摘要:

Slow release oral mesalazine (Pentasa®) contains microgranules covered by a semipermeable ethylcellulose membrane. The microgranules continuously release their content from duodenum to ileum in a pH- and time-dependent way. About 75% of the microgranules pass into the colon, where further release is slower. This release pattern does not appear to be affected by food, diarrhoea or the simultaneous use of H2antagonists. Rectal forms of mesalazine deliver active drug directly to the rectum and left colon.Plasma concentrations of mesalazine and its metabolite acetyl-5-aminosalicylic acid after oral or local administration are the result of systemic absorption and hepatic metabolism byN-acetyltransferase. Most studies report maximal plasma concentrations of less than 1 mg/L after oral administration of slow release mesalazine, much lower than those observed after uncoated mesalazine but generally higher than after azo-bound drugs such as sulfasalazine. Urinary recovery is an indicator of absorption and metabolism, and is lower after rectal administration (10 to 30%) than after oral administration (30 to 40%). Faecal recovery after oral administration of slow or delayed release mesalazine is lower than with azo-bound drugs.Mesalazine acts locally after absorption by colonic and ileal mucosa. Mean steady-state concentrations of 25.7 ± 2.2 µg/kg wet weight are found in ileocolonic biopsy specimens from patients with irritable bowel syndrome treated for 1 week with slow release mesalazine 1.5 g/day. Intramucosal concentrations after slow release mesalazine differ little between healthy individuals and patients with inflammatory bowel disease.Although significant differences are found between the various aminosalicylates in release patterns and the resulting pharmacokinetic parameters, no differences in therapeutic effects have been found in comparative studies. High doses of oral mesalazine (2 to 4 g/day) are more effective than lower doses in the treatment of patients with mild to moderate active ulcerative colitis. High doses (4 g/day) are also effective in the treatment of Crohn's disease, predominantly in patients with ileitis. In contrast, no dose ranging effects were demonstrated with local treatment forms: mesalazine 1g enema seems sufficient for patients with distal colitis. Higher serum concentrations and urinary recoveries after the administration of slow or delayed release mesalazine compared with azo-bound drugs suggest a higher risk for renal adverse effects, although the reported occurrence is extremely low.Although preliminary data support an association between mucosal concentrations of mesalazine and its clinical activity, further studies are needed to correlate the effects of this drug with its pharmacokinetic parameters.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Cerivastatin sodium, a novel statin, is a synthetic, enantiomerically pure, pyridine derivative that effectively reduces serum cholesterol levels at microgram doses. Cerivastatin is readily and completely absorbed from the gastrointestinal tract, with plasma concentrations reaching a peak 2 to 3 hours postadministration followed by a monoexponential decay with an elimination half-life (t½β) of 2 to 3 hours. Cerivastatin pharmacokinetics are linear: maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) are proportional to the dose over the range of 0.05 to 0.8mg. No accumulation is observed on repeated administration. Cerivastatin interindividual variability is described by coefficients of variation of approximately 30 to 40% for its primary pharmacokinetic parameters AUC, Cmaxand t½β.The mean absolute oral bioavailability of cerivastatin is 60% because of presystemic first-pass effects. Its pharmacokinetics are not influenced by concomitant administration of food nor by the time of day at which the dose is given. Age, gender, ethnicity and concurrent disease also have no clinically significant effects.Cerivastatin is highly bound to plasma proteins (>99%). The volume of distribution at steady state of about 0.3 L/kg indicates that the drug penetrates only moderately into tissue; conversely, preclinical studies have shown a high affinity for liver tissue, the target site of action.Cerivastatin is exclusively cleared via metabolism. No unchanged drug is excreted. Cerivastatin is subject to 2 main oxidative biotransformation reactions: demethylation of the benzylic methyl ether moiety leading to the metabolite M-1 [catalysed by cytochrome P450 (CYP) 2C8 and CYP3A4] and stereoselective hydroxylation of one methyl group of the 6-isopropyl substituent leading to the metabolite M-23 (catalysed by CYP2C8). The product of the combined biotransformation reactions is a secondary minor metabolite, M-24, not detectable in plasma. All 3 metabolites are active inhibitors of hydroxymethylglutaryl-coenzyme A reductase with a similar potency to the parent drug. Approximately 70% of the administered dose is excreted as metabolites in the faeces, and 30% in the urine.Metabolism by 2 distinct CYP isoforms renders cerivastatin relatively resistant to interactions arising from inhibition of CYP. If one of the pathways is blocked, cerivastatin can be effectively metabolised by the alternative route. In addition, on the basis ofin vitroinvestigations, there is no evidence for either cerivastatin or its metabolites having any inducing or inhibitory activity on CYP. The apparent lack of any clinically relevant interactions with a variety of drugs commonly used by patients in the target population supports this favourable drug-drug interaction profile.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

The optimisation of cyclosporin therapy remains a challenge because of the very narrow therapeutic window and the highly variable pharmacokinetics of the drug. Therefore, there has been a concerted effort in the clinical transplant community to explore and test cyclosporin monitoring tools and techniques that will allow blood concentrations of cyclosporin to be maintained within the narrow therapeutic window in order to maximise efficacy and minimise toxicity.Absorption profiling is a simple and accurate technique for adjusting dosages of cyclosporin microemulsion that utilises an estimation of the rate and extent of cyclosporin absorption in order to optimise immunosuppression in the individual patient. Two estimation tools in particular are an abbreviated area under the concentration-time curve (AUC) for the first 4 hours postdose and a single sampling point at 2 hours postdose. These 2 monitoring strategies have not only been validated as an accurate estimation of cyclosporin bioavailability but have been demonstrated to significantly improve clinical outcomes in patients compared with traditional trough concentration monitoring.The evidence presented in this review demonstrates that absorption profiling results in the following clinical benefits compared with trough concentration monitoring:reduced incidence of acute rejection;reduced severity of rejection episodes;reduced nephrotoxicity; anda rational basis for dosage adjustments.The optimisation of immunosuppressive therapy continues to be a major priority in the management of the organ transplant recipient. Absorption profiling is a sensitive and practical approach for optimising the dosage of cyclosporin microemulsion, and can further extend the benefits of cyclosporin immunosuppression in the individual patient.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Caffeine from dietary sources (mainly coffee, tea and soft drinks) is the most frequently and widely consumed CNS stimulant in the world today. Because of its enormous popularity, the consumption of caffeine is generally thought to be safe and long term caffeine intake may be disregarded as a medical problem. However, it is clear that this compound has many of the features usually associated with a drug of abuse. Furthermore, physicians should be aware of the possible contribution of dietary caffeine to the presenting signs and symptoms of patients.The toxic effects of caffeine are extensions of their pharmacological effects. The most serious caffeine-related CNS effects include seizures and delirium. Other symptoms affecting the cardiovascular system range from moderate increases in heart rate to more severe cardiac arrhythmia. Although tolerance develops to many of the pharmacological effects of caffeine, tolerance may be overwhelmed by the nonlinear accumulation of caffeine when its metabolism becomes saturated. This might occur with high levels of consumption or as the result of a pharmacokinetic interaction between caffeine and over-the-counter or prescription medications.The polycyclic aromatic hydrocarbon−inducible cytochrome P450 (CYP) 1A2 participates in the metabolism of caffeine as well as of a number of clinically important drugs. A number of drugs, including certain selective serotonin reuptake inhibitors (particularly fluvoxamine), antiarrhythmics (mexiletine), antipsychotics (clozapine), psoralens, idrocilamide and phenylpropanolamine, bronchodilators (furafylline and theophylline) and quinolones (enoxacin), have been reported to be potent inhibitors of this isoenzyme. This has important clinical implications, since drugs that are metabolised by, or bind to, the same CYP enzyme have a high potential for pharmacokinetic interactions due to inhibition of drug metabolism. Thus, pharmacokinetic interactions at the CYP1A2 enzyme level may cause toxic effects during concomitant administration of caffeine and certain drugs used for cardiovascular, CNS (an excessive dietary intake of caffeine has also been observed in psychiatric patients), gastrointestinal, infectious, respiratory and skin disorders. Unless a lack of interaction has already been demonstrated for the potentially interacting drug, dietary caffeine intake should be considered when planning, or assessing response to, drug therapy.Some of the reported interactions of caffeine, irrespective of clinical relevance, might inadvertently cause athletes to exceed the urinary caffeine concentration limit set by sports authorities at 12 mg/L. Finally, caffeine is a useful and reliable probe drug for the assessment of CYP1A2 activity, which is of considerable interest for metabolic studies in human populations.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

High dosage busulfan (1 mg/kg orally every 6 hours × 16 doses) is frequently used in preparative regimens for haemopoietic stem cell transplantation (HSCT). Busulfan is well absorbed after oral administration, exhibits low protein binding and is metabolised through conjugation with glutathione to form a thiophenium ion. At a given dose, there is considerable variability in the systemic exposure of busulfan, typically expressed as area under the plasma concentration-time curve (AUC) or average concentration at steady state (Css). Relative to that in adolescents and adults, patients less than 4 years of age have an increased apparent oral clearance (CL/F) of busulfan and a higher conjugation rate of busulfan with glutathione in the enterocyte.Several investigators have identified relationships between busulfan Cssand outcome in patients undergoing HSCT. Busulfan concentration-response relationships are regimen-, age- and disease-dependent. The busulfan/cyclophosphamide (BU/CY) regimen is the only regimen for which substantial concentration-outcome data exist. Generally, the risk of hepatic veno-occlusive disease is increased with busulfan Css> 900 µg/L.The impact of busulfan Csson veno-occlusive disease may be influenced by the age of the patient and the dose of cyclophosphamide. Lower rates of relapse in chronic myelogenous leukaemia occur in patients with a busulfan Css> 917 µg/L without an increased risk of toxicity. Busulfan Cssis also related to the engraftment rate in children, and escalating busulfan doses to achieve a target Css> 600 µg/L improves graft retention.Therapeutic drug monitoring of busulfan should be performed to maximise the likelihood of engraftment and minimise the risk of toxicity and relapse in HSCT patients receiving the BU/CY preparative regimen.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS