Although sirolimus (SRL) binds the immunophilin FK506-binding protein-12 (FKBP-12) with greater avidity than tacrolimus (TAC), animal studies have shown that SRL and TAC act synergistically to prevent rejection. Dose-related toxicity is more often the cause of TAC discontinuation than rejection. We hypothesized that SRL would allow for a substantial reduction in the concomitant dose of TAC after liver transplantation to levels less than the threshold for toxicity. A series of 56 liver transplant recipients were administered a combination of SRL and TAC (target trough levels, 7 and 5 ng/mL, respectively). Planned weaning of steroids commenced after 3 months. Pharmacokinetic (PK) studies were undertaken. Patient and graft survival were 52 patients (93%) and 51 grafts ( P hase III randomized controlled trials of sirolimus (SRL) performed for registration in North America of Rapamune (Wyeth-Ayerst, Princeton, NJ) were conducted using SRL in combination with full-dose cyclosporine (CsA) in renal transplantation. This combination was chosen because it was known that SRL synergistically increased the inhibitory effect of CsA on lymphocyte proliferation. 1 Both registration studies showed that the addition of SRL in a fixed-dose regimen of 2 or 5 mg/d halved the rate of acute rejection of renal allografts in the first year. 2,3 Patients administered the greater dose of SRL had greater serum creatinine levels at 1 year than the control group. This might have been caused by increased exposure to CsA in SRLtreated individuals. 4 Principle toxicities associated with SRL were bone-marrow suppression and hyperlipidemia. Phase II studies conducted in Europe in which concentration-controlled SRL was substituted for CsA confirmed the difference between SRL and CsA with respect to unwanted effects. 5

In this first Canadian study evaluating MTX hepatotoxicity in psoriatics, the incidence of severe hepatotoxicity is high: 23.1% (24 of 104 patients). This study shows that diabetic patients are particularly at increased risk of MTX hepatotoxicity. Occasional alcohol consumption is not associated with increased risk. Three patients who developed cirrhosis over two years of standard MTX therapy may represent a subset of psoriatics with increased hepatic susceptibility to MTX. Another three patients whose severe hepatic fibrosis had regressed upon discontinuation of MTX, but who developed accelerated recurrence of the severe hepatic fibrosis upon resumption of MTX therapy, also suggest the possibility of unusual sensitivity to the drug. These cases emphasize the need for continuing surveillance, with regular liver biopsies, of psoriatic patients on MTX.

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OBJECTIVE: To evaluate the efficacy of rescue therapy using rifabutin, amoxicillin and a proton pump inhibitor (PPI) in the eradication ofHelicobacter pyloriin patients who have failed at least one course of PPI-based triple therapy.METHODS: The present study was a single-centre case series of 16 consecutive patients who had received at least one course of standard eradication therapy. Pretreatment evaluation included endoscopy with biopsies for histology and culture forH pyloriinfection. Treatment consisted of a one-week regimen containing a PPI twice daily, amoxicillin (A) 1 g twice daily and rifabutin (R) 300 mg once daily (PPI-AR). Post-treatment evaluation consisted of a repeat endoscopy with biopsy for histology and culture, or a validated urea breath test at least four weeks after treatment was completed. Pretreatment antibiotic susceptibility to metronidazole, clarithromycin and A was evaluated using a validated epsilometer test.RESULTS: Of the 16 patients, four had previously received one course of triple therapy, 10 had received two courses and two had received more than two courses. The overall success rate of PPI-AR was 63% (10 of 16). Resistance to A was 0% (0 of 13), metronidazole 77% (10 of 13), clarithromycin 70% (seven of 10), and both metronidazole and clarithromycin 60% (six of 10). There was no correlation between resistance patterns and cure rate.CONCLUSIONS: An R-containing regimen such as PPI-AR is a viable option as rescue therapy forH pyloriinfection.