Page 319 - Read Online

Singh et al. Vessel Plus 2018;2:33 I http://dx.doi.org/10.20517/2574-1209.2018.28 Page 9 of 17

Numerous randomized controlled trials comparing tacrolimus to Ciclosporin have been done. Two mul-
ticentre studies comparing tacrolimus to oil-based Ciclosporin (Tradename: Sandimmune® Oral Solu-
tion, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey) showed no significant difference
between the groups at 12 months. Graft survival, renal function and infection rates were not significantly
different between the groups although more patients in the Ciclosporin group developed hypertension and
hypercholesterolaemia [78,79] .

A micro-emulsion formulation of Ciclosporin (Tradename: Neoral® Oral Solution, Novartis Pharmaceuticals
Corporation, East Hanover, New Jersey 07936) was developed and was shown to have a better bioavail-
[80]
ability profile with more predictable pharmacokinetics compared to the oil-based preparations . A multi-
center, randomized study of both preparations of Ciclosporin revealed fewer episodes of rejection requiring
antilymphocyte antibodies and fewer study discontinuations for treatment failures in the micro-emulsion
based Ciclosporin cohort of patients compared to those treated with oil-based Ciclosporin without any ad-
[81]
verse events .
When compared to tacrolimus, micro-emulsion based Ciclosporin (alongside cytolytic induction) and a
tapered steroid regime showed equivalent patient and graft survival at 19 months. However, there was an
increased incidence of biopsy proven acute rejection in the Ciclosporin group at 6 months. Tacrolimus was
associated with a higher incidence of new-onset diabetes mellitus, lower rates of post-transplant hyperten-
[82]
sion and lower incidences of dyslipidaemia . Similar findings were noted in another trial without cyto-
[83]
lytic induction .
Mycophenolate mofetil
Another agent that is commonly used is [mycophenolate mofetil (MMF); CellCept, Roche Laboratories,
Nutley, NJ]. It is an effective anti-proliferative agent that improves rejection and survival when used as part
of combination therapy. Its active metabolite, mycophenolic acid, is a non-competitive inhibitor of inosine
[84]
monophosphate dehydrogenase in the de novo pathway for purine synthesis . Therefore, MMF has some
selectivity for lymphocytes over other cell types as lymphocytes rely on this pathway for DNA replication
and proliferation. Studies have shown that heart transplant patients receiving MMF therapy had lower lev-
els of C-reactive protein, circulating B lymphocytes, activated T lymphocytes and natural killer (NK) cells
[85]
compared to patients receiving azathioprine .
Mechanistic target of rapamycin inhibitors
Everolimus (Tradename: Certican, Novartis Pharma Schweiz AG, Bern, Switzerland) and Sirolimus (Trade-
[86]
name: Rapamune, Wyeth Europa Ltd., Maidenhead, UK) are mechanistic target of rapamycin inhibitors .
They work by inhibiting proliferation signals by suppressing the cytokine-driven T-lymphocyte prolifera-
tion, resulting in an arrest of the cell cycle. Unlike the calcineurin inhibitors, they demonstrate little or no
nephrotoxic side effects. Recent studies have even shown a reduction in the incidence of chronic allograft
vasculopathy(CAV) with Everolimus as measured by IVUS among heart-transplant recipients after 1
year [87,88] . Sirolimus however is linked to an increase in total cholesterol and triglyceride levels [89,90] . Everoli-
mus on the other hand, is linked with an increase in total cholesterol levels, without increased triglyceride
[91]
levels, but a significant increase in HDL which may explain its attenuation of CAV .

Cytolytic induction therapy
Cytolytic Induction therapy comprises of immunosuppressive drugs that have been introduced into clini-
cal transplantation directed against human lymphoid cells. Several different forms of cytolytic induction
therapy have been used as identified in Table 1.

In heart transplantation especially, kidney dysfunction has been demonstrated to be risk factors for early
death [93,94] . Cytolytic induction allows post-operative renal recovery from a pre-renal aetiology without the