摘要:

Despite the fact that all new anticonvulsants have undergone extensive pharmacokinetic scrutiny prior to their introduction to the market, the opportunity to perform good prospective studies on their concentration-effect relationship has been largely missed, in some cases deliberately because therapeutic drug monitoring (TDM) is considered unfavourable for the marketing of a new drug. However, there are reasons to believe that TDM may play a useful role in maximising the therapeutic potential of new anticonvulsants. In fact, these drugs have a narrow therapeutic index, careful individualisation of dosage to optimise response is required, and inter- and intra-individual pharmacokinetic variability may translate into differences in dosage requirements. The wide interindividual variability in the serum concentrations at which therapeutic and toxic effects of these drugs are observed does not necessarily imply that TDM cannot be useful: indeed, a marked pharmacodynamic variability has also been reported for all the currently monitored older anticonvulsants.The new anticonvulsants which, based on their properties, are particularly attractive candidates for TDM include lamotrigine, topiramate, tiagabine, zonisamide and felbamate. However, in the absence on sound information on the target concentration ranges of these drugs, the routine concentration monitoring of these drugs cannot be recommended. Despite this, serial measurements of serum drug concentrations may be useful in selected patients, especially those suspected of poor compliance and those in whom pharmacokinetic changes caused by disease or administration of concomitant medication are anticipated. Even in the presence of marked interindividual pharmacodynamic variability, it is often possible to empirically determine the concentration at which each patient exhibits the best response, and apply that information in subsequent management. Prospective studies, using preferably a randomised concentration-controlled design, are necessary to better characterise concentration-effect relationships for these agents.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Isepamicin is an aminoglycoside antibacterial with properties similar to those of amikacin, but with better activity against strains producing type I 6′-acetyltransferase. The antibacterial spectrum includes Enterobacteriaceae and staphylococci. Anaerobes, Neisseriaceae and streptococci are resistant. The lower and upper break-points are 8 and 16 mg/L. Like other aminoglycosides, isepamicin exhibits a strong concentration-dependent bactericidal effect, a long post-antibiotic effect (several hours) and induces adaptive resistance.Isepamicin is administered intravenously or intramuscularly at a dosage of 15 mg/kg once daily or 7.5 mg/kg twice daily. Isepamicin is not bound to plasma proteins, and it distributes in extracellular fluids and into some cells (outer hair cells, kidney cortex) by active transport. Isepamicin is not metabolised and is eliminated solely via the renal route with an elimination half-life (t½β) of 2 to 3 hours in adults with normal renal function. The clearance of isepamicin is reduced in neonates, and 7.5 mg/kg once daily is recommended in children <16 days old. Clearance is also reduced in the elderly, but no dosage adjustment is required. In patients with chronic renal impairment, isepamicin clearance is proportional to creatinine clearance (CLCR); the recommended regimen is 8 mg/kg with an administration interval of 24 hours in moderate impairment, 48 hours in severe impairment, 72 hours for CLCR0.6 to 1.14 L/h (10 to 19 ml/min) and 96 hours for CLCR0.36 to 0.54 L/h (6 to 9 ml/min). In end-stage renal failure, isepamicin is eliminated by haemodialysis, but the administration interval should be determined by monitoring the plasma concentration.Compared with healthy volunteers, patients in the intensive care unit or with neutropenic cancer have an increased volume of distribution and a lower clearance, but the 15 mg/kg once daily regimen remains adequate. Isepamicin kinetics are linear in the range 7.5 to 25 mg/kg, so that dosage adjustments, if necessary, are straightforward. Isepamicin can induce nephro-, vestibulo- and oto-toxicity. However, animal and clinical studies show that isepamicin is one of the less toxic aminoglycosides.The usefulness of maintaining serum aminoglycoside concentrations within a therapeutic range remains controversial. With isepamicin, it is proposed to achieve a 1-hour concentration (30 minutes after a 30-minute infusion) >40 mg/L to maximise bactericidal efficacy, and a ‘trough’ concentration (at the end of the administration interval) <5 mg/L to minimise toxicity. These thresholds should be modified on an individual basis, considering covariates such as concomitant treatment, underlying disease, nature of bacterial strain and site of infection.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), is the first specific inhibitor of cyclo-oxygenase-2 (COX-2) approved to treat patients with rheumatism and osteoarthritis. Preliminary data suggest that celecoxib also has analgesic and anticancer properties. The selective inhibition of COX-2 is thought to lead to a reduction in the unwanted effects of NSAIDs. Upper gastrointestinal complication rates in clinical trials are significantly lower for celecoxib than for traditional nonselective NSAIDs (e.g. naproxen, ibuprofen and diclofenac).The rate of absorption of celexocib is moderate when given orally (peak plasma drug concentration occurs after 2 to 4 hours), although the extent of absorption is not known. Celexocib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 455 ± 166L in humans. The area under the plasma concentration-time curve (AUC) of celecoxib increases in proportion to increasing oral doses between 100 and 800mg. Celecoxib is eliminated following biotransformation to carboxylic acid and glucuronide metabolites that are excreted in urine and faeces, with little drug (2%) being eliminated unchanged in the urine. Celecoxib is metabolised primarily by the cytochrome P450 (CYP) 2C9 isoenzyme and has an elimination half-life of about 11 hours in healthy individuals. Racial differences in drug disposition and pharmacokinetic changes in the elderly have been reported for celecoxib.Plasma concentrations (AUC) of celecoxib appear to be 43% lower in patients with chronic renal insufficiency [glomerular filtration rate 2.1 to 3.6 L/h (35 to 60 ml/min)] compared with individuals with healthy renal function, with a 47% increase in apparent clearance. Compared with healthy controls, it has been reported that the steady-state AUC is increased by approximately 40% and 180% in patients with mild and moderate hepatic impairment, respectively.Celecoxib does not appear to interact with warfarin, ketoconazole or methotrexate; however, clinically significant drug interactions with fluconazole and lithium have been documented. As celecoxib is metabolised by CYP2C9, increased clinical vigilance is required during the coadministration of other substrates or inhibitors of this enzyme.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

AsHelicobacter pyloriplays an important role in the aetiopathogenesis of peptic ulcer, therapeutic strategies aimed at maintaining long term remission have shifted from the control of intragastric pH to targetingH. pylori. According to recent international guidelines the clinical goals − rapid ulcer healing and prevention of relapse − can be best accomplished by combination therapy consisting of an antisecretory drug (proton pump inhibitor or ranitidine) and 2 antimicrobial agents (preferable amoxicillin, clarithromycin or metronidazole).When applying such multidrug regimens, possible synergy between the agents suggests that pharmacokinetic considerations might help to improveH. pylorieradication rates, which should be above 85 to 90% on an intention-to-treat basis. The present review summarises the pharmacokinetic properties and interaction potential of all drugs presently used in the variousH. pylorieradication regimens, with emphasis on particular patient populations such as the elderly and those with renal impairment. The drugs considered are omeprazole, lansoprazole, pantoprazole, rabeprazole, ranitidine and ranitidine bismutrex, bismuth salts, amoxicillin, clarithromycin, azithromycin, roxithromycin, metronidazole, tinidazole and tetracycline.When addressing the clinically important questions of the efficacy, safety and costs of the recommended regimens, the impact of drug disposition onH. pylorieradication should not be neglected.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

The plasma protein binding of drugs, particularly those that are highly bound, may have significant clinical implications. Although protein binding is a major determinant of drug action, it is only one of a myriad of factors that influence drug disposition. The extent of protein binding is a function of drug and protein concentrations, the affinity constant for the drug-protein interaction and the number of protein binding sites per class of binding site.Age-related changes in protein binding are usually not clinically important in drug therapy. Albumin levels are generally decreased in the elderly, whereas α1-acid glycoprotein levels are not altered by ageper se. Alterations in plasma protein binding that occur in the elderly are generally not attributed to age, but rather to physiological and pathophysiological changes or disease states that may occur more frequently in the elderly and most often account for altered protein binding. Age-related physiological changes, such as decreased renal function, decreased hepatic function and decreased cardiac output, generally produce more clinically significant alterations in drug disposition than that seen with alterations in drug plasma protein binding.An understanding of the inter-relationships between drug concentrations, protein binding, the physiology of aging, disease, pharmacokinetics and pharmacodynamics is necessary for effective therapeutic monitoring. Monitoring of unbound drug concentrations simplifies these relationships and provides the fundamental information needed for dosage regimen development and adjustment. Drug therapy in the elderly should be individualised taking into account all of these factors.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS