Modification of c and n sources for enhanced production of cyclosporin 'a' by Aspergillus Terreus

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.

Is mycophenolate more than just an immunosuppressant?--An overview.

The development of immunosuppressant compounds, such as cyclosporine and tacrolimus was crucial to the success of transplant surgery and for treatment of autoimmune diseases. However, immunosuppressant therapy may increase the concentrations of reactive oxygen species (ROS), inducing oxidative damage such as an increased vascular damage. The major source of ROS in the vascular endothelial cells is NADPH oxidase. The subunit structure and function of this enzyme complex in vascular cells differs from that in phagocytic leucocytes. The enzyme subunits Nox1, Nox2 and Nox4 are only found in vascular cells. The GTP-dependent protein subunit Rac 1 needs to be activated for this enzyme to function. Inhibiting this protein subunit should reduce NADPH oxidase-induced oxidative stress. In the cardiovascular system, oxidative stress is observed as hypertension, hypertrophy, fibrosis, conduction abnormalities and endothelial dysfunction, as well as cardiac allograft vasculopathy in transplant patients. In contrast to cyclosporine and tacrolimus, the immunosuppressant mycophenolate inhibits the Rac 1 subunit thus inhibiting NADPH oxidase in the vasculature. This may reduce oxidative stress, prevent the development of cardiac allograft vasculopathy, decrease the deterioration of vascular function and improve cardiovascular function chronically in transplant patients. This overview discusses whether this antioxidant immunosuppressive property could translate into a more general protective role for mycophenolate in the prevention of cardiovascular disease.

Optimization of media composition for the production of cyclosporin A by Tolypocladium species.

BACKGROUND & OBJECTIVE: Cyclosporins are produced by certain species of the filamentous fungi, belonging to the genus Tolypocladium. While there are numerous reports on the use of cyclosporins in clinical studies, reports on the various aspects of their production have been very limited. Therefore, this study was carried to optimize the medium composition for the production of cyclosporin A, produced by a strain of the filamentous fungus, Tolypocladium species by static fermentation. METHODS: The effect of different nutrients on the production of cyclosporin A, produced by Tolypocladium species in stationary culture was studied by growing the fungus for 21 days at 25 +/- 2 degrees C under different media composition. Cyclosporin A was extracted by homogenizing the fungal cells with methanol and the cyclosporin A level was analyzed by high performance liquid chromatography (HPLC). RESULTS: Among the six different media studied for the production of cyclosporin A, medium 'f' containing glucose (8%), casein acid hydrolysate (3%), malt extract (2%), peptone (1%) and DL- alpha-amino butyric acid (0.5%) favoured the maximum production (2.22 +/- 0.02 g/l medium or 5.85 +/- 0.35 g/kg biomass). INTERPRETATION & CONCLUSION: This study showed that by optimizing the composition of fermentation media enhanced production of cyclosporin A was obtained. Since the strain Tolypocladium (VCRC F21 NRRL No.18950) produces a high level of cyclosporin A in the identified fermentation medium, it could be exploited for industrial production.

Mecanismos de rabdomiólise com as estatinas / Mechanisms of rhabdomyolysis with statins

A rabdomiólise é incomum, mas é o efeito adverso mais sério observado na terapia hipolipemiante com estatinas. A ocorrência de rabdomiólise fatal reportada nos Estados Unidos desde a introdução das estatinas no mercado, na década de 1980, foi muito rara (0,15 casos por milhão de pacientes tratados por ano). Entretanto, a miopatia, definida como: sintomas musculares associados com elevações da CK; é muito mais comum (1 por cento-5 por cento). Os mecanismos de miopatia mediada por estatinas não estão totalmente compreendidos. Várias hipóteses têm sido propostas: diminuição dos níveis celulares de isoprenóides e ubiquinona, incremento de apoptose, mudanças nos canais de cloro diminuindo a hiperpolarização da membrana celular e alterações da permeabilidade da membrana celular. Interação com outras drogas, e alterações metabólicas pré-existentes podem predispor a miopatia.

Impact of cyclosporin immunosuppression on serum magnesium and its fractional excretion in renal transplant recipients

To evaluate the effect of cyclosporine [CSA] on serum magnesium and its fractional excretion in renal transplant recipients. A cross sectional comparative study on 50 live related renal transplant recipients on CSA therapy with serum creatinine <2.0 mg/dl and 30 healthy controls. Serum creatinine, magnesium and its fractional excretion and CSA levels were monitored. Patients were followed at 6 months. The mean serum creatinine in patients was 1.41 +/- 0.42 mg/dl, cyclosporine 210 +/- 66 ng/ml at a dose of 4.8 +/- 1.4 mg/kg/day. The serum magnesium was 1.77 +/- 0.32mg/dl vs 1.98 +/- 0.17mg/dl in healthy controls [p<0.05].Fractional excretion was 5.05 +/- 2.53% in patients vs 2.8 +/- 1.05% in controls [p<0.05]. No correlation was found between CSA levels [100-400 ng/ml] and serum magnesium [r = 0.053] or FEMg% [r = 0.215]. Of the 50 recipients 27 [54%] had FEMg% in the control range. At 6 months follow up no difference in CSA levels was found between recipients with FEMg% in the normal range vs those with FEMg >5%. However, serum creatinine increased from 1.42 +/- 0.30 mg/dl to 1.68 +/- 0.82mg/dl [p< 0.05]. CSA therapy lowers serum magnesium as compared to healthy controls and there is marked increase in FEMg% in 50% of the patients. Patients with FEMg >5% developed renal function deterioration. FEMg% can thus be a good follow up marker of CSA chronic toxicity in stable transplant recipients

Cloning and characterization of Giardia intestinalis cyclophilin

The cyclophilins (Cyps) are family members of proteins that exhibit peptidylprolyl cis-trans isomerase (PPIase, EC 5.2.1.8) activity and bind the immunosuppressive agent cyclosprin A (CsA) in varying degrees. During the process of random sequencing of a cDNA library made from Giardia intestinalis WB strain, the cyclophilin gene (gicyp 1) was isolated. An open reading frame of gicyp 1 gene was 576 nucleotides, which corresponded to a translation product of 176 amino acids (Gicyp 1). The identity with other Cyps was about 58-71%. The 13 residues that constituted the CsA binding site of human cyclophilin were also detected in the amino acid sequence of Gicyp 1, including tryptophan residue essential for the drug binding. The single copy of the gicyp 1 gene was detected in the G. intestinalis chromosome by southern hybridization analysis. Recombinant Gicyp 1 protein clearly accelerated the rate of cis--

Farmacocinética da ciclosporina e de seus metabólicos em pacientes submetidos a transplante renal / Pharmacokinetics of cyclosporine and its metabolites in patients undergoing kidney transplantation

A farmacocinética da ciclosporina demosntra grande variaçäo inter e intra-individual e profundas mudanças säo, freqüentemente, observadas após o transplante renal. OBJETIVO. analisar seriadamente a farmacocinética da ciclosporina e de seus metabólitos através da determinaçäo de sua concentraçäo sanguínea, em pacientes submetidos a transplante renal. MÉTODOS. Foram realizados 70 estudos em 29 pacientes, sendo 26 antes e 44 após o transplante renal. Em cada estudo a curva de absorçäo foi analisada mediante a determinaçäo da concentraçäo sanguínea da ciclosporina, utilizando radioimunoensaio com anticorpos monoclonais específicos (RIE-MoSP) e inespecíficos (RIE-MoNP), em 17 amostras colhidas após a sua administraçäo oral ou endovenosa (0; 0,5; 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 12; 16; 20; 23; 24h). Resultados. A área sob a curva da concentraçäo sanguínea de ciclosporina em funçäo do tempo (AUC), a biodisponibilidade (F), a concentraçäo máxima (Cmax) e as concentraçöes sanguíneas obtidas 12 e 24 horas após a sua administraçäo (C12 e C24), determinadas com RIE-MoSP, foram inferiores àquelas encontradas com RIE-MoNP, enquanto a depuraçäo (CL) e o volume de distribuiçäo (Vd) foram maiores. A meia-vida de eliminaçäo foi semelhante utilizando os dois métodos (t1/2). A absorçäo seguiu uma cinética de ordem zero, sendo observada uma correlaçäo inversa entre a dose de ciclosporina e a AUC/dose (r = 0,55, RIE-MoSP e r = 0,42, RIE-MoNP). A fraçäo de absorçäo (F) variou entre 18 por cento e 68 por cento (RIE-MoSP), sendo superestimada quando determinada com RIE-MoNP (38 por cento a 100 por cento), conseqüência da extensa metabolizaçäo na primeira passagem pelo intestino e fígado...