ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Flurbiprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class. Although it possesses a chiral centre, with theS-(+)-enantiomer possessing most of the beneficial anti-inflammatory activity, both enantiomers may possess analgesic activity and all flurbiprofen preparations to date are marketed as the racemate. Flurbiprofen exhibits stereoselectivity in its pharmacokinetics. Stereoselectivity is exhibited at the level of protein binding and metabolite formation. Hence, the data generated using nonstereoselective assays may not be used to explain the pharmacokinetics of individual enantiomers.The absorption of flurbiprofen is rapid and almost complete when given orally. The area under the plasma concentration-time curve of flurbiprofen is proportional to the dose administered to patients. Sustained release dosage forms are available, which may be beneficial due to the short terminal phase elimination half-life of conventional immediate release flurbiprofen (3 to 6 hours). They may also decrease local gastrointestinal adverse effects. Although with these preparations the peak plasma drug concentration is reduced and time taken to achieve peak concentrations is prolonged, the bioavailability is the same as that with regular release counterparts. Flurbiprofen binds extensively to plasma albumin, apparently in a stereoselective manner. Substantial concentrations of the drug are attained in synovial fluid, which is the proposed site of action of NSAIDs. There is negligibleRtoSinversion after oral administration.Flurbiprofen is eliminated following extensive biotransformation to glucuroconjugated metabolites. Conjugates are excreted in urine, and approximately 20% of flurbiprofen is eliminated unchanged. The excretion of conjugates may be tied to renal function as accumulation of conjugates occurs in end-stage renal disease, but not in young individuals or elderly patients. Although flurbiprofen is excreted into breast milk, the amount of drug transferred comprises only a small fraction of the maternal exposure. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), coumarins and propranolol. The relationship between concentration and anti-inflammatory and analgesic effect has yet to be elucidated for this drug.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

The clinical effectiveness of rifabutin for prophylaxis of disseminatedMycobacterium aviumcomplex infection has recently been demonstrated in HIV-positive patients with low CD4 counts. Rifabutin is a newly marketed, semisynthetic antimycobacterial agent similar to rifampicin (rifampin) in structure and activity. However, rifabutin has important pharmacokinetic differences compared with rifampicin.Rifabutin has relatively low oral bioavailability; about 20% after single dose administration. With long term administration rifabutin induces its own metabolism and the metabolism of some other drugs. The elimination half-life of rifabutin is long (45 hours) but, as a result of a very large volume of distribution (>9 L/kg), average plasma concentrations remain relatively low after repeated administration of standard doses.In vitrorifabutin is more active againstM. avium-intracellularecomplex and at least as active againstM. tuberculosisas rifampicin.In vivothe advantage of rifabutin is less apparent due to its lower plasma concentrations at equivalent doses. Adverse effects are unusual at the recommended oral dosage of 300 mg/day, but become common as the total daily dose approaches 1g. Dose-limiting toxicity consists of a polyarthralgia/arthritis syndrome, possibly complicated by uveitis. More clinical studies are needed to establish the role of rifabutin in combination therapy forM. avium-intracellularecomplex and other mycobacterial infections.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Monoclonal antibodies to tumour-associated antigens have great theoretical potential for the specific targeting of radioactivity and anti-neoplastic agents to tumours. The clinical success of monoclonal antibody-based cancer diagnosis and therapy depends, however, on solving a number of pharmacokinetic delivery problems. These include: (i) slow elimination of monoclonal antibodies from the blood and poor vascular permeability; (ii) low and heterogeneous tumour uptake; (iii) cross-reactivity with normal tissues; (iv) metabolism of monoclonal antibody conjugates; and (v) immunogenicity of murine forms in humans.As a result of extensive pharmaceutical and pharmacokinetic research conducted over the past 10 to 15 years, several potential solutions to these delivery problems have been identified. Blood concentrations of antibody conjugates may be reduced through regional administration, the use of antibody fragments, interventional strategies and various pre-targeting techniques. Tumour uptake may be increased through administration of higher doses, or the use of agents to increase tumour vascular permeability. Tumour retention of antibody conjugates may be improved by inhibition of metabolism, by using more stable linkage chemistry. Alternatively, normal tissue retention may be decreased through the use of metabolisable chemical linkages inserted between the antibody and conjugated moiety.Very small antigen-binding fragments and peptides that exhibit improved tumour penetration and more rapid elimination from the blood and normal tissues have been prepared by genetic engineering techniques. Chimeric (mouse/human) and human monoclonal antibodies have been developed to circumvent the problem of immunogenicity. Future research will continue to be focused on improvements in the design of monoclonal antibodies for tumour targeting, with the ultimate goal of finally uncovering the ‘magic bullet’ envisioned by Paul Ehrlich almost a century ago.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Pharmacokinetic/pharmacodynamic surrogate relationships have been used to describe the antibacterial activity of various classes of antimicrobial agents. Studies that have evaluated these relationships were reviewed to determine which of these surrogate markers were further dependent on antimicrobial class.The fluoroquinolone and aminoglycoside agents exhibit concentration-dependent killing. Studies have demonstrated that peak serum concentration: minimum inhibitory concentration (MIC) and area under the serum concentration-time curve (AUC): MIC ratios are important predictors of outcome for these antimicrobial agents. Area under the inhibitory concentration-time curve (AUIC24) [i.e. AUC24/MIC] is a useful parameter for describing efficacy for these agents, while an adequate peak concentration: MIC ratio seems necessary to prevent selection of resistant organisms.For &bgr;-lactam antibiotics, the duration of time that the serum concentration exceeds the MIC (T > MIC) was the significant pharmacokinetic/pharmacodynamic surrogate in cases where the bacterial inoculum was low, or where very sensitive organisms were tested. However, in studies using more resistant organisms or larger inoculum sizes there is some concentration-dependence to the observed effect. Studies using reasonable dosage intervals have demonstrated covariance between T > MIC and AUC/MIC ratio for &bgr;-lactam antibiotics.Since glycopeptide antibiotics display relatively slow but concentration-independent killing, and are cell wall active agents similar to &bgr;-lactams, it has been presumed that T > MIC is the important pharmacokinetic surrogate related to efficacy for these agents. Some studies have shown that a concentration multiple of the MIC may be necessary for successful outcome with vancomycin. AUIC24may prove to be an important pharmacokinetic surrogate if both time and concentration are indeed important parameters.To select an appropriate antimicrobial agent, the clinician must consider many patient-specific as well as organism-specific factors. Utilisation of known pharmacokinetic/pharmacodynamic surrogate relationships should help to optimise treatment outcome.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Pregnancy is a specific dynamic state, and the potential usefulness of caring for a disorder in the fetus or the mother is now well established. Previously, pregnant women have been excluded from clinical trials, therefore only a few studies concerning evaluation of the pregestational metabolism or transplacental transfer (TPT) of drugs exist.Questions regarding the TPT of drugs are extensive and complex. For example, does TPT occur at a given gestational age, in the context of a particular type of pathology or when a drug is administered by a certain dosage regimen? If this is the case, what is the rapidity of penetration of the products of conception by the drug (bearing in mind its physicochemical characteristics)? Need harmful adverse effects on the child be feared? Is such penetration desirable, of no consequence, or dangerous? Does the possibility exist of accumulation in the placenta, fetal tissue or amniotic fluid? Should such findings modify the therapeutic regimens of drugs given to expectant mothers?Exchange mechanisms are complicated and models developedin vitroonly partially reflect the actual equilibria that exist between mother and fetus. These include: (i) the perfused cotyledon model, which while simple, elegant and inexpensive, offers only a localised, restricted and fixed view of pregnancy; (ii) isolated anatomical fractions that are informative, but which straddle the border between physiology and pharmacology; and (iii) the necessary study, using microsomes, of placental metabolic capacity (enzyme cartography).In vivostudy of TPT is based upon various multicompartmental pharmacokinetic models, some of which have been relatively validated in animals. The simplest indicator for thein vivoevaluation of TPT of a drug in the human species is determination of a feto-maternal blood concentration ratio (usually performed at the time of placental separation). However, the usefulness and limitations of this parameter are controversial, and it would seem preferable to associate it with a pharmacokinetic profile of variations in blood concentrations established in the mother. Furthermore, any extrapolation of a single result to fetal and adjacent tissues must be done with the greatest caution.Although, no drug should be used in pregnancy unless there is a clear therapeutic indication, study of the TPT of therapeutically useful agents is essential to the understanding of their metabolism and is a prerequisite to the safe use of medications during pregnancy.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS