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RATIONALE: Cyclosporin A (CsA) rearranges to its isomer isocyclosporin A (isoCsA) upon acid hydrolysis and also during ionization in the ion source of the mass spectrometer. It has been reported that both compounds could not be differentiated by tandem mass spectrometry (MS/MS) using atmospheric pressure ionization (API) sources and ambiguously differentiated by using other sources. In order to analyze these compounds which are common fungal metabolites, it is relevant to develop a simple method for their differentiation. METHODS: CsA and isoCsA were analyzed by liquid chromatography/mass spectrometry (LC/MS) with post-column addition of metal ion solutions in a quadrupole time-of-flight instrument equipped with an electrospray ionization (ESI) source. RESULTS: Mass spectra of CsA obtained upon post-column addition of solutions of Ca(II), Cu(II) and Zn(II) showed complexes between cyclosporin and the metal, including [2CsA + Me](2+) and [CsA-H + Me](+). These complexes were not observed in the spectra of isoCsA. The same results were observed at different metal concentrations. CONCLUSIONS: Differentiation via metal complexation in positive ion mode LC/ESI-MS was performed to simultaneously distinguish CsA and its isomer isoCsA.

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Most of the studies regarding cyclosporin 'A' production through fungi concentrate around Tolypocladium inflatum. This is mainly due to lower reported production of this drug in other fungi. The present study was therefore conducted to explore indigenous isolates of Aspergillus terreus for synthesis of this drug and defining a production medium for obtaining high yield of cyclosporin 'A'. For this purpose carbon and nitrogen sources were optimized for the selected best strain of A. terreus. Overall results depicted that the best cyclosporin 'A' yield from selected Aspergillus terreus (FCBP58) could be obtained by using production medium containing glucose 10 percent as carbon source and peptone 0.5 percent as nitrogen source. This modification in production medium enhanced drug synthesis by selected fungi significantly. The production capabilities when compared with biomass of fungi there was found no relationship between the two confirming that the medium modification increased overall drug synthesis powers of the fungi.

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Objetivo: Relatar um caso de síndrome de dor óssea induzida por inibidores da calcineurina. Relato de caso: Paciente masculino de 54 anos, branco, foi que submetido a transplante renal haploidêntico e, ao fim do terceiro mês pós-transplante, apresentou dor espontânea, de forte intensidade, em joelhos, tornozelos e pés, de maneira simétrica, com incapacidade funcional, induzida por inibidores da calcineurina. O diagnóstico foi comprovado por ressonância magnética e cintilografia óssea. Evolução: Houve remissão espontânea e completa dos sintomas no fim do sexto mês após o transplante. Conclusão: A síndrome de dor osteoarticular induzida por inibidores da calcineurina é uma condição clínica incomum, mas que pode comprometer a qualidade de vida e a boa evolução do paciente transplantado. Seu diagnóstico correto deve ser feito prontamente por meio de estudos de ressonância magnética e de cintilografia óssea.

Objective: To present a case of calcineurin inhibitor-induced bone pain syndrome. Case report: A 54-year-old Caucasian male patient underwent a haploidentical kidney transplant and, at the end of the third postoperative month, developed severe, spontaneous, symmetrical pain in his knees, ankles, and feet, associated with functional impairment, induced by calcineurin inhibitors. The diagnosis was confirmed by MRI and bone scan. Evolution: The patient presented spontaneous remission of symptoms at the end of the sixth postoperative month. Conclusion: Calcineurin inhibitorinduced bone pain syndrome is an uncommon clinical condition, but it can impair the quality of life and good evolution of transplant recipients. Correct and prompt diagnosis with MRI and bone scan is recommended.

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AIMS: To evaluate the antagonistic activity of Fusarium oxysporum nonpathogenic fungal strain S6 against the phytopathogenic fungus Sclerotinia sclerotiorum and to identify the antifungal compounds involved. METHODS AND RESULTS: The antagonistic activity of Fusarium oxysporum strain S6 was determined in vitro by dual cultures. The metabolite responsible for the activity was isolated by chromatographic techniques, purified and identified by spectroscopic methods as cyclosporine A. The antifungal activity against the pathogen was correlated with the presence of this metabolite by a dilution assay and then quantified. Cyclosporine A caused both growth inhibition and suppression of sclerotia formation. In a greenhouse assay, a significant increase in the number of surviving soybean (Glycine max) plants was observed when S. sclerotiorum and F. oxysporum (S6) were inoculated together when compared with plants inoculated with S. sclerotiorum alone. CONCLUSION: Fusarium oxysporum (S6) may be a good fungal biological control agent for S. sclerotiorum and cyclosporine A is the responsible metabolite involved in its antagonistic activity in vitro. SIGNIFICANCE AND IMPACT OF THE STUDY: Cyclosporine A has not been previously described as an inhibitor of S. sclerotiorum. Its minimum inhibitory concentration (MIC) of 0.1 microg disc(-1) makes it suitable to use as a biofungicide. In vivo experiments showed that F. oxysporum (S6) is a good candidate for the biocontrol of S. sclerotiorum in soybean.

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Sophisen, a new ophthalmic drug carrier, was characterized using physicochemical and morphological criteria. Diclofenac belongs to a nonsteroidal anti-inflammatory molecule group and its ophthalmic use avoids side effects produced by steroid drugs. Cyclosporine-A is a cyclic peptide used as an immunosuppressive when administrated systemically. Its application in ophthalmology has been reported, but it is a very poor soluble drug. Diclofenac sodium and Cyclosporine-A were mixed with Sophisen to render two new ophthalmic solutions that were named 3A Ofteno and Modusik-A Ofteno, respectively. Based on transmission electron microscopy and dynamic light scattering studies, we concluded that Sophisen is a polydisperse solution with a molecular weight of 413 +/-122 kDa, whereas 3A Ofteno and Modusik-A Ofteno are monodisperse solutions with molecular weights of 169 +/- 44 and 153 +/- 10, respectively. Sophisen was shown to be a good carrier for diclofenac sodium as evaluated by passive diffusion through the cornea. A comparative study suggests that diclofenac applied as eye drops was better tolerated when associated with Sophisen. In addition, Modusik-A Ofteno, a new aqueous solution of Cyclosporine-A, improved tear production in patients with moderate or severe dry eye condition.

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The objective of this study was to examine the development of pulpal lesions in the lower molar of control and cyclosporin A (CyA) treated rats. The pulps of the firts lower molars of 20 normal and 20 CyA treated rats were exposed and left open into the oral cavity. Five animals of each group were killed at 7, 14, 21, and 28 days after the pulp exposure. The especimens were sectioned sagittally at a thickness of 7 µm and stained with hematoxylin and eosin. The pulpal lesions were similar for both normal and CyA treated rats in all studied periods and the differences between both groups were not statistically significante by the Student t test at the 5 per cent (0.05) level of significance, indicating that the immunosupression did not alter the evolution of the inflammatory process

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