 2002; Fukagawa et al., 1999; Uchio et al., 2000). Dysfunctional cellular immune response in AKC patients is demonstrated by reduction or abrogation of the cell-mediated response to Candida and the inability of some patients to become sensitized to dinitrochlorobenzene (Nimmo Wilkie et al., 1991). The serum of AKC patients has been found to contain increased levels of IgE, eosinophil cationic protein, eosinophil neurotoxin, and IL-2 receptor (Tuft et al., 1991; Leonardi et al., 2000a; Geggel, 1994; Akova et al., 1993). A recent study shows eosinophils and their products deposited in the ulcers and stroma of corneas from AKC patients (Messmer et al., 2002).

In summary, AKC patients demonstrate an increased number of conjunctival mast cells and evidence of mast cell activation. Whether mast cell mediator release is an inducing event or a consequence of a generalized inflammatory response is not known. Furthermore, a complex immune cell profile implicates more than the mast cell alone.

3. Diagnosis

Paramount to both diagnosis and treatment in AKC is a careful history. The patient typically describes severe, persistent, periocular itching associated with dermatitis. There is usually a family history of atopic disease in one or both parents, and commonly other atopic manifestations in the patient, such as asthma (65%) or allergic rhinitis (65%) (Power et al., 1998). A history of seasonal or exposure-related exacerbations is usually present. History

and examination reveal features to help differentiate AKC from other atopic ocular conditions. The lack of contact lens wear aids in differentiating AKC from GPC. AKC patients are usually older and have major lid involvement compared to patients with VKC. SAC patients have no, or markedly diminished, symptoms out of their season and show no evidence of chronic inflammation in the conjunctiva. The significant past history or concurrent presence of eczema cannot be emphasized enough as a finding in patients with AKC. The serum level of IgE is often elevated in patients with AKC. A Giemsa stain of a scraping of the upper tarsal conjunctiva may reveal eosinophils.

4. Treatment

The approach to treatment is multifaceted and includes environmental controls, as well as topical and systemic medications. It is unlikely that the AKC patient will see the ophthalmologist without also being under the care of a medical physician. However, the patient must remove environmental irritants in both the home and the employment or school setting. The nature of the irritants may be better defined through skin testing.

The topical application of a vasocon- strictor–antihistamine combination may bring transient relief of symptoms but is unlikely to intervene in the immunopathologic process or its sequelae. Currently available drops include naphazoline hydrochloride and pheniramine maleate or naphazoline hydrochloride and antazoline phosphate. The potent antihistamines levocabastine and emadastine offer much greater H1 receptor antagonism than the other two over-the-counter antihistamines. The topical administration of steroids, such as prednisolone acetate, 8 times per day for 7 to 10 days is clearly beneficial in controlling symptoms and signs. Both steroids and vasoconstrictor–antihistamine combinations must be used judiciously, since the chronic nature of the disease may encourage overuse. The patient must be specifically instructed that steroid use

must be transient only and must be carefully monitored for efficacy; he or she must also be warned of the potential for causing cataract and glaucoma. Steroid sparing medications, including the mast cell stabilizer sodium cromolyn 4%, have been shown to be effective in reducing itching, tearing, and photophobia (Ostler et al., 1977; Jay, 1981). Its use 4 times daily is recommended year-round in patients with perennial symptoms. If an exacerbation occurs and the patient is not taking cromolyn sodium, its use should be initiated 4 times daily concurrent with a short burst of topical steroids (for 7 to 10 days). From 2 to 4 weeks of dosing may be needed before cromolyn sodium becomes effective. Other mast cell stabilizers or combination mast cell stabilizers – antihistamines such as nedocronial, lodoxamide, olopatadine, azelastine, ketotifen, or epinastine – may be helpful. CSA, both orally and topically, has been shown effective at treating AKC, as well as reducing the amount of topical steroid use (Hoang-Xuan et al., 1997; Hingorani et al., 1998b; Akpek et al., 2004). Topical Tacrolimus has been shown effective at reducing signs and symptoms of AKC when applied to the lid margins (Rikkers et al., 2003; Joseph et al., 2005).

Foster and Calonge (1990) recommend maximizing the use of systemic antihistamines. H1 receptors seem most responsible for the symptoms of AKC, and newer antagonists are fairly specific for the H1 receptor. Only in rare cases of uncontrolled dermatitis with vision-threatening complications are oral steroids indicated. The role of systemic desensitization is similar to that in VKC. Plasmapharesis has been shown effective in the treatment of AKC (Aswad et al., 1988; Mach et al., 1992).

Lid and ocular surface abnormalities may require treatment other than that directed toward the underlying pathologic condition of AKC. Trichiasis or lid position abnormalities, if contributing in any way to corneal compromise, must be corrected. Any staphylococcal blepharitis

should receive adequate antibiotic treatment. If, despite adequate control of signs and symptoms of AKC, corneal punctate staining persists, artificial tears should be used to avoid the development of corneal epithelial defects. It may be extremely difficult to achieve re-epithialization in these defects and surgical approaches have been attempted (Thoft, 1984). Lid or ocular surface herpes simplex virus (HSV) infection should be treated with topical antiviral agents. Care should be taken in using these to achieve viral eradication without sustained use and subsequent epithelial toxicity. If frequent recurrent episodes of epithelial HSV keratitis occur, one may consider oral acyclovir (400 mg orally twice daily) as prophylaxis against frequent recurrences.

Interleukin-2 (IL-2) has been used successfully to treat atopic dermatitis, but has not been used specifically for AKC. After treatment with IL-2, the skin biopsy of atopic dermatitis patients shows depletion of the abnormally high number of CD4 cells, but no change in the number of Langerhans’ cells. The decreased CD4 count may result in the abrogation of the exaggerated antigen processing and cellular activation. The effect of IL-2 is short lived, with a return of symptoms 2 to 6 weeks after therapy ceases (Hsieh et al., 1991). In summary, topical steroids will control most patients with AKC. The chronic use of steroids must be avoided and, early in treatment, steroid sparing strategies must be considered.

D. Drug Discovery Considerations

While differences exist among GPC, AKC, and VKC, there are similarities that provide clues particularly relevant to drug discovery. First, these diseases are not solely Type 1 immediate hypersensitivity responses. Investigators have reported positive skin test sensitization to allergens in VKC patients ranging from a low of 19% to 80% (Ballow and Mendelson, 1980; Easty et al., 1980). Bonini et al. (2004) reported that

VKC was not associated with a positive skin test or radio-allergo-sorbent test (RAST) in approximately half of the cases studied. In a series of 195 patients they demonstrated a lack of positive skin test responses and positive RAST responses in 43 and 48% of the patients tested. These investigators also noted that they have never observed a positive RAST assay conducted using tears when there is a negative result using serum, casting doubt upon the possible local production of allergen-specific IgE providing sensitization on the ocular surface in VKC patients. Zhan et al. (2003) have reviewed AKC and report that, in contrast to SAC and PAC, which are IgE-dependent mast cell driven reactions, AKC involves primarily T-lymphocytes. Tears and conjunctival biopsies taken from patients with AKC contain increased numbers of lymphocytes. Activated CD4 T-cells and an increase in the ratio of T-helper/T-suppressor cells have been described (Avunduk et al., 1998b). IL-2 mRNA, as well as IFN-γ has been reported to be significantly upregulated in AKC. These findings suggest that lymphocytes are the dominant cells involved in AKC. Finally, GPC appears to be induced by biological coatings on contact lenses and the trauma contact lenses inflict upon the conjunctiva. GPC has also been reported in patients with ocular prostheses, exposed sutures, filtering blebs, and foreign bodies (Donshik, 2003). A neutrophilic chemotactic factor has been identified in the tears of GPC patients. This material has been collected from conjunctival cells and injected into the tarsal conjunctiva of rabbits. Analysis of the resulting inflammatory cell infiltrate revealed polymorphonuclear leukocytes and plasma cells (Donshik, 1994). Metz and co-workers (1996) used immunohistochemistry to identify T-cell subsets in the conjunctiva of GPC patients. They found significantly increased numbers of CD4 , CD45RO , and HLA-DR T-cells in these patients, consistent with an inflammatory response. Typically, the inflammation resolves upon removal of the offending

object and treatment with classical antiinflammatory medication.

Second, classical anti-inflammatory drugs provide the most effective therapy for these three conditions. When Michael Hogan (1953) first described 5 cases of AKC, he included treatment information and an assessment of efficacy. Two patients were given cortisone via injection. Clinical responses to this therapy were noted as “very satisfactory” with disappearance of skin, corneal, and conjunctival lesions within 4 days of injection. The remaining 3 patients were treated topically with cortisone acetate and improved within days. Within this same report, he noted that one of the patients was treated with antihistaminic drugs without improvement, providing an additional clue regarding pathophysiology and relevant therapeutic targets for AKC. Zhan et al. (2003), 40 years later, wrote that topical steroids are very effective in treating symptoms of AKC and may be necessary to control the inflammatory process. Similarly, in VKC, the most effective therapy for moderate to severe clinical cases is topical corticosteroids (Bonini et al., 2000). Additionally, there are reports in the literature describing beneficial effects of non-steroidal anti-inflamma- tory drugs (NSAIDs) in VKC. Abelson et al. (1983) reported positive effects with aspirin and D’Angelo et al. (2003) reported benefits with diclofenac applied topically. A report by Wood et al. (1988) also claimed beneficial effects of an NSAID in GPC patients. These investigators compared the effect of the NSAID suprofen to placebo in reducing the signs and symptoms of GPC associated with contact lens wear. They reported that sustained use of the NSAID for up to 4 weeks was required to observe improvement. Interestingly, NSAID cyclooxygenase inhibitors do not provide significant benefit in immediate hypersensitivity diseases, suggesting that therapies tailored for VKC and GPC should be directed at non-Type 1 immediate hypersensitivity targets.

1. Pharmacology

AKC and VKC therapies directed at lymphocytes have been used clinically with reported success (Hingorani et al., 1999, 1998b; Secchi et al., 1990; BenEzra et al., 1988; Pucci et al., 2002). The most studied anti-lymphocyte therapy for these indications has been cyclosporine A (CSA). CSA is a cyclic undecapeptide fungal metabolite. Its primary immunological target is the T-lymphocyte. CSA binds to cytosolic proteins of the cyclophilin family and forms a stable complex that associates with calcineurin, a serine-threonine-specific Ca -calmodulin dependent phosphatase (Mascarell and Truffa-Bachi, 2003). Calcineurin dephosphorylates nuclear factor of activated T-cells (NFAT), making it more permeable for nuclear membranes. The dephosphorylated NFAT can then trigger promoters that induce transcription. The binding of CSA–cyclophilin complex to calcineurin inhibits the phosphatase activity of calcineurin, which prevents NFAT from translocating to the nucleus, thereby keeping the IL-2 gene silent (Jorgensen et al., 2003). CSA not only inhibits transcription of the gene encoding for IL-2; it also inhibits the genes encoding for IL-3, IL-4, IL-5, IL-8, IL-13, GM-CSF, and IFNγ (Kiani et al., 2000).

Tacrolimus (FK-506) is another immunosuppressant with activities similar to CSA. Tacrolimus was isolated from

Streptomyces tsukubaensis (Kino et al., 1987) and is a more potent immunosuppressant than CSA (Bertelmann and Pleyer, 2004). This drug also binds to cyclophilin and the complex formed prevents the translocation of NFAT to the nucleus and limits T-lymphocyte activation. The anti-T-cell activity of tacrolimus has led investigators to examine the drug’s effect in ophthalmology on corneal allograft rejection in experimental animals (Okada et al., 1996; Benelli et al., 1996) and patients (Sloper et al., 2001). Positive effects were observed in these tests. An additional study used topical ocular dosing of tacrolimus in a small group of patients with atopic blepharoconjunctivitis.

Patients’ symptoms were reduced on the study medication (Mayer et al., 2001).

Rapamycin is also a cyclic macrolide isolated from Streptomyces hygroscopicus. It possesses significant immunosuppressive activity and has been used successfully in renal transplantation. While rapamycin and FK-506 were isolated from the same genus of microorganisms, their mechanisms of action are distinct. Rapamycin blocks cell proliferation by inhibiting cell cycle progression at the G1 phase to S (Wiederrecht et al., 1995). Intraperitoneal injection has been used to assess the effect of rapamycin in ophthalmic inflammation models (endotoxin-induced uveitis, auto-immune uveitis). Anti-inflam- matory effects were observed (Kulkarni, 1991; Roberge et al., 1993). Topical application of rapamycin has been hampered by the drug’s poor aqueous solubility and instability. An ester of rapamycin has been produced that is converted to an active metabolite, sirolimus, in vivo. Clinical evaluations of this molecule in oncology have been initiated; however, no topical ocular use has been reported (Meric-Bernstam and Mills, 2004).

Inhibition of T- and B-lymphocyte replication has also been demonstrated with the drug mycophenolic acid. The drug inhibits purine synthesis by inhibiting inosine monophosphate dehydrogenase. Lymphocytes are dependent upon this enzyme and pathway for the production of guanosine required for DNA replication (Allison et al., 1991). Non-lymphocytes are able to use other pathways for purine synthesis and thus are not affected by mycophenolic acid. Clinical use of mycophenolate mofetil (MMF), an ester prodrug of mycopeholic acid, in ophthalmology has been reported. Larkin and Lightman (1999) conducted an open label, uncontrolled pilot study in 11 patients with uncontrolled ocular inflammation. Patients received 1 gram of MMF twice a day in addition to steroids. The investigators noted that the addition of MMF to steroid regimens led to an improvement in 10 of the 11 patients with few side effects. Kilmartin et al. (2001)

evaluated the drug in patients with uveitis and assessed the effect of the drug on CD69 T-lymphocytes in peripheral blood. They reported that during MMF therapy, a significant reduction in CD69 T-cells was observed in patients with moderate to severe uveitis. The above studies used high, daily, systemic doses of MMF. To minimize systemic side effects local administration has been considered. Knapp et al. (2003) applied MMF topically in rabbits and assessed intraocular bioavailability. A drop of drug (1%) solution or suspension was instilled onto the eye and samples were collected beginning 30 minutes after dosing. Aqueous humor levels of active mycophenolic acid, 24 μg/mL, were detected. This study suggests topical delivery is possible.

All of the drugs discussed above are candidates for use in VKC, AKC, and even GPC because of their direct anti-lymphocyte effects. Topical delivery has been problematic because of formulation and comfort. Side effects with chronic ocular use have not been fully assessed with the majority of these compounds. CSA has been the most studied of these agents, with reported clinical success in VKC and AKC patients. The incidence of

these conditions is small in comparison to SAC and PAC. Attempts have been made to expand the use of these immunosuppressants in conditions that are classical Type 1 immediate hypersensitivity reactions, based upon reports that CSA inhibited the release of preformed and newly synthesized proinflammatory mediators from mast cells and basophils (Triggiani et al., 1989; Cirillo et al., 1990). However, when the compound has been evaluated using a substantial systemic dose (100mg/kg) in animal models (mice, rats, and guinea pigs) of immediate hypersensitivity, CSA failed to inhibit the allergic responses in the skin or lung resulting from mast cell activation (Geba et al., 1991). Interestingly, in patients treated with CSA for atopic dermatitis, clinical benefit has been observed. However, allergic responses to house dust mites in these same patients were not inhibited (Munro et al., 1991). These in vivo results led Chapman and Mazzoni (1994) to conclude that “cyclosporine A does not suppress acute manifestations of mast cell activation in vivo”.

2. Drug discovery