摘要:

Bayesian forecasting offers several important advantages for dosage individualisation in children, although, unlike for adults, its use in this population is much lower. Indeed, currently Bayesian methods are underused in this patient population. The paucity of paediatric population pharmacokinetic parameters, and the unavailability of specific clinical pharmacokinetic software for the whole paediatric population, are the main limitations to the application of Bayesian methods in these patients. When these problems have been overcome, this approach will allow clinicians to achieve therapeutic concentrations more readily, faster and more precisely, thus making the methodology highly attractive in the paediatric setting.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Tiaprofenic acid is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid (2-APA) class. A common structural feature of 2-APA NSAIDs is asp3-hybridised tetrahedral chiral carbon heteroatom within the propionic acid side chain moiety, with theS-enantiomer possessing most of the beneficial anti-inflammatory activity. However, all tiaprofenic acid preparations to date are marketed as the racemate. Tiaprofenic acid has been suggested to exhibit limited pharmacokinetic stereoselectivity.The synovium is the proposed site of action of NSAIDs when used for musculoskeletal disorders, and substantial concentrations of tiaprofenic acid are attained in synovial fluid. Recent data suggest the possibility of stereoselective distribution of tiaprofenic acid into synovium and cartilage. Hence, data generated using non-stereospecific assays may not always be extrapolated to explain the disposition of the individual enantiomers.Tiaprofenic acid is rapidly and almost completely absorbed when given orally. The area under the plasma concentration-time curve (AUC) of tiaprofenic acid is proportional to the oral dose administered.A sustained release dosage form is available, which may be beneficial due to the short terminal phase half-life of tiaprofenic acid (3 to 6 hours). The bioavailability is the same as that with conventional rapid release preparations, although the peak plasma drug concentration is reduced and time to peak is prolonged.Tiaprofenic acid binds extensively to plasma albumin. There is negligibleRtoSinversion upon oral administration.Tiaprofenic acid is eliminated following extensive biotransformation to glucuronide-conjugated metabolites. Approximately 60% is eliminated as conjugates excreted in urine, and little drug is eliminated unchanged. The rate of excretion of tiaprofenic acid and its conjugates may be related to renal function; accumulation of conjugates occurs in end-stage renal disease, but not in young individuals or elderly patients.Potentially clinically important drug interactions with tiaprofenic acid have been demonstrated for some anticoagulants and probenecid. Relationships between tiaprofenic acid concentrations in biological matrices and therapeutic or toxic effects have not yet been elucidated for this drug.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is the key enzyme of cholesterol synthesis. HMG-CoA reductase inhibitors are potent reversible inhibitors of this enzyme, which act by competing for the substrate HMG-CoA.This review is mainly devoted to the 4 main HMG-CoA reductase inhibitors used today: lovastatin, simvastatin, pravastatin and fluvastatin. Depending upon the dosage, these drugs are able to reduce plasma cholesterol levels by more than 40%. After absorption, each undergoes extensive hepatic first-pass metabolism. Up to 5 primary metabolites are formed, some of which are active inhibitors. The elimination half-lives vary from 0.5 to 3.5 hours and excretion is mainly via the faeces. A limited number of drug interactions has been reported. Increases in liver enzymes and muscle creatine kinase activity are among the most severe adverse effects.These powerful drugs should be reserved for patients with high plasma cholesterol levels and/or those with cardiovascular disease.New therapeutic approaches to atherosclerosis are currently under investigation. HMG-CoA reductase inhibitors are the cornerstone of this research.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

The elderly frequently use psychoactive drugs including alcohol (ethanol), benzodiazepines and opioid analgesics, which have a propensity to cause abuse and dependence. Theoretically, the changes in pharmacokinetics of these agents in the elderly may modify their abuse and dependence potential. In the elderly, blood alcohol concentrations following an oral dose are higher, alcohol withdrawal syndrome follows a more severe and protracted clinical course and requires treatment with higher doses of chlordiazepoxide than needed for younger adults. However, there is no direct evidence that supports an increased direct abuse and dependence potential of alcohol because of its altered kinetics in the elderly.In the case of oxidatively metabolised benzodiazepines, both age-related pharmacokinetic and pharmacodynamic changes may increase their clinical effects in the elderly. The hypothesis that benzodiazepines have an increased abuse and dependence potential in the elderly has not been tested. Many of the benzodiazepines (e.g. alprazolam, triazolam and midazolam) are metabolised by the cytochrome P450 (CYP)3A subfamily. The pharmacokinetics of these agents may be modified by inhibition of CYP3A due to concurrently administered medications such as selective serotonin reuptake inhibitors. Unfortunately, data on the direct measures of abuse and dependence potential of benzodiazepines are not available in the elderly. Thus, a conclusive statement on the contribution of agerelated pharmacokinetic changes to benzodiazepine abuse and dependence cannot be made at the present time.The clinical effects of codeine do not appear to change with age. Codeine isO-demethylated to its active metabolite morphine by the genetically polymorphic CYP2D6 isozyme. The activity of this isozyme is unaltered by age, gender or smoking habits; however, it is subject to potent inhibition by some of the frequently used medications in the elderly, such as the antidepressants paroxetine and fluoxetine. This may result in an impairment inO-demethylation of codeine to morphine and may lead to a decrease in the abuse and dependence potential of codeine. Conversely, those with a very rapid CYP2D6 catalytic activity may have an increased potential for codeine abuse and dependence.The clinical significance of age-related pharmacokinetic changes should be evaluated within the context of clinical practice. Most physicians are inclined to prescribe lower doses to the elderly, which may offset the potential impact of altered pharmacokinetics on the abuse and dependence potential of psychoactive agents.In summary,the available data are not sufficient for a definitive conclusion on whether the pharmacokinetic changes in the elderly translate to an increase in the abuse and dependence potential of alcohol, benzodiazepines or opioids. In particular, the data on age-associated changes in direct measures of abuse potential of these agents are missing. Future comparative systematic pharmacokinetic-pharmaco-dynamic studies assessing pertinent outcome measures on abuse and dependence potential of commonly used psychoactive drugs are required to resolve the ongoing controversy on risk factors for drug abuse and dependence in the elderly.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Gastro-oesophageal reflux disease (GORD) is a very common disorder of upper gastro-intestinal motility, differing widely in severity and prognosis. Medical therapy of GORD has involved antacids, alginates, prokinetic agents and antisecretory compounds, primarily H2receptor antagonists and proton pump inhibitors. Knowledge of the pharmacokinetics of these compounds is important, to optimise the therapeutic benefit in each patient.GORD patients are often elderly and pharmacokinetics are more variable in this group. Furthermore, they often suffer from other diseases needing medical therapy and may need a combination of drugs to heal reflux oesophagitis and relieve reflux symptoms. The ideal therapy for GORD will have linear pharmacokinetics, a relatively long plasma half-life (t½), a duration of action allowing once daily administration, and a stable effect independent of interactions with food, antacids and other drugs.Over-the-counter antacids and alginates are widely used, but may affect absorption of H2receptor antagonists like cimetidine and ranitidine. Aluminiumcontaining antacids may, over time, cause toxicity in patients with renal insufficiency. In the treatment of GORD, cisapride presents important advantages over earlier prokinetic compounds, with a longer plasma t½, low penetration of the blood-brain barrier and fewer adverse effects.The group of H2receptor antagonists is still the most frequently used therapy for GORD. Linear pharmacokinetics make dose adjustments easy and safe. In individual patients, suppression of gastric secretion is related to the area under the plasma concentration-time curve (AUC), but there is wide interindividual variation in the effect of the same oral dose. Only with frequent administration and high doses will acid suppression approximate that of proton pump inhibitors. Tolerance, with loss of effect over time, however, is most pronounced in this situation.H2receptor antagonists seem well suited for on-demand treatment of reflux symptoms, due to the rapid onset of effect and a decreased likelihood of the development of tolerance. Effervescent formulations provide more rapid absorption and almost immediate clinical effect. Cimetidine, however, causes interference with the metabolism of several other drugs in common use. In elderly patients elimination is delayed and in patients with renal insufficiency, dose reductions of all H2receptor antagonists are recommended.The most effective medical therapy for any severity of GORD, particularly in severe oesophagitis, are the proton pump inhibitors. The substituted benzimidazoles (omeprazole, lansoprazole and pantoprazole), are prodrugs which once trapped and activated in the acid milieu of the gastric glands potently suppress gastric secretion of acid and pepsin. Their long duration of action, more related to the slow turnover of parietal cell H+-K+ATPase molecules, allows once daily administration in most patients. Interindividual variation in bioavailability sometimes calls for higher doses or twice daily administration.Acid suppression is closely related to the AUC. Omeprazole is prone to interaction with the metabolism of other drugs, some of which may be clinically important. Lansoprazole seems to have an earlier onset of action than omeprazole, ascribed to higher bioavailability during the first days of treatment. Proton pump inhibitors have a slow onset of action, which makes them unsuited for on-demand therapy.Clinical practice in GORD calls for the use of not one but several substances, according to the severity and symptom pattern of the patient. Pharmacokinetic optimisation in the treatment of GORD is a question of selecting the most suitable substances and administration schemes within each group. Cisapride is superior to other prokinetics in terms of longer plasma t½ and less toxicity. Amongst H2receptor antagonists, the more long-acting compounds, ranitidine and famotidine, will improve acidity control throughout 24 hours and also cause less metabolic interaction with other drugs than cimetidine.Lansoprazole has a higher bioavailability than omeprazole from the first day of therapy, resulting in the more rapid relief of symptoms. Pantoprazole may cause fewer drug interactions than other proton pump inhibitors.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS