Drugs
-
Review Comparative Study
Calcineurin inhibitors in renal transplantation: what is the best option?
Recently, new calcineurin inhibitors, such as tacrolimus (FK-506) and microemulsion cyclosporin, have been approved for maintenance immunosuppression in renal transplant recipients and short-term outcomes have been accumulating. In the majority of patients, these calcineurin inhibitors have been used in combination with new immunosuppressive drugs, such as mycophenolate mofetil (MMF) or sirolimus. Under these circumstances, a comparison of cyclosporin and tacrolimus provides the answer to a very important controversial issue. ⋯ In conclusion, well tolerated and effective immunosuppression is feasible with both cyclosporin and tacrolimus. In the current immunosuppressive regimens, a calcineurin inhibitor, either tacrolimus or cyclosporin, is the essential basic standard immunosuppressant. Clinicians need to decide the best means of optimising therapy for individual patients, based on various risk factors, such as risk of rejection, i.e. sensitisation, delayed graft function and ABO-incompatibility, and some adverse events, such as hypertension, hyperlipidaemia and cosmetic changes.
-
Tranexamic acid (Transamin), Cyklokapron, Exacyl, Cyklo-f) is a synthetic lysine derivative that exerts its antifibrinolytic effect by reversibly blocking lysine binding sites on plasminogen and thus preventing fibrin degradation. In a number of small clinical studies in women with idiopathic menorrhagia, tranexamic acid 2-4.5 g/day for 4-7 days reduced menstrual blood loss by 34-59% over 2-3 cycles, significantly more so than placebo, mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone at clinically relevant dosages. Intrauterine administration of levonorgestrel 20 microg/day, however, produced the greatest reduction (96% after 12 months) in blood loss; 44% of patients treated with levonorgestrel developed amenorrhoea. ⋯ Although it was not as effective as intrauterine administration of levonorgestrel, the high incidence of amenorrhoea and adverse events such as intermenstrual bleeding resulting from such treatment may be unacceptable to some patients. Comparative studies of tranexamic acid with epsilon - aminocaproic acid, danazol and combined oral contraceptives, as well as long-term tolerability studies, would help to further define the place of the drug in the treatment of menorrhagia. Nevertheless, tranexamic acid may be considered as a first-line treatment for the initial management of idiopathic menorrhagia, especially for patients in whom hormonal treatment is either not recommended or not wanted.
-
Lopinavir is a novel protease inhibitor (PI) developed from ritonavir. Coadministration with low-dose ritonavir significantly improves the pharmacokinetic properties and hence the activity of lopinavir against HIV-1 protease. Coformulated lopinavir/ritonavir was developed for ease of administration and to ensure both drugs are taken together, as part of combination therapy with other antiretroviral agents. Coformulated lopinavir/ritonavir-based regimens provide adequate and durable suppression of viral load and sustained improvements in CD4+ cell counts, as demonstrated in randomised trials in antiretroviral therapy-naive and -experienced adults and children. To date, development of primary resistance to lopinavir/ritonavir has not been observed in 470 antiretroviral therapy-naive patients treated for >48 weeks. The lopinavir/ritonavir-based regimen was more effective than nelfinavir in antiretroviral therapy-naive HIV-1-infected patients in a phase III trial. The coformulation is also effective as 'salvage' therapy, as shown by low cross-resistance rates in patients who failed to respond to treatment with other PIs in phase II trials. Coformulated lopinavir/ritonavir was well tolerated in both antiretroviral therapy-naive and -experienced HIV-1-infected adults and children with low rates of study drug-related treatment discontinuations. The most common adverse event in adults associated with lopinavir/ritonavir was diarrhoea, followed by other gastrointestinal disturbances, asthenia, headache and skin rash. The incidence of moderate-to-severe adverse events in children was low, skin rash being the most common. Changes in body fat composition occurred with equal frequency in lopinavir/ritonavir- and nelfinavir-treated naive patients, through week 60 in a phase III study. Although laboratory abnormalities occurred with similar frequency in both treatment groups, triglycerides grade 3/4 elevations were significantly more frequent with lopinavir/ritonavir. Total cholesterol and triglycerides grade 3/4 elevations appear to occur more frequently in PI-experienced than in PI-naive lopinavir/ritonavir-treated patients. A number of clinically important drug interactions have been reported with lopinavir/ritonavir necessitating dosage adjustments of lopinavir/ritonavir and/or the interacting drugs, and several other drugs are contraindicated in patients receiving the coformulation. ⋯ Coformulated lopinavir/ritonavir has the potential to interact with wide variety of drugs via several mechanisms, mostly involving the CYP enzymes. Coadministration of lopinavir/ritonavir is contraindicated with certain drugs (i.e. flecainide, propafenone, astemizole, terfenadine, ergot derivatives, cisapride, pimozide, midazolam and triazolam) that are highly dependent on CYP3A or CYP2D6 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Coadministration with lopinavir/ritonavir is also not recommended for drugs or herbal products (i.e. rifampicin [rifampin] and St. John's wort [Hypericum perforatum]) that may substantially reduce lopinavir plasma concentrations, or drugs whose plasma concentrations elevated by the coformulation may lead to serious adverse reactions (i.e. simvastatin and lovastatin). However, a recent study in healthy volunteers suggests that adequate lopinavir concentrations may be achieved during rifampicin coadministration by increasing the twice-daily dosage of lopinavir/ritonavir in conjunction with therapeutic drug monitoring. The liquid (but not the capsule) formulation of lopinavir/ritonavir contains 42.4% ethanol (v/v) and should not be coadministered with drugs capable of producing disulfiram-like reactions (e.g. disulfiram, metronidazole). Coadministration with saquinavir or indinavir requires no dosage adjustment, whereas coadministration with amprenavir, nevirapine or efavirenz requires a dosage increase of the coformulation typically by 33%. As the oral bioavailability of both didanosine and lopinavir/ritonavir is significantly affected by concurrent food ingestion, didanosine should be administered 1 hour before or 2 hours after lopinavir/ritonavir has been taken with food. Interactions between lopinavir/ritonavir and other nucleoside reverse transcriptase inhibitors (NRTIs) are not expected. The coformulation is also likely to increase plasma concentrations of non-antiretroviral drugs metabolised through the CYP3A pathway. To reduce the risk of their toxicity when coadministered with lopinavir/ritonavir, the recommended actions include: (i) monitoring of the drug plasma concentration (antiarrhythmics and immunosuppressants) or the international normalised ratio (warfarin); (ii) the use of alternative treatment (atorvastatin) or birth control methods (ethinylestradiol); and (iii) dosage adjustment (clarithromycin [only in patients with renal failure], rifabutin, dihydropyridine calcium-channel blockers, atorvastatin, ketoconazole and itraconazole). (ABSTRACT TRUNCATED)
-
Nesiritide (Natrecor) is a recombinant form of human B-type (brain) natriuretic peptide that has beneficial vasodilatory, natriuretic, diuretic and neurohormonal effects. The drug is administered intravenously for the management of patients with decompensated congestive heart failure (CHF). In the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) study, patients hospitalised with acute decompensated CHF who received nesiritide had significantly greater mean reductions from baseline in pulmonary capillary wedge pressure 3 hours after starting treatment than nitroglycerin or placebo recipients (-5.8 vs -3.8 and -2 mm Hg, respectively); all patients also received standard therapy (e.g. intravenous diuretics). Improvements in other haemodynamic parameters were also seen in nesiritide recipients. In addition, significantly more nesiritide than placebo recipients reported an improvement in dyspnoea after 3 hours' treatment in VMAC, whereas there was no significant difference between nitroglycerin and placebo recipients. Improvements in global clinical status, dyspnoea and fatigue were also seen with nesiritide in another active-comparator study and in a placebo-controlled study. In VMAC, there was no significant difference between nesiritide and nitroglycerin recipients in 6-month mortality. In the other active-comparator trial, 6-month mortality was significantly lower in recipients of nesiritide 0.015 micro g/kg/min than in dobutamine recipients (although mortality was not a prespecified endpoint and this result should be interpreted with caution). In this same study, the 21-day all-cause hospital readmission rate was significantly lower with nesiritide 0.015 micro g/kg/min than with dobutamine and the duration of active drug treatment was significantly shorter with nesiritide than with dobutamine. Nesiritide is generally well tolerated. In VMAC, significantly more adverse events occurred with nitroglycerin than with nesiritide. The most common adverse events reported during the first 24 hours of therapy in nesiritide and nitroglycerin recipients included general pain, abdominal pain, catheter-related pain, headache, nausea, asymptomatic and symptomatic hypotension, nonsustained ventricular tachycardia and angina pectoris. Most episodes of symptomatic hypotension resolved spontaneously or after an intravenous volume challenge of =250 ml. In addition, nesiritide does not appear to be proarrhythmic. ⋯ Short-term intravenous infusion of nesiritide is associated with haemodynamic and symptomatic improvements in patients with acutely decompensated CHF. Nesiritide may offer tolerability and practical advantages over currently used vasodilators, inodilators and inotropes in this condition; in particular, nesiritide does not appear to have proarrhythmic effects. Nesiritide also appears to be effective and well tolerated in patients receiving concomitant beta-blocker therapy and in patients with renal insufficiency. Thus, nesiritide is a suitable first-line option for the treatment of patients with acutely decompensated CHF and is a welcome addition in an area where intravenous agents are few.
-
Stress of critical illness is often accompanied by hyperglycaemia, whether or not the patient has a history of diabetes mellitus. This has been considered to be part of the adaptive metabolic response to stress. The level of hyperglycaemia in patients with acute myocardial infarction (MI) or stroke upon admission to the hospital has been related to the risk of adverse outcome. ⋯ Intensive insulin therapy reduced intensive care mortality by more than 40% and also decreased a number of morbidity factors including acute renal failure, polyneuropathy, ventilator-dependency and septicaemia. Future studies will be needed to further unravel the mechanisms that explain the beneficial effects of this simple and cost-saving intervention. Although available evidence supports implementation of intensive insulin therapy in surgical intensive care, the benefit for other patient populations, such as patients on medical intensive care units or hospitalised patients who do not require intensive care but who do present with stress-induced hyperglycaemia, remains to be investigated.