ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Zalcitabine (ddC) was the first drug to be approved under the US Food and Drug Administration's (FDA's) accelerated drug approval process. Zalcitabine is a potent nucleoside analogue inhibitor of reverse transcriptase used in the treatment of HIV infection. It is approximately 10-fold more potent than zidovudine (AZT) on a molar basisin vitro.Zalcitabine is well absorbed orally and reaches maximal plasma concentrations within 1 to 2 hours. In humans it is mainly eliminated by renal excretion of unchanged drug, and patients with renal failure may exhibit a prolonged half-life. A variety of clinical trials have evaluated the efficacy of zalcitabine based on improved survival and decreased frequency of opportunistic infections and on a surrogate marker of HIV disease, the CD4 count, or the concentration of an antigen associated with HIV, p24. Alternating zalcitabine therapy with zidovudine therapy was associated with increased CD4+ lymphocyte counts and reduced plasma p24 antigen levels. Zalcitabine can cause peripheral neuropathy (in 17 to 31% of patients), which is dose-related and is completely reversible when the drug is discontinued. Zalcitabine will continue to play a role in chemotherapeutic approaches to HIV.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Several new cephalosporins have been developed in recent years. These agents include several oral and parenteral agents with extended activity against Gramnegative pathogens. The pharmacokinetic literature for these agents is quite extensive; therefore, we have summarised this information and presented it in tabular form for critical comparison. With a few exceptions, the newer cephalosporins share similar pharmacokinetic properties. Cefixime, cefetamet pivoxil and ceftibuten differ from the others in that they exhibit nonlinear pharmacokinetic properties. The nonlinear nature of these agents is reflected by decreasing maximal concentrations with escalating doses of cefixime and cefetamet pivoxil, decreasing area under the serum concentration-time curve with increasing doses for cefixime, and a reduced bioavailability with large doses of ceftibuten. Attention to such characteristics aid the clinician in selecting appropriate dosage regimens that will optimise drug absorption.The majority of agents are primarily renally eliminated; however, renal elimination accounts for only 20% of cefixime elimination. The pharmacokinetic parameters noted for the newer cephalosporins are not influenced by multipledose administration, suggesting lack of drug accumulation over time. The pharmacodynamics of antimicrobials should be considered when extrapolating pharmacokinetic information into the clinical arena. In the case of the &bgr;-lactams, the time which drug concentrations remain above some critical threshold, such as the minimal inhibitory concentration, appears to have the greatest influence on bactericidal activity. Therefore, it is important to select dosage regimens that will optimise the time serum concentrations remain above this threshold.We present an evaluation of these agents with respect to their activity against a variety of pathogens in an effort to demonstrate a pharmacokinetically-based process of antimicrobial selection.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Pain in childhood has not always been managed as actively as that in adults because of the limited amount of research available to provide guidelines for the management of paediatric pain. However, for many years now the pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children have been studied intensively.Morphine is the standard for opioid analgesics and its pharmacology is the best studied in paediatric patients. During the neonatal period, the volume of distribution (Vd) appears to be smaller in neonates than in adults, but adult values are reached soon after the neonatal period. Although morphine is absorbed both orally and rectally, there is little information on the pharmacokinetics of morphine administered by these routes. The bioavailability of morphine after rectal administration appears to be highly variable.For all the opioid analgesics studied, the elimination of the opioids is slower in neonates than in adults. However, the rate of elimination usually reaches and even exceeds adult values within the first year of life. The high rate of drug metabolism means higher dosage requirements. In regard to the pharmacodynamics of opioid analgesics, infants and children do not appear to be more sensitive to the effects of opioids than adults. Thus, except for the neonatal period, the pharmacokinetics and pharmacodynamics of opioid analgesics are not markedly different from those of adults, and the risk of using opioids in infants and children is not higher.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

The pharmacokinetics of furosemide (frusemide) in patients with oedema have been relatively well studied, but in many studies it is unclear whether the disease or the oedemaper sehas the major effect. The rate of absorption of oral furosemide in patients with oedema was decreased, but total bioavailability was almost unchanged. The peak serum concentration (Cmax) and time taken to achieve Cmaxwere either decreased or unchanged. Binding of furosemide to plasma proteins is lower in patients with congestive heart failure (CHF), decompensated liver cirrhosis (DLC) and nephrotic syndrome, probably as a result of hypoalbuminaemia. The elimination half-life (t½) can be unchanged (CHF, DLC) or prolonged (chronic renal failure: CRF). Plasma and renal clearance are reduced in patients with CRF and nephrotic syndrome, but are almost unchanged in CHF and DLC. Disease-induced disorders are mainly responsible for the alterations of furosemide pharmacokinetics in oedematous conditions, while the influence of oedemaper seis probably not clinically relevant.The pharmacokinetics of digoxin have been studied in a small number of studies only. In patients with CHF, considerable interindividual differences have been found. Because digoxin has a narrow therapeutic window, this drug should be administered cautiously to oedematous patients.Theophylline has higher bioavailability in patients with oedema, with a significantly higher Cmaxin patients with hepatic cirrhosis and CHF than in healthy volunteers (29 and 22%, respectively). Furthermore, clearance decreases and t½increases in these patients.Angiotensin converting enzyme (ACE) inhibitors are often administered as prodrugs, and their pharmacokinetic profile could be influenced by the diseases that accompany oedematous states. However, the effect of oedema is difficult to discriminate from that of the disease. Individual ACE inhibitors are affected differently, but importantly the dosage of perindopril should be reduced in patients with CHF, while for most other ACE inhibitors the changes in pharmacokinetic parameters are clinically irrelevant.In conclusion, studies on pharmacokinetic changes in oedema are limited. Besides affecting absorption (after oral administration) and conversion of the prodrug to the active form, probably as a result of the associated disease, oedema has not been proven to cause any clinically relevant changes in pharmacokinetic parameters for individual drugs. However, further studies of this aspect of pharmacokinetics are needed.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Histamine H1-receptor antagonists are reversible, competitive inhibitors of the actions of histamine, a critical mediator in the pathophysiology of the allergic response. This review is mainly devoted to second generation antihistamines that possess a low sedation potential compared with first generation compounds. The pharmacokinetic and pharmacodynamic data of 10 compounds have been updated. Some values are lacking for drugs under development, but also for older antihistamines. Thereafter, pharmacokinetic-pharmacodynamic relationships are reported from published or original documents.A linear pharmacokinetic-pharmacodynamic relationship has been found for acrivastine, astemizole, cetirizine, ebastine and terfenadine, whereas nonlinear relationships have been calculated for ebastine (in the dog), levocabastine, mizolastine, noberastine and terfenadine. It must be concluded that this type of approach for therapeutic optimisation is very fruitful and may enable large numbers of clinical studies to be avoided.Trends for the future include: (i)in vitrobinding studies with the human H1-receptor obtained by molecular biology; (ii) the characterisation of the cytochromes P450 responsible for the biotransformation of antihistamines; (iii) the calculation of the pharmacokinetic-pharmacodynamic relationship in healthy individuals; and (iv) prospective effect-controlled clinical studies.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS