Cyclosporine animal studies

Results from animal studies indicate that while furosemide enhanced cephaloridine nephrotoxicity no increased renal toxicity was observed by combining of piperacillin with furosemide [142]. Latamoxef and flo-moxef may decrease nephrotoxicity of vancomycin by inhibiting its uptake into the kidney [146,147]. The results of a retrospective study including renal transplant patients indicate that aztreonam can be safely administered with cyclosporine [148]. Combination therapy with ampicillin/aztreonam in neonates showed a lower renal toxicity than in the group with concurrent administration of oxacillin/ amikacin [149]. 

In this context, studies on transformants of LLC-PKi cells that expressed P-gp derived from human, monkey, canine, rat, and mouse impressively showed altered efflux activities and rankings depended on the species for substances such as clarithromycin, daunorubicin, digoxin, etoposide, paclitaxel, quinidine, ritonavir, saquinavir, verapamil, and vinblastine [76]. Subsequent experiments confirmed different inhibitory effects of verapamil and quinidine on the transport of daunorubicin, digoxin, and cyclosporin A across LLC-PKi cells with P-gp from different species [77]. These reports clearly pointed out that qualitative statements, whether a substance is a transporter substrate or not, are possible. But it was also underlined that one has to be really careful when applying permeability data of in vitro experiments or in vivo animal studies to human conditions. In general, the functional consequences of species variation may vary from compound to compound, and further studies are needed on this aspect [78]. 

Theoretically, astragalus could be incompatible with immune suppressant drugs such as cyclosporine and corticosteroids (Upton 1999). A limited number of human studies have indicated that astragalus increases the therapeutic effects of corticosteroids and cyclophosphamide in patients with autoimmune disease (Cai et al. 2006 Pan et al. 2008 Su et al. 2007), while animal studies have indicated a reversal of cyclophosphamide-induced immune suppression (Chu et al. 1988b, 1988c). 

The juice of bitter orange fruit and extracts of whole bitter orange fruits have been shown to affect the metabolism of certain drugs in ways similar to, but not precisely the same as, grapefruit juice (Malhotra et al. 2001 Di Marco et al. 2002). Animal studies have found that decoctions of the fruit significantly decreased blood levels of the drug tacrolimus in rats, whereas an article described as the peel of the ripe fruit had no effect on the drug (Lin et al. 2011) and increased plasma concentrations of cyclosporine in swine (Hou et al. 2000). 

Chatteijee et al., 1984 Sens et al., 1988), and cyclosporine (TrifiUis et al., 1984). Studies reported by Tay et al. (1988) in rabbit proximal tubule cultures with cisplatin revealed biochemical effects upon DNA synthetic activty that correlated with in vivo histochemical effects of this antitumor agent in animals. With respect to studies involving mercuric chloride and aminoglycoside antibiotics in primary renal cultures, light and electron microscopy revealed similar patterns of cellular pathology in vitro as compared to in vivo exposure in animals (Chatteijee et al., 1984 Aleo et al., 1987). 

As is true for all biopharmaceuticals, toxicity studies should be performed in relevant animal models. For cellular therapies these models are often in animal models intended to mimic the human disease. When possible the intended human cells are utilized for assessments with or without low-dose immunosuppressants (e.g., lOmg/kg, i.p. dose of cyclosporine A in rats). The immunosuppressive drug is generally administered prior to the cell dose and extended for a specified period after the transplant. In cases where it is not feasible to use the intended clinical material, largely due to the inability of the cells to engraft sufficiently into the host, analogous cells can be used to assess preclinical safety and activity. In such cases it is important to understand the potential impact of any differences between the analogous product and the clinical product in order to improve extrapolation of safe and active cell doses to humans. 

Whether these requirements are better met by primary cultures or renal cell lines is still subject of debate and will depend on the type of investigation. Techniques for the isolation and culture of primary cells of the renal tubular epithelium, glomerular mesangial cells, podocytes and endothelial cells have been developed for various species including human. Although cells in primary culture tend to dedifferentiate, the characteristics of those cells are usually closer to the in vivo situation than are animal cell tines, at least for a limited culture period. Primary cultures have been used successfully to study the in vitro effects of numerous nephrotoxins including, cyclosporine A (CsA), gentamicin, mercuric chloride and Ochratoxin A [38-42]. 

Acute and chronic rejection are major problems compromising transplant and patient survival. Many studies indicate that aerosolized cyclosporin A is useful for reducing the risk of acute rejection. The lung concentrates and retains cyclosporin A better after inhalation [152,153]. A number in investigators have found that aerosolized cyclosporin reduces acute rejection in animals [154-157], and some studies suggest efficacy in treating acute [158] and chronic [159,160] rejection in human transplant recipients. 

Additional studies carried out in animal models of temporal lobe epilepsy (TLE) further support the use of selective ABCBl inhibitors to reverse drug resistance in RE. Thus, tariquidar potentiates the effect of phenytoin and countervails resistance to phenobarbital in a rat model of TLE. Furthermore, cyclosporin A helps reverse resistance to phenytoin in a rat model of AED-resistant status epilepticus. Finally, verapamil counteracts resistance to oxacarbazepine in rats with pilocarpine-induced seizures [42]. 

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