Effect of prolonged administration of Cyclosporin A on (pro)insulin biosynthesis and insulin release by rat islets of Langerhans

Functional and morphological study of cultured pancreatic islets treated with cyclosporine

“…This was supported by similar findings of Merrell et al (1984), Engfeldt et al (1986), Hahn et al (1986a,b), Tyden et al (1987), Menegazzo et al (1998), Dean et al (2002) and Dieterle et al (2004). Basadonna et al (1988), Chandrasekar and Mukherjee (1988), Muller et al (1988), Gillson et al (1989), Bani-Sacchi et al (1990), Shi et al (1993), Sai et al (1994), Menegazzo et al (1998), Dufer et al (2001), Dean et al (2002), Paty et al (2002), Yu et al (2003) and Dieterle et al (2004).…”

“…Some authors recognized morphological alterations in B-cells of animals treated with CsA in the form of decreased immunoreactivity to insulin in stained sections (Chandrasekar and Mukherjee, 1988;Bani-Sacchi et al, 1990;Drachenberg et al, 1999), degranulation (Fehman et al, 1987;Lucke et al, 1991), and vacuolation (Whiting et al, 1990;Lucke et al, 1991;Drachenberg et al, 1999). Reduced volume density of B-cells was also described by Hahn et al (1986a,b) and Lucke et al (1991); that is comparable to the finding of reduced islet mass in our in vitro studies.…”

The safety, efficacy and regulatory triangle in drug development: Impact for animal models and the use of animals

“…In order to measure graft function, these evaluations are almost exclusively performed in diabetic NHPs, which is highly relevant with the perspective of the intended clinical situation and the fact that PK/PD are altered in diabetics when compared with normal healthy individuals (Alkharfy, 2009;Dostalek et al, 2012). Animal studies identified islet-toxic effects of calcineurin inhibitors with corresponding clinical data, and likewise can be credited for showing efficacy of calcineurin inhibitor-sparing protocols that are now preferred in the clinic (Adams et al, 2002;Alejandro et al, 2008;Berney et al, 2004;Chandrasekar and Mukherjee, 1988;Larsen et al, 2005;Posselt et al, 2010;Ricordi et al, 1991Ricordi et al, , 1992aVincenti et al, 2005).…”

Validity of animal models of type 1 diabetes, and strategies to enhance their utility in translational research

“…Substantial improvements in graft survival and function have been realized under the cover of immunosuppressive regimens (efficacy) and the effect of these regimens on the recipient (tolerability/safety). One example where the model can be credited was the identification of islet-toxic effects of calcineurin inhibitors with concordant clinical data, and another example with similar credits is the demonstration of effective calcineurin inhibitor-sparing protocols that subsequently developed in effective protocols in the clinic (Adams et al, 2002;Alejandro et al, 2008;Berney et al, 2004;Chandrasekar and Mukherjee, 1988;Larsen et al, 2005;Posselt et al, 2010;Ricordi et al, 1991Ricordi et al, , 1992aVincenti et al, 2005). Also in-vivo product testing in the immunodeficient mouse model with spontaneous or induced diabetes (e.g., nude, SCID or beige) is used as a potency assay for pharmacologic activity, amongst others used in centers participating in the Clinical Islet Transplantation consortium (DAIT, NIAID, NIH, 2008).…”