Epithelial-to-mesenchymal transition, inflammation, subsequent collagen production, and reduced proteinase expression cooperatively contribute to cyclosporin-A-induced gingival overgrowth development.

Drug-induced gingival overgrowth (DIGO), induced by certain immunosuppressive drugs, antihypertensive agents, and antiepileptic drugs, may contribute to the formation of deeper periodontal pockets and intractableness in periodontitis. To date, multiple factors such as enhanced matrix production, inflammation, and reduced matrix degradation might be involved in the pathogenesis of DIGO. We have previously reported that SPOCK-1, a heparan sulfate proteoglycan, could affect gingival thickening by promoting epithelial-to-mesenchymal transition (EMT) in gingival keratinocytes. However, few studies have investigated whether a combination of these factors enhances the DIGO phenotype in animal models. Therefore, we investigated whether SPOCK-1, periodontal inflammation, and cyclosporin-A (CsA) could cooperatively promote gingival overgrowth. We first confirmed that Spock-1 overexpressing (Spock1-Tg) mice showed significantly thicker gingiva and greater alveolar bone loss than WT mice in response to ligature-induced experimental periodontitis. DIGO was induced by the combination of CsA administration and experimental periodontitis was significantly enhanced in Spock1-Tg mice compared to that in WT mice. Ligature-induced alveolar bone loss in CsA-treated Spock1-Tg mice was also significantly greater than that in CsA-treated WT mice, while being accompanied by an increase in Rankl and Col1a1 levels and a reduction in matrix metalloprotease expression. Lastly, SPOCK-1 promoted RANKL-induced osteoclast differentiation in both human peripheral blood mononuclear cells and murine macrophages, while peritoneal macrophages from Spock1-Tg mice showed less TNFα and IL-1ß secretion than WT mice in response to Escherichia coli lipopolysaccharide. These results suggest that EMT, periodontal inflammation, and subsequent enhanced collagen production and reduced proteinase production contribute to CsA-induced DIGO pathogenesis.

Effect of cyclosporine A - tempol topical gel for the treatment of alopecia and anti-inflammatory disorders.

Over the years, extensive research has been carried out to develop new chemical entities for hair loss treatment. Despite these efforts, the newly developed topical and oral treatments have not proven to be curative. Hair loss can result from underlying mechanisms, such as inflammation and apoptosis around hair follicles. We have developed a nanoemulsion based on Pemulen gel for topical application, tentatively addressing both mechanisms. The novel formulation contains two well-known molecules: Cyclosporin A (CsA), an immunosuppressant calcineurin inhibitor, and Tempol, a potent antioxidant. The in vitro permeation study on human skin revealed that the CsA-Tempol gel formulation effectively delivered CsA into the skin's inner target layer, the dermis. The effects of the CsA-Tempol gel on hair regrowth were further demonstrated in the in vivo well-established androgenetic model induced in female C57BL/6 mice. The beneficial outcome was statistically confirmed by quantitative analysis of hair regrowth, measured by color density. The results were further supported by histology analysis. Our findings revealed a topical synergy effect, resulting in lower therapeutic concentrations of both actives unlikely to cause systemic side effects. Overall, our research suggests that the CsA-Tempol gel is a highly promising platform for treating alopecia.

Effectiveness of Topical Cyclosporin-A 0.1% Compared to Combined Topical Cyclosporin-A 0.1% with Topical Sodium Hyaluronate on Interleukin-6 Levels in the Tears of Patients with Dry Eye Disease.

INTRODUCTION: Pro-inflammatory cytokines are important contributors to dry eye disease (DED). The cytokine interleukin (IL)-6 has become a therapeutic target in several DED drug studies. This randomized controlled trial aimed to determine the effectiveness of topical cyclosporin-A 0.1% compared to the combination of topical cyclosporin-A 0.1% and sodium hyaluronate in reducing tear IL-6 levels in DED patients. METHODS: The participants were 20 patients, each with two eyes, who had moderate-to-severe DED. Before and after treatment, the clinical degree of DED was examined in each group, using ocular surface disease index (OSDI) scores, tear break-up time (TBUT), fluorescent tests, and Schirmer I tests. In addition, tear samples were taken to examine IL-6 levels through the ELISA method. The results were analyzed using the t-test, Wilcoxon test, and Mann-Whitney test. The correlation between tear IL-6 levels and the severity of DED was analyzed using the Spearman correlation test. RESULTS: The study showed a significantly lower tear IL-6 level, OSDI score, and degree of ocular staining after either topical cyclosporin-A 0.1% or a combination of topical cyclosporin-A 0.1% and sodium hyaluronate (all values p < 0.05). CONCLUSIONS: The combination therapy was superior in reducing tear IL-6 levels. In addition, a correlation existed between tear IL-6 levels and the severity of DED based on the TBUT, although it was weak and not statistically significant.

Comparison of the inhibitory effect of topical cyclosporine A 0.1% and topical anti-VEGF application in an experimental model of corneal neovascularization / Comparação do efeito inibitório da ciclosporina A 0,1% tópica e aplicação de anti-VEGF tópica em um modelo experimental de neovascularização da córnea

ABSTRACT Purpose: The aim of this study was to compare the effects of topical cyclosporine 0.1% and bevacizumab on experimentally induced corneal neovascularization in a rat model. Methods: A total of 30 adult Sprague-Dawley rats were used in this experimental study. The central cornea of the rats was cauterized chemically. The rats were randomly enrolled into three groups as follows: Group 1 received bevacizumab 1%, Group 2 received cyclosporine 0.1%, and Group 3 received isotonic saline twice a day for 28 days. Slit-lamp examination of all rats was performed at the 3rd and 28th day. The rats were then sacrificed, and the corneas were excised. The number of blood vessels, state of inflammation, and collagen formation were evaluated histopathologically in the corneal sections. Results: Corneal opacity and edema grades were significantly lower in Group 2 than in Group 3 (p=0.04 and 0.00, respectively). In the histopathological examination, Group 2 demonstrated significantly lesser number of blood vessels than Group 3 (p=0.001). Regarding collagen formation, Group 2 exhibited more regular collagen formation than Groups 1 and 3 (p=0.03). Inflammation grades were significantly lower in Groups 1 and 2 than in Group 3 (p=0.014 and 0.001, respectively). Conclusion: Topical bevacizumab is effective in inhibiting newly formed corneal neovascularization. The topical cyclosporine 0.1% treatment appears to be more effective than the topical bevacizumab treatment.

RESUMO Objetivo: Comparar os efeitos da ciclosporina tópica 0,1% e do bevacizumabe na neovascularização da córnea produzida experimentalmente em um modelo com ratos. Métodos: Trinta ratos Sprague-Dawley adultos foram usados neste estudo experimental. A córnea central dos ratos foi cauterizada quimicamente. Os ratos foram distribuídos aleatoriamente em três grupos. O grupo 1 recebeu bevacizumabe a 1%, o grupo 2 recebeu ciclosporina tópica a 0,1% e o grupo 3 recebeu solução salina isotônica duas vezes ao dia durante 28 dias. O exame de lâmpada de fenda de todos os ratos foi realizado no terceiro e no vigésimo oitavo dias. Os ratos foram então sacrificados e as córneas excisadas. Nos cortes da córnea, o número de vasos sanguíneos, o estado de inflamação e a formação de colágeno foram avaliados em uma análise anatomopatológica. Resultados: No Grupo 2, os graus de opacidade e de edema da córnea foram significativamente menores que no Grupo 3 (p=0,04 e 0,00, respectivamente). No exame histopatológico, o Grupo 2 apresentou um número significativamente menor de vasos sanguíneos do que o Grupo 3 (p=0,001). Em relação à avaliação da formação de colágeno, esta mostrou-se mais regular no Grupo 2 que no Grupo 1 e no Grupo 3 (p=0,03). Os graus de inflamação foram significativamente menores no Grupo 1 e no Grupo 2 em comparação com o Grupo 3 (p=0,014 e 0,001, respectivamente). Conclusão: O bevacizumabe tópico é eficaz na inibição da neovascularização da córnea recém-formada. O tratamento tópico com ciclosporina a 0,1% parece ser mais eficaz em comparação ao tratamento tópico com bevacizumabe.

Preconditioning and anti-apoptotic effects of Metformin and Cyclosporine-A in an isolated bile duct-ligated rat heart.

Despite all previous studies relating to the mechanism of cirrhotic cardiomyopathy (CCM), the role of cirrhosis on Ischemic Preconditioning (IPC) has not yet been explored. The present study strives to assess the cardioprotective role of IPC in bile duct ligated (BDL) rats as well as the cardioprotective role of Cyclosporin-A (CsA) and Metformin (Met) in CCM. Cirrhosis was induced by bile duct ligation (BDL). Rats' hearts were isolated and attached to a Langendorff Apparatus. The pharmacological preconditioning with Met and CsA was done before the main ischemia. Myocardial infarct size, hemodynamic and electrophysiological parameters, biochemical markers, and apoptotic indices were determined at the end of the experiment. Infarct size, apoptotic indices, arrhythmia score, and incidence of VF decreased significantly in the IPC group in comparison with the I/R group. These significant decreases were abolished in the IPC (BDL) group. Met significantly decreased the infarct size and apoptotic indices compared with I/R (BDL) and normal groups, while CsA led to similar decreases except in the level of caspase-3 and -8. Met and CsA decreased and increased the arrhythmia score and incidence of VF in the BDL groups, respectively. Functional recovery indices decreased in the I/R (BDL) and IPC (BDL) groups. Met improved these parameters. Therefore, the current study depicted that the cardioprotective effect of Met and CsA on BDL rats is mediated through the balance between pAMPK and apoptosis in the mitochondria.

Lessons to Learn From Low-Dose Cyclosporin-A: A New Approach for Unexpected Clinical Applications.

Cyclosporin-A has been known and used for a long time, since its "fast track" approval in the early 80's. This molecule has rapidly demonstrated unexpected immunosuppressive properties, transforming the history of organ transplantation. Cyclosporin's key effect relies on modulation on T-lymphocyte activity, which explains its role in the prevention of graft rejection. However, whether cyclosporin-A exerts other effects on immune system remains to be determined. Until recently, cyclosporin-A was mainly used at a high-dose, but given the drug toxicity and despite the fear of losing its immunosuppressive effects, there is nowadays a tendency to decrease its dose. The literature has been reporting data revealing a paradoxical effect of low dosage of cyclosporin-A. These low-doses appear to have immunomodulatory properties, with different effects from high-doses on CD8+ T lymphocyte activation, auto-immune diseases, graft-vs.-host disease and cancer. The aim of this review is to discuss the role of cyclosporin-A, not only as a consecrated immunosuppressive agent, but also as an immunomodulatory drug when administrated at low-dose. The use of low-dose cyclosporin-A may become a new therapeutic strategy, particularly to treat cancer.

Effect of synergists on ivermectin resistance in field populations of Rhipicephalus (Boophilus) microplus from Punjab districts, India.

The status of ivermectin resistance in Rhipicephalus (Boophilus) microplus collected from various districts of the Punjab state, India was determined using larval immersion test (LIT). Regression graphs of probit mortality of larval ticks of various field isolates were plotted against log values of increasing concentrations of technical grade ivermectin for determination of slopes of mortality, lethal concentrations for 50% (LC50) and resistance factors (RF). Values for the coefficient of determination (R2) in LIT assay ranged from 0.82 to 0.98 indicating the model to be a good fit. The RF values against ivermectin ranged from 1.65 to 9.07 revealing resistance status in all the field isolates. Pre-exposure to a single pre-determined sub-lethal concentration of ATP-binding cassette transporter inhibitors (cyclosporin-A, MK571) and p-glycoprotein inhibitor (verapamil) lead to reduction in LC50 values of ivermectin in different field tick isolates. Among the various field isolates, the highest synergistic factor for MK571 and verapamil was recorded in the Moga isolate as 4.97 and 3.21, respectively whereas for cyclosporin-A, the highest value was recorded in the Mansa isolate as 2.81. Among the three synergists used in the current study, MK571 caused the highest increase in toxicity against ivermectin in the field ticks. Therefore, combination products of ivermectin with the above synergists could prolong the useful life of this drug for effective control of ticks.

Efficacy of azithromycin and metronidazole combined therapy on rats' gingival overgrowth induced by cyclosporine-A: An experimental animal study.

AIMS: To evaluate the therapeutic efficacy of azithromycin (azm) and/or metronidazole (mtz) on the histopathological features of rats' gingival overgrowth (GO) induced by cyclosporine-A (CsA) in an animal model. METHODS: Ninety male albino rats were divided randomly into six equal groups. The rats of group I received corn oil via gastric feeding for 7 weeks. Group II rats were administered CsA for the same period. Groups III, IV, and V rats received CsA for 6 weeks and simultaneously in the 7th week received a monotherapy of placebo gel, azm suspension, mtz gel, respectively. Group VI rats were handled as groups III, IV, and V and instead received a combined therapy of azm suspension, and mtz gel. Rats were euthanized at the end of the experiment and routine tissue processing was carried out. The obtained specimens were stained with H&E, TGF-ß, MMP-1, and IL-6 antibodies. RESULTS: One-way MANOVA test for TGF-ß, MMP-1, and IL-6 revealed an overall significant difference between the different groups (P = 0.000). LSD post hoc test for multiple comparisons of TGF-ß revealed nonsignificant difference between groups I and VI and between groups IV and V. Nonsignificant difference was found between groups II and III considering the amount of MMP-1 immune expression. In addition, nonsignificant difference was found between groups V and VI regarding the amount of immune expression for IL-6. CONCLUSION: Combined therapy of azm suspension and mtz gel significantly improved the histopathological features of CsA-induced GO better than a monotherapy of azm suspension or mtz gel.

Influence of Calcineurin Gene Polymorphisms on the Efficacy of Cyclosporine A / 中国药房

OBJECTIVE:To study the influence of calcineurin gene polymorphism on the efficacy of cyclosporine A (CsA). METHODS:The blood samples of patients treated with CsA were collected. The trough blood concentration of CsA was detected by EMIT. The genotype of PPP3CA and PPP3CB was assayed by RFLP-PCR method. The expression of NFAT-regulated gene IL-2, IFN-γand GM-CSF were measured by RT-qPCR,which were used to define the index of indirect efficacy of CsA. The relationship of gene polymorphism with CsA efficacy was study by relationship analysis and multiple factor regression method,etc. RESULTS:A to-tal of 100 blood samples were collected. There was no significant correlation between the expression of CsA efficacy-related NFAT-reg-ulated gene GM-CSF and trough concentration of CsA(rGM-CSF=-0.04,P=0.238);the expression of IL-2 and IFN-γ were negatively correlated with trough concentration of CsA significantly(rIL-2=-0.384 3,P0.05). Stratified analysis showed that among patients with immune disease underwent renal transplantation,efficacy of patients with PPP3CB rs3763679 genovariation(TC+TT) were better than those with wild-type gene (CC)(P<0.05). After the efficacy was normalized by CsA trough concentration, multivariate analysis showed that normalized efficacy of CsA was negatively correlated with gender,PPP3CB rs3763679,lactate dehy-drogenase and creatinine significantly,but positively correlated with PPP3CA rs3804358,leucocyte count,usea nitrogen,glycerin trilaurate,etc. CONCLUSIONS:PPP3CB rs3763679 gene polymorphism influence the efficacy of CsA;among patients with immune disease underwent renal transplantation,efficacy of patients with PPP3CB rs3763679 TT+TC is better than that of CC type. At the same time,gender,PPP3CA rs3804358,leucocyte count,usea nitrogen,glycerin trilaurate and other factors all can influence the nor-malized efficacy of CsA to different extent. Multiple factors should be considered when using CsA.

Oxidative capacities of cardiac and skeletal muscles of heart transplant recipients: mitochondrial effects of cyclosporin-A and its vehicle Cremophor-EL.

Chronic immunosuppressive treatment was suspected to alter maximal muscle oxidative capacity (Vmax ) of heart transplant recipients, leading to a limitation of their exercise tolerance. It remains undefined whether the mitochondrial respiratory chain (MRC) of right ventricle (RV) and vastus lateralis (VL) muscles were altered by immunosuppressants and/or their vehicles. Vmax was measured polarographically in saponin-skinned fibres of RV and VL biopsies of patients and compared with Vmax of healthy VL and myocardium. Effects of increasing concentrations (1-10-100 µM) of Sandimmune(®) , its vehicle, Cyclosporine (CsA) in ethanol (EtOH), or EtOH alone were tested. The vehicle's effects on MRC complexes were investigated using specific substrates and inhibitors. Ten months after grafting, Vmax of RV and VL of immunosuppressed patients were similar to their Vmax at time of transplantation and to that of control tissues. In Vitro, Sandimmune(®) significantly decreased Vmax while CsA in EtOH or EtOH exerted small and similar effects. Effects of the vehicle were higher than (RV) or identical to (VL) those of Sandimmune(®) . The sites of action of the vehicle on MRC were located on complexes I and IV. While unchanged under chronic immunosuppressive therapy, Vmax of RV and VL muscles was depressed by acute exposure to intravenous Sandimmune(®) in vitro, an effect attributed to its vehicle by inhibition of complexes I and IV of the MRC. This work provides an in vitro proof of a toxic effect on the mitochondria respiratory chain of the vehicle used in the intravenous formulation of Sandimmune(®) but with no clinical consequences in chronically immunosuppressed patients.

Pharmacokinetics of cyclosporin: a microemulsion in children with idiopathic nephrotic syndrome

OBJECTIVE: We present a prospective study of a microemulsion of cyclosporin to treat idiopathic nephrotic syndrome in ten children with normal renal function who presented cyclosporin trough levels between 50 and 150 ng/ml and achieved complete remission with cyclosporin. To compare the pharmacokinetic parameters of cyclosporin in idiopathic nephrotic syndrome during remission and relapse of the nephrotic state. METHOD: The pharmacokinetic profile of cyclosporin was evaluated with the 12-hour area under the timeconcentration curve (auc0-12) using seven time-point samples. This procedure was performed on each patient during remission and relapse with the same cyclosporin dose in mg/kg/day. The 12-hour area under the timeconcentration curve was calculated using the trapezoidal rule. All of the pharmacokinetic parameters and the resumed 4-hour area under the time-concentration curve were correlated with the 12-hour area under the timeconcentration curve. ClinicalTrials.gov:NCT01616446. RESULTS: There were no significant differences in any parameters of the pharmacokinetic of cyclosporin during remission and relapse, even when the data were normalized by dose. The best correlation with the 12-hour area under the time-concentration curve was the 4-hour area under the time-concentration curve on remission and relapse of the disease, followed by the 2-hour level after cyclosporin (c2) dosing in both disease states. CONCLUSIONS: These data indicate that the same parameters used for cyclosporin therapeutic monitoring estimated during the nephrotic state can also be used during remission. Larger controlled studies are needed to confirm these findings.

The expression of FGF-5 and FGF-7 in the cyclosporin a-induced gingival hyperplasia

Cyclosporin A-induced gingival hyperplasia is frequently found in the patients who have been received an immunosuppressant for the organ transplantation. However, its exact mechanism is still unknown. The expression of FGF-5 and FGF-7 were studied in cyclosporine A-induced gingival hyperplasia (CGH) and inflammatory gingival hyperplasia (IGH). Immunohistochemistry and in situ hybridization were used for localization of protein and mRNA. The expression of FGF-5 and FGF-7 was different from CGH and IGH. FGF-5 and FGF-7 was strongly expressed in fibroblast in CGH (P<0.005 and P<0.05, respectively). FGF-5 mRNA was localized in the middle portion of connective tissue. FGF-7 mRNA was also identified in fibroblasts and mast cells. In conclusion, FGF-5 and FGF-7 were produced excessively by fibroblasts in CGH. Considering their known functions, their expression in CGH is important for production of collagen and proliferation of fibroblasts.

Involvement of apoptotic signals in cyclosporin A-induced proliferation of human gingival fibroblast / 대한치주과학회지

No abstract available.

Anti-cancer effect of Cyclosporin A on oral squamous cell carcinoma cell line

Squamous cell carcinoma is the most prevalent oral cancer, which is characterized by its low survival rate, high malignancy, mortality with facial defects, and poor prognosis. Exact cause and pathogenesis of the squamous cell carcinoma is still unknown. Various routes including smoking, radiation, and viral infections predispose its genesis, and recent studies revealed that genetic defects which fail to prevent cancer proliferation play a role. Generally, a cancer develops from the decreased rate of apoptosis which is an active and voluntary cell death, and from the altered cell cycles. Anticancer effect can be obtained by recovering the apoptotic process, and by suppressing the cell cycles. Among the apoptosis related factors, bcl-2, caspase-9, and VDAC (voltage-dependent anion channel)are produced in mitochondria of the cell. Cyclosporin-A is known to induce apoptosis through its activation with VDAC. This study was to reveal the anticancer effect of Cyclosporin A to the oral squamous cell carcinoma. The inverted microscope was used to find alterations in the tissue, and sensitivity test to the anticancer cells was performed with MTT (Tetrazolium-based colorimetric) assay. Following cell line culture of primary and metastastic oral squamous cell carcinoma, electrophoresis was performed with extracted total RNA. Finally, semi-quantitative study was carried out through RT-PCR (Reverse Transcription-Polymerase Chain Reaction). The results of this study are as follows: 1. The inverted microscopic observation revealed a poorly defined cytoplasm at 2000ng.3000ng/ml, indistinct nucleus, and apoptosis. 2. The Growth of cancer cells was decreased at 1000ng/ml of cyclosporin-A. No cancer cell growth was observed at over 2000ng/ml concentration of cyclosporin-A, and at one week, growth of cancer cells was ceased. 3. The MTT assays were decreased as cyclosporin-A concentration was increased. This means that the activation of succinyl dehydrogenase in mitochondria was decreased following administration of cyclosporin A. 4. A result of RT-PCR showed that amount of mRNA of VDAC-2 was decreased half times at a cyclosporine-A concentration of 2000ng/ml. In bcl-2, amount of mRNA was significantly decreased 1/5 times at 2000ng/ml. caspase-9, however, showed slight increase compared to the control group. From the results obtained in this study, administration of cyclosporin-A to the cell lines of oral squamous cell carcinoma induced alterations in morphology and growth of the cells as its concentration increased. Since apoptosis related factors such as VDAS-2, bcl-2, and caspase-9 also showed distinct alterations on their mRNAs, further research on cyclosporin A as an anti-cancer agent will be feasible.

Effects of Topical Cyclosporin-A in the Treatment of Alopecia Areata / 대한피부과학회지

BACKGROUND: Alopecia areata(AA) is believed to be an autoimmune disease in which a mononuclear cell infiltrate develops in and around anagen hair follicles. There is no clearly superior therapy in the treatment of AA, especially AA with atopic dermatitis and alopecia universalis. The theory of autoimmune pathogenesis of alopecia areata suggests a potential therapeutic effect of cyclosporin-A(CsA). OBJECTIVE: The purpose of this study is to evaluate the effectiveness of CsA in the treatment of AA. METHOD: 12 patients with severe or refractory AA were treated with DPCP for at least 12 months. They showed resistance to treatment using DPCP. CsA was made up as a 0.01M, 0.005M solution in an ethanol preparation. 1cc of 0.01M CsA solution was applied on the Lt. side scalp and 1cc of 0.005M CsA solution was applied on the Rt. side scalp. The drug was applied once per week. Response to treatment was evaluated as follows: complete recovery, more than a 80% extent of hair regrowth; marked recovery, hair regrowth of 60% to 80%, moderate recovery, hair regrowth of 40% to 60%; slight recovery, hair regrowth of 20% to 40%; no response, hair regrowth of 0% to 20%. RESULT: The Six patients with focal type AA showed a moderate recovery. Of the six patients with alopecia totalis, 4 patients showed a moderate recovery, two patients showed no response. CONCLUSION: Topical CsA therapy is recommended in severe and refractory AA.

The Effect of Azithromycin on the Cyclosporin- Ainduced Gingival Fibroblast Overgrowth / 대한치주과학회지

No abstract available.

Prepae B-lymphoblastoid cell lines of HLA novel allele B ~*5610 in a family / 中国输血杂志

Objective To prepare B-lymphoblastoid cell lines of HLA novel allele B*5610 in a family for further study and identification . Method Isolate mononuclear cells under aseptic conditions from the peripheral blood. After infection with Epstein-Barr virus, the cells were cultured in 20% FBS, 2?g/ml CsA RPMI 1640. Results Immortalized B-lymphoblastoid cell lines of five B *5610 carriers in a family were achieved, and the new genes were inherited stably. Conclusion Our work is important for storing and breeding the precious material of biomedicine because the B *5610 genes in the immortalized B-lymphoblastoid cell lines were inherited stably.

A Case of Acquired Amegakaryocytic Thrombocytopenia Responding to Immunosuppressive Therapy / 대한혈액학회지

Acquired amegakaryocytic thrombocytopenia is a relatively rare bone marrow failure disorder characterized by severe thrombocytopenia associated with a total absence or a marked reduction in the number of bone marrow megakaryocytes. We report a case of acquired amegakaryocytic thrombocytopenia. A 39-year old man admitted our hospital because of gingival bleeding and purpura on the thigh, his initial complete blood cell counts were white blood cell 5.6 103/micro liter hemoglobin 9g/dL, and platelet 1 103/micro liter On the bone marrow study, megakaryocyte was not observed and cytogenetic analysis of marrow was 46, XY, inv(9). (p11q13). Other autoimmune markers were negative. The patient received steroid therapy during 8 weeks, but there was no significant improvement and then he received immunosuppressive therapy with antithymocyte globulin and cyclosporin-A. Thereafter the platelet count increased to 80 103/micro liter, and this level continued for 10 months

A Case of Acute Leukemia Remitted by Adding Cyclosporin-A Previously Failed with Induction Therapy

Clinical chemotherapy refractoriness is characterized by resistance to multiple drugs. Multidrug resistance(MDR) is caused by over-reactivity of a unidirectional drug efflux pump, transmembrane glycoprotein(P-glycoprotein), which is encoded by the MDR1 gene. P-glycoprotein leads to increased drug efflux and decreased intracellular drug concentration. Clinical trials that attempt to reverse or modulate MDR have been done. Cyclosporin-A and verapamil are the most extensively studied agents and several trials of cyclosporin-A as a MDR modulator have been reported. We report a case of an 8-year-old girl with acute mixed type leukemia who failed to respond 3 times to remission-induction therapy. It led us to conclude she had multidrug resistance. We tried a fourth induction chemotherapy including cytarabine, idarubicin and 6-thioguanine to which cyclosporin-A was added. Then, she showed signs of severe bone marrow depression and fulminant perianal cellulitis. But she recovered and successfully achieved complete remission. The addition of cyclosporine could be useful in achieving complete remission for cases of acute leukemia that resist to usual chemotherapy. Futher observation including more cases will be needed to assess long-term survival and efficacy of adding cyclosporine.