摘要:

Cyclosporin is an immunosuppressive agent with a narrow therapeutic index. The total concentration of cyclosporin in blood is usually monitored to guide dosage adjustment and to compensate for substantial interindividual and intraindividual variability in cyclosporin pharmacokinetics. Cyclosporin is a highly lipophilic molecule and widely distributes into blood, plasma and tissue components. It mainly accumulates in fat-rich organs, including adipose tissue and liver. In blood, it binds to erythrocytes in a saturable fashion that is dependent on haematocrit, temperature and the concentration of plasma proteins. In plasma, it binds primarily to lipoproteins, including high-density, low-density and very-low-density lipoprotein, and, to a lesser extent, albumin. The unbound fraction of cyclosporin in plasma (CsAfu) expressed as a percentage is approximately 2%.It has been shown that both the pharmacokinetic and pharmacodynamic properties of cyclosporin are related to its binding characteristics in plasma. Furthermore, there is some evidence to indicate that the unbound concentration of cyclosporin (CsAU) has a closer association with both kidney and heart allograft rejection than the total (bound + unbound) concentration. However, the measurement of CsAfuis inherently complex and cannot easily be performed in a clinical setting. Mathematical models that calculate CsAfu, and hence CsAU, from the concentration of plasma lipoproteins may be a more practical option, and should provide a more accurate correlate of effectiveness and toxicity of this drug in transplant recipients than do conventional monitoring procedures.In conclusion, the distribution characteristics of cyclosporin in blood, plasma and various tissues are clinically important. Further investigations are needed to verify whether determination of CsAUimproves the clinical management of transplant recipients.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The evidence is reviewed for effective serum lithium concentrations for the acute and prophylactic treatment of mania and depression in patients with bipolar disorder. The efficacy of lithium in the treatment of acute manic episodes has been recognised for several decades, primarily using concentrations in the range of 0.8 to 2 mmol/L. The number of patients responding increases as the serum lithium concentration increases, although individual patients may respond at lower concentrations (<0.8 mmol/L). Lithium doses and serum concentrations similar to those used to treat acute mania have been studied in bipolar depression, with no evaluation of a relationship between concentration and clinical response. Several prospective controlled trials have evaluated this relationship in the prophylactic treatment of bipolar disorder. Maintaining higher serum lithium concentrations (0.8 to 1 mmol/L) improves the likelihood of good effect in prophylactic treatment, although individual patients may do well on lower concentrations. Despite the paucity of evidence to specifically support the efficacy of lithium at lower serum lithium concentrations in the elderly, lower target ranges (0.5 to 0.8 mmol/L) are commonly recommended due to an increased sensitivity to adverse effects, particularly neurotoxicity. The serum lithium concentrations recommended in adults have been applied to children; however, this has not been studied.Overall, the evidence suggests a relationship between serum lithium concentration and therapeutic effect, although the exact nature of this relationship is not clear. For example, it is not known why some people respond to lower concentrations and others do not. There are many factors that influence studies trying to elucidate this relationship. Many of these factors are related to the interpretation of the serum lithium concentration.In summary, patients have an increased chance of responding to lithium if 12-hour serum lithium concentrations at steady state are above 0.8 mmol/L. Many patients will respond to lower concentrations (0.4 to 0.7 mmol/L), but we are unable to identify these patientsa priori. The relationship between serum lithium concentrations and adverse effects is also very important in determining appropriate target lithium concentrations. The current best advice is to individualise the target serum lithium concentrations based on efficacy and tolerability and to optimise the interpretation of these concentrations by ensuring within-patient consistency with respect to dosage schedule, lithium preparation and the timing of blood sampling.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Oral mucosal drug delivery is an alternative method of systemic drug delivery that offers several advantages over both injectable and enteral methods. Because the oral mucosa is highly vascularised, drugs that are absorbed through the oral mucosa directly enter the systemic circulation, bypassing the gastrointestinal tract and first-pass metabolism in the liver. For some drugs, this results in rapid onset of action via a more comfortable and convenient delivery route than the intravenous route. Not all drugs, however, can be administered through the oral mucosa because of the characteristics of the oral mucosa and the physicochemical properties of the drug.Several cardiovascular drugs administered transmucosally have been studied extensively. Nitroglycerin is one of the most common drugs delivered through the oral mucosa. Research on other cardiovascular drugs, such as captopril, verapamil and propafenone, has proven promising.Oral transmucosal delivery of analgesics has received considerable attention. Oral transmucosal fentanyl is designed to deliver rapid analgesia for breakthrough pain, providing patients with a noninvasive, easy to use and nonintimidating option. For analgesics that are used to treat mild to moderate pain, rapid onset has relatively little benefit and oral mucosal delivery is a poor option.Oral mucosal delivery of sedatives such as midazolam, triazolam and etomidate has shown favourable results with clinical advantages over other routes of administration. Oral mucosal delivery of the antinausea drugs scopolamine and prochlorperazine has received some attention, as has oral mucosal delivery of drugs for erectile dysfunction.Oral transmucosal formulations of testosterone and estrogen have been developed. In clinical studies, sublingual testosterone has been shown to result in increases in lean muscle mass and muscle strength, improvement in positive mood parameters, and increases in genital responsiveness in women. Short-term administration of estrogen to menopausal women with cardiovascular disease has been shown to produce coronary and peripheral vasodilation, reduction of vascular resistance and improvement in endothelial function. Studies of sublingual administration of estrogen are needed to clarify the most beneficial regimen.Although many drugs have been evaluated for oral transmucosal delivery, few are commercially available. The clinical need for oral transmucosal delivery of a drug must be high enough to offset the high costs associated with developing this type of product. Drugs considered for oral transmucosal delivery are limited to existing products, and until there is a change in the selection and development process for new drugs, candidates for oral transmucosal delivery will be limited.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

ObjectiveTo evaluate the pharmacokinetic interactions between efavirenz and rifampicin (rifampin) in patients with HIV infection and tuberculosis.DesignNonblind, randomised, pharmacokinetic study.Patients24 patients (21 male, 3 female; mean age 37 years) with HIV infection and tuberculosis.InterventionsPatients were randomised to one of the following treatments: group A (n = 16) received antituberculosis drugs without rifampicin, plus highly active antiretroviral therapy (HAART) including efavirenz 600mg once daily, on days 1 to 7. Patients were then switched to rifampicin in bodyweight-adjusted fixed-dose combination plus HAART including efavirenz 600mg once daily (group A-1; n = 8) or efavirenz 800mg once daily (group A-2; n = 8). Group B (n = 8) received rifampicin in bodyweight-adjusted fixed-dose combination on days 1 to 7; on day 8, HAART including efavirenz 800mg once daily was added. Blood samples were obtained on days 7 and 14.MethodsPlasma concentrations of efavirenz and rifampicin were quantified by using validated high performance liquid chromatography assays, and pharmacokinetic parameter values were determined by noncompartmental methods. The differences between pharmacokinetic parameters on days 7 and 14 were used to assess interactions.ResultsThere was a correlation between the pharmacokinetic parameters of efavirenz and the dose/kg administered. For efavirenz, mean (median) peak concentration, trough concentration and area under the concentration-time curve over the administration interval decreased 24% (24%), 25% (18%) and 22% (10%), respectively, in the presence of rifampicin. Large interpatient variability was observed, suggesting that plasma concentration monitoring of efavirenz may be advisable. Overall, the pharmacokinetics of efavirenz 800mg plus rifampicin were similar to those of efavirenz 600mg without rifampicin. The pharmacokinetics of rifampicin did not change substantially in the presence of efavirenz. Differences in patients' bodyweight appeared to cause further differences in exposure to efavirenz. Plasma concentrations of efavirenz in patients weighing <50kg were similar to those previously described in HIV-infected patients without concomitant tuberculosis. However, plasma concentrations in patients weighing ≥50kg were almost halved compared with those in patients weighing <50kg.ConclusionsAlthough the minimal effective efavirenz plasma concentration that assures virological success is not currently known, it may be advisable to increase the dosage of efavirenz to 800mg once daily when it is coadministered with rifampicin. Rifampicin can be used with efavirenz without dosage modification.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS