No abstract

Tacrolimus (FK506), mycophenolate mofetil, sirolimus (rapamycin), gusperimus, and monoclonal antibody preparations are new immunosuppressive agents, some of which are already approved for clinical use, while others are currently undergoing clinical trials. The present article provides an overview of adverse drug interactions between these immunosuppressants and other drugs which may be used concomitantly. Preliminary data suggest that a pharmacodynamic interaction can occur between tacrolimus and nonsteroidal anti-inflammatory drugs, associated with an increased risk of nephrotoxicity. Erythromycin, clarithromycin, clotrimazole, fluconazole, ketoconazole, and danazol have been shown to increase tacrolimus blood concentrations, while rifampicin (rifampicin) was found to decrease tacrolimus blood concentrations. Evidence from experimental studies suggest that several other drugs also known to affect cytochrome P450 activity may have significant effects on the pharmacokinetics of tacrolimus. On the other hand, tacrolimus itself may inhibit the metabolism of coadministered drugs. This interaction may be attributed to the enhanced renal impairment which has been observed in patients treated with tacrolimus and cyclosporin. The bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, has been reported to be reduced by aluminium/magnesium hydroxide-containing antacids and cholestyramine. Mycophenolic acid, sirolimus and gusperimus may impair bone marrow function and this adverse effect may be enhanced by concomitant administration of other myelosuppressive drugs. There is some evidence that coadministered sirolimus and cyclosporin cause an increase in each other's blood concentrations. An increased risk of central nervous system adverse effects has been described following the combined use of indomethacin and the monoclonal antibody muromonab CD3 (OKT3).

The physical and chemical stability of a combination of drugs commonly administered into the epidural or intrathecal space for the treatment of chronic pain was investigated. The concentrations of bupivacaine hydrochloride, morphine hydrochloride, and clonidine hydrochloride were measured using high performance liquid chromatography. The solutions were stored in reservoir bags for up to 90 days. No macroscopic or microbiological signs of precipitation, change in color, or contamination were observed, and pH remained stable. None of the three drugs declined in concentration during the observation period. A small increase in concentration of all three drugs did occur over time, most probably due to evaporation processes. In conclusion, no problems in physical or chemical stability are to be expected when combining morphine, bupivacaine, and/or clonidine for long-term epidural or intrathecal administration. In the case of clinically apparent loss of analgesic efficacy, other mechanisms should be considered.

No abstract

ACE inhibitors are used widely in the treatment of hypertension and congestive heart failure, but there is only limited information on adverse interactions between ACE inhibitors and other cardiovascular or noncardiovascular drugs. The present article provides an overview of this issue, with emphasis on those interactions having the greatest clinical implications. In patients who have been sodium and/or volume depleted by thiazide or loop diuretics, the additional use of ACE inhibitors can lead to an excessive reduction in blood pressure and symptomatic hypotension. An increase in serum potassium levels may occur after coadministration of potassium-sparing diuretics and ACE inhibitors, resulting in hyperkalaemia especially in patients with renal insufficiency. The incidence of acute renal failure may be associated with ACE inhibitor therapy when these drugs are combined with nonsteroidal anti-inflammatory agents and given to patients whose renal function becomes increasingly dependent on angiotensin II and prostaglandins. There is some evidence, albeit scant, linking ACE inhibitors with the induction of lithium toxicity in patients maintained on lithium, and with the occurrence of severe hypersensitivity reactions in patients undergoing haemodialysis, venom immunisation or concomitant allopurinol therapy.