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Biomedical subjects

R Y Calne

Publications and source records attributed to R Y Calne.

At least 19 recordsLinked to original sources
PubMed1999

Potential for improved therapeutic index of FK506 in liposomal formulation demonstrated in a mouse cardiac allograft model.

BACKGROUND: FK506 is a potent immunosuppressant that has improved clinical outcomes in kidney and liver transplantation both as a primary and as a rescue immunosuppressive agent. Despite these benefits, the potential value of FK506 is limited by toxic side effects that result in a narrow therapeutic index. By encapsulating the active drug within liposomes (LipoFK506), a new formulation has been developed that might improve this therapeutic index. METHODS: The biodistribution of tritiated-FK506 administered i.v. showed that the drug remained associated with the liposomal carrier in vivo, and that its tissue distribution was increased in heart and spleen compared to nonliposomal FK506. The immunosuppressive efficacy of lipoFK506 compared with conventional FK506 formulation was tested in vivo. CBA (H2k) mice were engrafted with BALB/c (H2d) mouse hearts with daily immunosuppression using either 1 mg/kg FK506, or 1 mg/kg LipoFK506, from day 0 to 14. RESULTS: At day 7 the blood trough level of FK506 in the FK506 group was 10-fold higher (25 microg/L) than that in the LipoFK506 group. In both groups the median heart allograft survival was similar at around 26 days. The possibility that FK506, or LipoFK506, might influence antibody-mediated tolerogenesis was addressed in the same model: neither formulation prevented tolerance induction by CD4 and CD8 blockade. CONCLUSION: LipoFK506 is a novel formulation of FK506 that is efficacious at low blood trough FK506 levels. This property has a direct potential benefit for clinical organ transplantation.

Animals↗
PubMed1998

Graft loss and the antiphospholipid syndrome following liver transplantation.

BACKGROUND/AIMS: The antiphospholipid syndrome is characterised by arterial and venous thromboses affecting small and large vessels, together with the presence of lupus anticoagulant and anticardiolipin antibodies. METHODS: We report two cases of the antiphospholipid syndrome following liver transplantation which resulted in hepatic vessel thrombosis and subsequent graft loss, and we discuss the value of anticoagulation in prevention of further thrombotic episodes. Identification of these cases prompted a retrospective analysis for the presence of IgG anticardiolipin antibody, the most useful laboratory marker of vascular thrombosis in the antiphospholipid syndrome. Serum taken at 2 to 4 weeks following transplantation (when thrombotic events might be anticipated) was analysed further in 132 patients undergoing liver transplantation. RESULTS: Hepatic vessel thrombosis occurred in 21/132 (16%) post transplantation. Anticardiolipin IgG was present in 2/21 (8.8%) recipients who developed a hepatic vessel thrombosis following liver transplantation, compared to 7/111 (6.3%) (p=0.59) in whom transplantation was not complicated by hepatic vessel thrombosis. CONCLUSIONS: The presence of IgG anticardiolipin antibody was uncommon in recipients following liver transplantation and was not associated with an increased risk of hepatic vessel thrombosis. In contrast, the antiphospholipid syndrome which is rare may result in hepatic artery occlusion and graft loss, and so prompt recognition of the clinical syndrome is critical. Although screening for the antibody is not warranted in liver transplant recipients, it is important to be aware of the syndrome as optimal management of such cases may prevent graft loss.

Antibodies, Anticardiolipin↗
PubMed1997

Tacrolimus-based immunosuppression after liver transplantation: a randomised study comparing dual versus triple low-dose oral regimens.

To evaluate the efficacy and safety of oral tacrolimus-based immunosuppressive induction therapy, 130 primary orthotopic liver transplant (OLT) recipients were randomised to treatment in an open, parallel-group, European multicentre trial. Following OLT, patients were immediately administered either tacrolimus (0.10 mg/kg) and prednisolone (dual therapy group) or tacrolimus (0.06 mg/kg) in conjunction with prednisolone and azathioprine (triple therapy group) both orally. Patient survival at 1 year was 79.4% for the dual therapy group and 88.7% for the triple therapy group (P = 0.194); 1-year graft survival rates were 76.5% in the dual therapy group and 80.6% in the group receiving triple therapy (P = 0.615). The frequencies of rejection (dual therapy 42.6%, triple therapy 50.0%; P = 0.482), infection, and other complications (renal, neurological and glucose metabolic disorders) were similar in both groups. Tacrolimus whole blood trough concentrations were detectable on days 1 and 2, respectively, in the dual and triple therapy treatment groups whilst median tacrolimus blood concentrations in the triple therapy group reached levels similar to those in the dual therapy group on postoperative day 11 following a steady increase in dose. After 1 year, 54.4% of the patients randomised to dual therapy were receiving tacrolimus monotherapy and only 56.4% of the patients randomised to triple therapy continued to receive azathioprine. In conclusion, oral tacrolimus-based immunosuppression is both potent and safe when administered as induction therapy after OLT. Treatment may commence at either 0.06 or 0.10 mg/ kg per day, but doses may need to be increased to the latter value within the first 10 days to maintain effective immunosuppression.

Administration, Oral↗
PubMed1997

Thrombocytopenia following liver transplantation is associated with platelet consumption and thrombin generation.

Thrombocytopenia frequently occurs immediately after orthotopic liver transplantation. We have investigated the cause of this phenomenon in a cohort of 45 consecutive liver transplant recipients. The median preoperative platelet count (range) of 129 x 10(9)/l (14-719) fell to 56 x 10(9)/l (23-334) by the fourth postoperative day. The median preoperative reticulated platelet percentage (range) of 6.7% (2.2-23.9) increased to 16.4% (4.6-40.8) on day 7. There was a significant rise in prothrombin fragment F1.2 by the first postoperative day which was followed by rises in fibrinogen and fibrin degradation products. There was no increase in platelet-associated immunoglobulin or markers of endothelial activation. We conclude that there is an increased rate of platelet consumption associated with thrombin generation that reflects the magnitude of liver transplant surgery.

Adolescent↗
PubMed1996

Donor arterial variations in liver transplantation: management and outcome of 527 consecutive grafts.

The impact of donor arterial variations and their management was investigated retrospectively in 527 consecutive allografts. Anomalous arteries were found in 161 grafts (30.6 per cent). There was no significant difference in the overall incidence of arterial complications between grafts with normal (3.6 per cent) and abnormal (5.6 per cent) anatomy. However, there was a higher incidence of arterial complications in transplants requiring multiple arterial anastomoses (P = 0.02), or anastomosis of donor vessels to recipient aorta with (P = 0.0003) or without (P = 0.04) an interposition graft for arterial reconstruction. The incidence of biliary complications was similar in grafts with a normal (18.8 per cent) or anomalous (18.0 per cent) arterial supply. Anomalies of hepatic arterial anatomy occur in one-third of all livers and do not compromise graft outcome unless multiple anastomoses or direct anastomosis to the recipient aorta are required for arterial reconstruction.

Aneurysm↗
PubMed1996

Successful use of size-mismatched liver allografts in children by delayed primary closure of the abdominal wall.

Children who are too ill to await a liver graft of suitable size may be transplanted with a relatively oversized graft by leaving the abdominal wound partially open, the defect reduced being bridged with polypropylene mesh and the mesh reduced in stages until it can be removed and the wound directly closed. This technique has been used in seven children who received nine grafts (five reduced and four full size). Their mean age was 7.3 (range 0.5-11) months and mean weight 5.8 (range 2.3-7.2) kg. Progressive reduction in the size of the transplanted liver made primary closure possible in survivors in up to four stages. Over a follow-up period of 3 to 58 months, five of the nine grafts and five of the seven patients survived. No significant complications attributable to the technique were encountered. The technique of delayed primary abdominal wall closure may be of benefit in children at risk of graft failure because of a size-mismatched graft.

Female↗
PubMed1996

Ischemia and reperfusion injury of the rat liver: the role of nimodipine.

The protective effect of the calcium channel blocker nimodipine on liver ischemia and reperfusion was studied in the rat. The homeostasis of intracellular calcium ions seems to be a determinant factor in the cell injury that appears after ischemia and reperfusion. Nimodipine was used to downregulate the calcium levels in the cytosol of the ischemic cell, the hypothetical role of Ca2+ in the pathogenesis of ischemia and reperfusion injury. The experimental procedure consisted of the temporary interruption of blood flow to the left lateral and medial lobes of the rat liver and subsequent reperfusion after a period of 45 min of ischemia. Nimodipine (10 micrograms/kg body wt) was administered either before or after the onset of ischemia. The postischemic liver blood flow and liver oxyhemoglobin saturation were recorded using a He-Ne laser Doppler flowmeter and photometer, which showed, in the pretreated group, a recovery of reperfusion blood flow (58.1%) and liver reflectance (85.5%) significantly better (P < 0.01 and P < 0.001) than those in the respective untreated controls of flow (32.8%) and reflectance (70.5%). In the group that received nimodipine after ischemia, the recovery of the blood flow and the postreperfusion liver reflectance were not significantly better than those in the untreated control group. ALT levels (P < 0.05), galactose elimination capacity (P < 0.001), and histological studies also showed a protective effect of calcium antagonist nimodipine when administered before ischemia.

Animals↗
PubMed1996

[Xenotransplantation].

This paper describes the rationale behind the need for xenotransplantation and the physiological and immunological barriers associated with xenografting from pig to man. The scientific strategies developed for overcoming the immunological barriers associated with hyperacute rejection are described in detail as is the technology for producing transgenic pigs. Data on perfusion studies of transgenic pig hearts with human blood demonstrates the validity of this scientific approach.

Animals↗
PubMed1996

Heart-lung-liver transplantation.

We report three patients with cystic fibrosis and one patient with primary biliary cirrhosis and plexogenic pulmonary hypertension who have undergone heart-lung-liver transplantation as a combined procedure. Liver transplantation was necessary in the three patients with cystic fibrosis because of portal hypertension secondary to either hepatic fibrosis or established cirrhosis in addition to their advanced lung disease. Three of the four patients were alive at 20, 50, and 100 months after transplantation (one patient with cystic fibrosis died on day 16 of pneumonia) with well-preserved pulmonary function (forced expiratory volume in 1 second 110%, 49%, and 100% predicted, respectively), normal hepatic function and New York Heart Association class 1 performance status. Heart-lung and concurrent liver transplantation is a feasible and successful procedure with a satisfactory long-term outcome in selected patients with advanced pulmonary and hepatic disease.

Adult↗