Effect of topical 0.05% cyclosporine A on corneal endothelium in patients with dry eye disease

· AIM: To determine the effect of topical 0.05% cyclosporine A (CsA) on corneal endothelium in patients with dry eye disease. · METHODS: Observational, prospective, case series study. Fifty-five eyes of 29 consecutive patients (9 males and 20 females; median age: 66.8 years, interquartile range: 61 -73.2 years) with moderate -severe dry eye disease were evaluated. All patients were treated with topical 0.05% CsA ophthalmic emulsion twice a day in addition to lubricant eyedrops 5 times a day. The follow- up period was 12 months. Before treatment and at 3 and 12 months post -treatment central corneal specular microscopy was performed. The endothelial cell density (ECD), coefficient of variation of cell size (CoV), and percentage of hexagonal cells (Hex %) were analyzed. ·RESULTS: The median ECDs pre-treatment and at 3 and 12 months post-treatment were 2 352.5/mm 2 (inter- quartile range, 2 178 -2548.5), 2 364/mm 2 (interquartile range, 2 174.25 -2 657.5), and 2 366 cells/mm 2 (inter - quartile range, 2 174.75-2 539.75), respectively (P=0.927, one way ANOVA). The median CoVs pre-treatment and at 3 and 12 months post -treatment were 34.5 (interquartile range, 30 -37), 35 (interquartile range, 30 -38), and 34 (interquartile range, 30.75-38.25), respectively (P=0.7193, one way ANOVA). The median Hex % values pre - treatment and at 3 and 12 months post -treatment were 53 (interquartile range, 47 -58), 54 (interquartile range, 45.75 -59), and 50.5 (interquartile range, 45.75 -58), respectively (P=0.824, one way ANOVA). · CONCLUSION: Treatment of patients with dry eye disease for 12 months with topical 0.05% CsA does not seem to cause substantial changes on corneal endothelium.

Treatment of ocular rosacea: comparative study of topical cyclosporine and oral doxycycline

AIM: To compare the effectiveness of topical cyclosporine A emulsion with that of oral doxycycline for rosacea associated ocular changes and dry eye complaints.METHODS: One hundred and ten patients with rosacea were screened. Thirty-eight patients having rosacea associated eyelid and ocular surface changes and dry eye complaints were included in the study. Patients were randomly divided into two groups: nineteen patients were given topical cyclosporine twice daily and nineteen patients were given oral doxycycline 100 mg twice daily for the first month and once daily for the following two months. Symptom and sign scores, ocular surface disease index questionnarie and tear function tests were evaluated at baseline and monthly for 3mo. Three months after results were compared with that of baseline.RESULTS: Mean values of symptom, eyelid sign and corneal/conjunctival sign scores of each treatment group at baseline and 3mo after treatments were compared and both drugs were found to be effective on rosacea associated ocular changes(P 【0.001). Cyclosporine was more effective in symptomatic relief and in the treatment of eyelid signs(P =0.01). There was statistically significant increase in the mean Schirmer score with anesthesia and tear break up time scores in the cyclosporine treatment group compared to the doxycycline treatment group(P 【0.05).CONCLUSION: Cyclosporine as a topical drug can be used in the treatment of rosacea associated ocular complications because it is more effective than doxycycline. In addition ocular rosacea as a chronic disease requires long term treatment and doxycycline has various side effects limiting its long term usage.

Effect of topical 0.05% cyclosporine A on the tear protein lacritin in a rat model of dry eye

AIM: To observe the effect of topical 0.05% cyclosporine A(CsA) on the ocular surface and tear protein lacritin in a botulinum B-induced dry eye rat model. METHODS: A total of 36 female SD rats were randomly divided into 3 groups, botulinum B was injected into the right lacrimal gland of all rats. Group A and group B were treated with 0.05% CsA and 0.1% sodium hyaluronate, respectively, 3 times daily. The control group was not treated. Basal tear flow, corneal epithelial defects, and lacritin levels were measured. RESULTS: Tear secretion in all rats was reduced on day 3 and was even lower on day 7 postoperation(P<0.05). Tear secretion in group A increased by day 14 and was at the preoperative level on day 42. Tear secretion in group B and control rats was lower on days 14 and 42 compared with preoperative level(P<0.05). Corneal fluorescein staining in group A was higher on day 3, peaked on day 7, and then decreased gradually from day 7 until day 14, returning to normal by day 42 post-procedure. However, in group B, corneal fluorescein staining had improved, but was not fully recovered by day 42. Corneal fluorescein staining was more intense than before the operation and then in the control group at all time points. Tear protein lacritin levels reached the lowest levels on day 7 in all groups. In group A, tear protein lacritin levels began to increase on day 14 and were normal on day 42. In group B, tear protein lacritin levels began to increase on day 14, but had not completely recovered on day 42. In the control group, tear protein lacritin levels remained low post-procedure. CONCLUSION: CsA 0.05% prompts tear protein lacritin expression in a rat model of dry eye and improves the signs and symptoms of dry eye disease.

Application of sustained delivery microsphere of cyclosporine A for preventing posterior capsular opacification in rabbits

AIM:To explore the inhibitory effect of a sustained cyclosporin A (CsA) delivery microsphere (CsA-MS) on posterior capsular opacification (PCO) in rabbit eyes after cataract extraction. ·METHODS:Twenty New Zealand white rabbits accepted cataract extraction plus intraocular lens implantation and their left eyes were intraoperatively injected CsA-MS prepared using polymer polylactioglycolic acid (PLGA) as a carrier and their right eyes were injected with empty MS. The changes in cornea, anterior chamber reaction, intraocular pressure, PCO and CsA concentration in aqueous humor were examined postoperatively and all the eyes were enucleated 3 months after surgery for histopathological and morphological examination with light microscopy and electron microscopy. · RESULTS:Conjunctival hyperemia, corneal edema, intraocular pressure and anterior chamber response of experimental and control eyes were similar, while PCO in CsA MS injected eyes was greatly improved compared with that in control eyes. Posterior capsules in CsA-MS injected eyes were smooth and lens epithelial cells (LEC) did not proliferate significantly (P 】0.05), while LEC in posterior capsule of control eyes had different degrees of proliferation and cortical regeneration. LEC in CsA-MS injected eyes were not functionally active and underwent apoptosis, whereas LEC in control eyes were functionally active (F-test, P =0.025). In addition, the cornealultrastructure showed no differences between CsA-MS and MS injected eyes. CONCLUSION:CsA-MS has high bioavailability in rabbit eyes and could inhibit postoperative PCO occurrence and development during the study period, suggesting that CsA-MS may be a promising, effective and safe administration route to prevent PCO in clinic.

Azathioprine is essential following cyclosporine for patients with steroid-refractory ulcerative colitis

AIM: To evaluate long-term prognosis following cyclosporine treatment by examining the rate of surgery avoidance among cyclosporine responders.METHODS: We retrospectively reviewed clinical records for 29 patients diagnosed with severe steroid-refractory ulcerative colitis in our hospital from August 1997 to August 2008 and treated with cyclosporine by continuous intravenous infusion.All patients were treated with intravenous corticosteroids for more than 5 d prior to cyclosporine therapy.Administration was continued for up to 21 d under serum monitoring to maintain cyclosporine levels between 400 and 600 ng/mL.Clinical activity was assessed before and after cyclosporine therapy using the clinical activity index score,with a reduction of ≥ 5 considered to indicate a response.Among responders,we defined cases not requiring surgery for more than 5 years as exhibiting long-term efficacy of cyclosporine.Factors considered to be possibly predictive of long-term efficacy of cyclosporine were sex,age,disease duration,clinical activity index score,C-reactive protein level,hemoglobin level,disease extent,endoscopic findings,and clinical course.RESULTS: Cyclosporine was not discontinued due to side effects in any patient.Nineteen(65.5%) of 29 patients were considered responders.A statistically significant(P = 0.004) inverseas sociation wa s observed between an endoscopic finding of "mucosal bleeding" and responsive cases.Fifteen(9 males,6 females) of these 19 patients were followed for 5 years or more,of whom 9(60%) exhibited long-termefficacy of cyclosporine.Of the 10 non-responders,9(90%) underwent surgery within 6 mo of cyclosporine therapy.None of the following factors had a significant impact on the long-term efficacy of cyclosporine: sex,age,duration of disease,clinical activity index score,C-reactive protein level,hemoglobin level,extent of disease,endoscopic findings,or clinical course.In contrast,a significant association was observed for maintenance therapy with azathioprine after cyclosporine therapy(P = 0.0014).CONCLUSION: Maintenance therapy with azathioprine might improve the long-term efficacy of continuously infused cyclosporine for severe steroid-refractory ulcerative colitis patients.

Inhibitory effect of cyclosporine A on hepatitis B virus replication in vitro and its possible mechanisms

BACKGROUND: Hepatitis B related end-stage liver disease is recently acknowledged as one of the main indications for orthotopic liver transplantation (OLT). However, the high recurrence rate of hepatitis B virus infection following transplantation is regarded as a major factor affecting the long-term survival of transplant recipients especially in Chi- na. Cyclosporine A (CsA), which is routinely used to pre- vent the allograft rejection, is reported to have the inhibito- ry activity on hepatitis B virus (HBV) replication in vitro. In this paper, we review the inhibitory effect and its possi- ble mechanisms of CsA on HBV replication in vitro. DATA RESOURCES: An English-language literature search was conducted using MEDLINE (1990-2004) on cyclospo- rine A, hepatitis B virus, mitochondria, calcium and other related reports and review articles. RESULTS: Hepatitis B x protein (HBx) is essential to HBV replication. The cytosolic calcium signaling mediated by mitochondria and the Src kinase pathway were involved during HBx activation of HBV replication. CsA inhibits the HBV replication in vitro by its binding to mitochondrial cy- clophilin D, then blocking the mitochondria-mediated cy- tosolic calcium signaling. The derivates of CsA also have the HBV replication inhibitory effect in vitro. CONCLUSIONS; By interacting with mitochondria, pre- venting the release of intramitochondrial calcium, and then blocking the cytosolic calcium signaling, CsA inhibits the HBV replication in vitro. The derivates of CsA also have this activity.

The effects of diltiazem in renal transplantation patients treated with cyclosporine A

Objective： To investigate the effects of diltiazem and cyclosporine A （CsA） combination therapy on protecting the kidney, promoting graft functioning and improving post-transplanted kidney recovery. Methods： The blood con- centrations of CsA, the condition of the post-transplant kidney, the rate of acute rejection （AR）, as well as hepatic and renal toxicity in 636 cases of renal transplant recipients were determined after being treated by CsA, with or without diltiazem. Results： Compared with the control group which received CsA, mycophenolate mofetil （MMF） and prednisolone （Pred） but lacked diltiazem, the group receiving these agents together with diltiazem required reduced dosage of CsA （P 〈 0.01）, while blood concentrations of CsA were significantly increased （P 〈 0.01）; the recovery time of graft function was reduced from （6.2± 1.5） d to （3.9± 1.4） d （P 〈 0.01）, and the rate of AR was decreased from 13.2% to 7.9% （P 〈 0.01）. Conclusion： In renal transplantation patients treated with CsA and diltiazem, blood concentrations of CsA were increased while the dosage was decreased. This efficient combination therapy reduced patients economic burden, at the same time retained kidney function, promoted graft function recovery and decreased hepatic and renal toxicity and the rate of AR.

Combining cytochrome P-450 3A4 modulators and cyclosporine or everolimus in transplantation is successful

AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors(CNI) alone or combined with everolimus. METHODS: This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one(n = 59) received everolimus(target blood level, 3-8 ng/m L) and the other(n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl(MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4(CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/m L in 2 mo, and 50-65 ng/m L thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/m L until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators.RESULTS: The clinical characteristics of these two cohorts were similar. During the follow up(66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group(20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate thanthe other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses. CONCLUSION: Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.

Clinical efficacy of combined topical 0.05%cyclosporine A and 0.1%sodium hyaluronate in the dry eyes with meibomian gland dysfunction

AIM： To investigate the efficacy of combined topical 0.05% cyclosporine A（CsA; Restasis~？, Allergan pharmaceuticals, USA） and 0.1% sodium hyaluronate treatment in dry eyes with meibomian gland dysfunction（MGD）.METHODS： In a retrospective analysis, 53 patients（106 eyes） with MGD were enrolled and performed lid warm massage for 10 min daily and be instilled preservative free sodium hyaluronate 0.1% eye drops 4 times daily. Patients were divided into subjects treated with topical 0.05% CsA and preservative free sodium hyaluronate vehicle（experimental group, n=74 eyes） and subjects treated with the preservative free sodium hyaluronate vehicle（control group, n=32 eyes）. They were evaluated at baseline and 1, 2, and 3 mo for subjective symptoms and objective signs including tear film break-up time（t BUT）, Schirmer test, corneal staining（CS） score, lid margin telangiectasia（LMT）, meibomian gland secretion（MGS）, and conjunctival injection（CI）.RESULTS： In the short-term treatment, the experimental group showed a statistically significant improvement in the ocular surface disease index（OSDI; P〈0.001）, tBUT（P=0.004）, Schirmer test score（P=0.008） and LMT（P=0.021） by repeated measure ANOVA. Additionally, mean changes from baseline in OSDI（P〈0.001）, tBUT（P=0.001）, Schirmer test score（P=0.029）, CS score（P=0.047）, LMT（P=0.002）, CI（P=0.030） were improved better in the experimental group than in the control group at 3 mo. However, there was no significant difference between the two groups in MGS（P=0.67）.CONCLUSION： In dry eyes with MGD, 0.05% CsA improves the tear film stability as well as subjective ocular discomfort, and is effective in controlling lid margin inflammation.

Cyclosporine A stimulated hair growth from mouse vibrissae follicles in an organ culture model

Hypertrichosis is one of the most common side effects of systemic cyclosporine A therapy.It has been previously shown that cyclosporine A induces anagen and inhibits catagen development in mice.In the present study,to explore the mechanisms of cyclosporine A,we investigated the effects of cyclosporine A on hair shaft elongation,hair follicle cell proliferation,apoptosis,and mRNA expression of selected growth factors using an organ culture model of mouse vibrissae.In this model,cyclosporine A stimulated hair growth of normal mouse vibrissae follicles by inhibiting catagen-like development and promoting matrix cell proliferation.In addition,cyclosporine A caused an increase in the expression of vascular endothelial growth factor（VEGF）,hepatocyte growth factor（HGF）,and nerve growth factor（NGF）,and inhibited follistatin expression.Our findings provide an explanation for the clinically observed effects of cyclosporine A on hair growth.The mouse vibrissae organ culture offers an attractive model for identifying factors involved in the modulation of hair growth.

Tacrolimus confers lower acute rejection rates and better renal allograft survival compared to cyclosporine

AIM To compare the impact of tacrolimus(FK) and cyclosporine(CYA) on acute rejection and graft survival and to assess the predominant causes of graft loss between patients receiving these two calcineurin inhibitors(CNIs).METHODS Retrospective review of 1835 patients who received a kidney transplant(KTX) between 1999-2012. Patients were grouped based on initial CNI utilized: 1195 in FK group, 640 in CYA group. Data on baseline characteristics, clinical outcomes, and causes of graft loss in both groups were analyzed. RESULTS Cumulative acute rejection rates were 14% in the FK vs 24% in the CYA group. Despite more marginal donor characteristics in the FK group, these patients had better graft survival rates compared to the CYA group. Three and five year graft survival rates were 88% and 84% respectively in the FK group compared to 79% and 70% respectively in the CYA group(P < 0.001). After multivariate analysis, which controlled for confounders, FK use was a strong predictor for lower acute rejectionrates [odds ratio(OR) 0.60, 95%CI: 0.45-0.79] and better renal allograft survival(OR 0.740, 95%CI: 0.58-0.94). Death with a functioning graft was the most common cause of graft loss in both groups. Common causes of death included cardiovascular disease, infections, and malignancies. Chronic allograft nephropathy was also found to be an important cause of graft loss, being more prevalent in the CYA group. CONCLUSION The use of FK-based maintenance immunosuppression therapy is associated with a significantly lower rate of acute rejection and better graft survival compared to CYA-based regimen. Individualizing immunosuppression through risk-stratified CNI choice may lead to improved outcomes across all spectra of KTX patients.

Higher plasma bilirubin predicts veno-occlusive disease in early childhood undergoing hematopoietic stem cell transplantation with cyclosporine

AIM: To analyze the association between plasma bilirubin levels and veno-occlusive disease(VOD) in non-adult patients undergoing hematopoietic stem cell transplantation(HSCT) during cyclosporine therapy.METHODS: A total of 123 patients taking cyclosporinewere evaluated using an electronic medical system at the Seoul National University Children's Hospital from the years 2004 through 2011. Patients were grouped by age and analyzed for incidence and type of adverse drug reactions(ADRs) including VOD. RESULTS: The HSCT patients were divided into three age groups: G#1 ≥ 18; 9 ≤ G#2 ≤ 17; and G#3 ≤ 8 years of age). The majority of transplant donor types were cord blood transplantations. Most prevalent ADRs represented acute graft-vs-host disease(a GVHD) and VOD. Although the incidences of a GVHD did not vary among the groups, the higher frequency ratios of VOD in G#3 suggested that an age of 8 or younger is a risk factor for developing VOD in HSCT patients. After cyclosporine therapy, the trough plasma concentrations of cyclosporine were lower in G#3 than in G#1, indicative of its increased clearance. Moreover, in G#3 only, a maximal total bilirubin level(BILmax) of ≥ 1.4 mg/d L correlated with VOD incidence after cyclosporine therapy. CONCLUSION: HSCT patients 8 years of age or younger are more at risk for developing VOD, diagnosed as hyperbilirubinemia, tender hepatomegaly, and ascites/weight gain after cyclosporine therapy, which may be represented by a criterion of plasma BILmax being ≥ 1.4 mg/d L, suggestive of more sensitive VOD indication in this age group.

Effect of 0.05% topical cyclosporine for the treatment of symptomatic subepithelial infiltrates due to adenoviral keratoconjunctivitis

Dear Sir,Iam Yonca A.Akova,MD-from the Department of Ophthalmology,Bayindir Kavaklidere Hospital,Turkey.I wrote this letter to evaluate the efficacy of 0.05%topical cyclosporine A（CsA）eye drops（Restasis Allergan,Irvine,USA）in symptomatic patients with recurrent subepithelial infiltrates（SEIs）due to adenoviral keratoconjunctivitis following steroid eye drops tapering or discontinuation.

Cyclosporine-Associated Nephrotoxicity

Cyclosporine (CsA) has revolutionized transplant medicine and is currently one of the most important immunosuppressive agents for a wide range of organ transplantations and of autoimmune and inflammatory diseases, such as rheumatoid arthritis, uveitis, psoriasis, and atopic dermatitis. Renal impairment represents the main limitation to CsA long-term continuous therapy. However, it has been shown that nephrotoxicity is associated with longer treatment duration, larger cumulative doses and higher daily dose of CsA. With low dose regimens (<5 mg/kg/day), stable serum creatinine levels have been observed up to 15-20 years after kidney transplantation. Intermittent therapy may offer a good therapeutic strategy to limit long-term renal dysfunction, given the fact that renal structural changes are dose- and time-dependent. The best predictor of permanent renal damage is a persistent increase in serum creatinine level one month after treatment withdrawal. In patients with autoimmune diseases, the percentage increase in serum creatinine above baseline value during CsA therapy has been shown to predict CsA-induced nephropathy. Before CsA therapy initiation, patients should undergo a thorough baseline evaluation including laboratory assessments, in particular electrolytes, serum creatinine, and urea levels. Furthermore, patients should be evaluated for factors that might increase the risk of nephrotoxicity, such as obesity, older age, hypertension, concomitant use of nephrotoxic drugs, and pre-existing renal conditions. In the present paper, CsA-induced nephropathy will be reviewed in terms of pathophysiology, pathologic and clinical findings, and strategies for prevention and management.

Development of self-micellizing solid dispersion system employing amphipathic copolymer for the improvement of dissolution and oral bioavailability of cyclosporine A

The main objective of the present study is to develop a selfmicellizing solid dispersion(SMSD)system of cyclosporine A(CsA)using an amphiphilic copolymer,poly[MPC-co-BMA](pMB)to improve the biopharmaceutical properties of CsA(Fig.1A).Unlike conventional carrier compounds,pMB would perform the bifunctional ability as both polymeric carrier of solid dispersion system and solubilizer derived from a high micellizing property,which could be considered beneficial for the production of highly water soluble formulation of poorly water soluble compound[1].Improvement in the aqueous solubility has been believed to be a key consideration for acquiring potent pharmacological effects of BCS class II drug like CsA.

Angiotensin Ⅱ stimulates expression of transcription factors c-Jun and c-Fos in cyclosporine induced human gingival fibroblasts

The present study demonstrates that the expression of c-Jun and c-Fos are elevated in gingival fibroblast cells treated with angiotensin Ⅱ and cyclosporine.The healthy human gingival tissues were collected and gingival fibroblasts were isolated and cultured.We used RT-PCR and Western blot analysis to identify the expression of c-Jun and c-Fos in cyclosporine and angiotensin II treated human gingival fibroblast cells.We found that angiotensin Ⅱ in combination with cyclosporine induces c-Jun and c-Fos expressions significantly;however,the angiotensin Ⅱ antagonist losartan inhibits the expression of c-Jun and c-Fos(p<0.01).The data suggest that angiotensin Ⅱ in combination with cyclosporine modulates the expression of c-Jun and c-Fos in human gingival fibroblast cells.

Effects of Cyclosporine A on Angiotensin Ⅱ-induced Cardiomyocyte Hypertrophy in Neonatal Rats

Summary： The effects of cyclosporine A （CsA） on Angiontensin Ⅱ （Ang Ⅱ ）-induced protein contents, c los protein levels and cytosolic Ca^2＋ level （[Ca^2＋]i） in cultured eardiomyocytes of neonatal rats were observed. Total protein contents were determined by Bradford method. The expression of c-fos protein was detected by Western blot. （[Ca^2＋]i） labeled with fluorescent probe Fluo-3/AM was measured under a laser scanning confoeal microscope. The results revealed that as compared with control, the total protein contents were increased in cardiomyocytes treated with Ang Ⅱ （10-1 mol/ L）, which could be inhibited by CsA in a dose-dependent manner. It was found that Ang Ⅱ could increase the c-los protein expression, which could be inhibited by CsA in a dose-dependent manner. Ang Ⅱ induced the [Ca^2＋]i elevation in cardiomyocytes. CsA did not influence the resting intracellular Ca^2＋ , but inhibited significantly the Ang Ⅱ-induced [Ca^2＋]i elevation. It was concluded that CsA can suppress the Ang Ⅱ-induced c-fos protein expression and [Ca^2＋]i elevation in single cardiomyocyte, which might play a role in the prevention of Ang Ⅱ-induced cardiomyocyte hypertrophy by CsA.

Cyclosporine Inhibits Apoptosis in Experimental Murine Xerophthalamia Conjunctival Epithelium

Summary： This study examined the inhibitory effect of topical cyclosporine （CsA） treatment on conjunctiva epithelial apoptosis in a murine model of xerophthalamia. Dry eye was induced in 3 groups of C57BL6 mice by subcutaneous injection of scopolamine （t.i.d） and exposure to an air draft and low-humidity environment for 16 h each day for 12 days. The dry eye control group received no topical treatment; another group received 1 μL of 0.05 % CsA topically （t.i.d, dry eye＋CsA）; and the third group received 1 μL of the castor oil vehicle of CsA topically （t.i.d, dry eye ＋ vehicle）. Normal mice were used as untreated controls. Twelve days later, the mice were killed, and their conjunctivas were excised. The number of the conjunctival goblet cells was counted in tissue sections stained with periodic acid Schiff （PAS） reagent. Their conjunctiva epithelium had been investigated by immuno-histochemical staining to detect the goblet cells and the expression of Caspase-3, Bax and bcl-2 Our results showed that compared with dry eye control and dry eye mice ＋ vehicle groups, the number of conjunctival epithelial goblet cells was significantly greater in the untreated controls and dry eye mice receiving CsA （P 〈 0.01 for both groups）. There was no significant difference in the number of conjunctival epithelial goblet cells between the dry eye control and dry eye＋vehicle group. It was also true of the number of conjunctival epithelial goblet cells when comparison was made between the normal group and the dry eye＋CsA group. Expressions of Caspas-3 and Bax were increased and ex-pression of bcl-2 was decreased in conjunctival epithelial cells in dry eye control and dry eye mice＋vehicle groups. There was a significant positive correlation between goblet cell number and the number of cells that expressed bcl-2, and a negative correlation between goblet cells and Caspase-3 and Bax expression. It is concluded that the topical use of CsA could significantly reduce conjuncti-val epithelial apoptosis and protect goblet cell against the loss in experimental murine xerophathala-mia. Inhibition of apoptosis appears to be a key mechanism responsible for the therapeutic effect of CsA on xerophthalamia.

Gingival enlargement induced by cyclosporine in Medullary aplasia:A case report

BACKGROUND Cyclosporine is an immunosuppressive agent used effectively for treatment of a rare haematological disorder known as medullary aplasia.This drug prevents several side effects,including gingival enlargement(GE)which compromises aesthetics,phonetics and chewing,and also predisposes patients to periodontitis.CASE SUMMARY This clinical case reports a 41-year-old woman who presented with cyclosporineinduced GE with underlying periodontitis and medullary aplasia.The management of the disease was approached through multidisciplinary strategy which allowed for accurate diagnosis and a strategic treatment based on the systemic condition and severity of oral pathology.The diagnosis was confirmed through histopathological analysis.The treatment was carried out in phases:Initial(oral hygiene motivation,mechanical supragingival plaque control,and non-surgical therapy);systemic treatment,corrective treatment,and maintenance.CONCLUSION Multidisciplinary management of cyclosporine-induced GE and medullary aplasia allows for correct diagnosis and effective treatment of this pathological expression through a phased therapeutic approach.

Clinical efficacy of 0.05%cyclosporine nano-emulsion in the treatment of dry eye syndrome associated with meibomian gland dysfunction

AIM:To evaluate the clinical efficacy of topical 0.05%cyclosporine nano-emulsion in the treatment of dry eye syndrome(DES)with meibomian gland dysfunction(MGD).METHODS:This prospective study included 64 patients with DES and MGD who were randomly assigned to three groups:Group 1(n=24,conventional cyclosporine),Group 2(n=21,nano-emulsion cyclosporine),and Group 3(n=19,control).Lid margin telangiectasia(LMT),meibomian gland secretion(MGS),conjunctival injection(CI),corneal staining(CS),tear break-up time(TBUT),Schirmer test I(STI),Ocular Surface Disease Index(OSDI),and lipid layer thickness(LLT)was evaluated at 4,8,and 12wk of treatment.RESULTS:In Group 3(control),LMT,CS,and CI improved after 8wk,MGS,TBUT after 12wk of treatment.In Group 1(conventional cyclosporine),LMT,MGS,and TBUT improved significantly after 4wk,whereas CS,CI,STI,and LLT improved significantly after 8wk,and OSDI at 12wk.In Group 2(nano-cyclosporine),LMT,MGS,CS,CI,TBUT,and OSDI significantly improved after 4wk,and STI after 8wk.Especially,LLT was significantly higher than other groups after 4wk.CONCLUSION:Cyclosporine and nano-cyclosporine shows significant improvement in DES with MGD than the control group.In contrast,the nano-cyclosporine group shows more statistically improved CI and CS at 4wk,especially LLT at 4,8,and 12wk compared to the conventional cyclosporine group.