摘要:

Conventional antiarrhythmia therapy by oral or intravenous routes of administration is often ineffective and results in drug-associated complications and toxicity. In addition, poor bioavailability and a high first-pass effect limit therapeutic applications of several investigational antiarrhythmic compounds, which are otherwise more potent and less toxic than available agents. The regional nature of the several cardiac diseases, such as ischaemia, restenosis or heart valve calcification, may require a high concentration of drug at the location of the disease, which by conventional routes may not be attainable due to systemic toxicity of the drug.Localised cardiac delivery of antiarrhythmic agents, based on drug-polymer implants, may have several advantages, including enhanced drug effects and reduced systemic drug toxicity. Computer-assisted automated feedback systems may further enhance the usefulness of this therapy in the clinical setting.Before clinical application of this method of drug delivery further study will be required, but it is hypothesised that pharmacokinetic variability for drugs delivered in this manner will be reduced and therefore efficacy and toxicity will be more predictable.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

The successful introduction of angiotensin converting enzyme (ACE) inhibitors in the treatment of patients with essential hypertension or heart failure has increased interest in the (patho)physiological role of the renin-angiotensin system (RAS). ACE is not only involved in the formation of angiotensin II from angiotensin I, but also inactivates vasoactive substances such as bradykinin and substance P. Accumulation of these substances during treatment with ACE inhibitors may contribute to both their therapeutic action and certain adverse effects associated with their use, such as cough and angioneurotic oedema.Renin inhibitors offer an alternative approach to inhibit the RAS. The major advantage of these, still experimental, drugs is their high specificity for the RAS since angiotensinogen is the only known substrate of renin. The currently available renin inhibitors are pseudopeptides that are rapidly taken up by the liver and excreted in the bile. Consequently, these drugs are subjected to a considerable first pass effect which limits their oral bioavailability. Additionally, plasma elimination half-life times are short and the duration of action is limited. Despite these shortcomings, single oral or intravenous administration results in a 80 to 90% inhibition of plasma renin activity and a slight reduction in blood pressure in patients with hypertension. The extent of blood pressure reduction is dependent on the patient's salt balance.After 1 week of oral treatment with the renin inhibitor remikiren, the antihypertensive effect was reduced in salt-repleted hypertensive patients. Subsequent intravenous administration of the drug did not further affect blood pressure, indicating that it was not the first pass effect that was limiting the efficacy of remikiren. The reactive increase in immunoreactive renin, alternative routes of angiotensin II formation and counteracting blood pressure regulating mechanisms may also be involved in the limited haemodynamic response to renin inhibitors.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Burn injury induces many different pathological changes in the human body, which potentially alter pharmacokinetic parameters such as bioavailability, protein binding, volume of distribution (Vd) and clearance. The extent of these alterations depends on the drug, the type and extent of injury and the time that elapsed between injury and drug administration. Bioavailability of large and hydrophilic molecules may be increased because of enhanced intestinal permeability. The free fraction of a drug in plasma can be increased (when primarily bound to albumin) or decreased (when primarily bound to &agr;1-acid glycoprotein). Vd may change as a consequence of altered protein binding or an enlarged extracellular fluid volume. Alterations in clearance may be due to changes in glomerular filtration, tubular secretion, hepatic blood flow, drug-metabolising activity, protein binding and to the presence of additional elimination pathways. Elimination half-life changes when Vd and/or clearance is affected following burn injury.The therapeutic consequences of pharmacokinetic alterations are discussed in principle, and for specific treatment with antibacterials, anti-ulcer drugs, analgesics, muscle relaxants, anxiolytics, phenytoin and cyclosporin. If significant changes in pharmacokinetic disposition occur following thermal injury, therapeutic drug monitoring and dosage adjustment may be required to ensure rational and well tolerated drug therapy in patients with burns. Future studies should focus on the impact of specific patient variables (e.g. type of injury and size of burn) on the extent of pharmacokinetic alterations.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

When monitoring of the plasma concentrations of anticonvulsant drugs first came into use 25 years ago, it appeared to have a major impact on improving the effectiveness and safety of anticonvulsant therapy. However, as time has passed, prescribers have absorbed many of the lessons to be learned from the monitoring, and now apply this knowledge without necessarily monitoring plasma anticonvulsant concentrations as frequently as in the past. Therefore, the effect of the drug concentration monitoring on the cost effectiveness of anticonvulsant therapy is probably not as significant now as it originally was.In theory, drug concentration monitoring is often unlikely to decrease the cost of contemporary anticonvulsant drug therapy, but it may enhance the efficacy of the therapy. Thus, monitoring may reveal unrecognised under- or overdosage, detect failure of compliance or drug-drug interactions, or indicate when there is little point in persisting with a particular anticonvulsant drug.Despite a good deal of anecdotal testimony, surprisingly little has been published demonstrating the benefits of anticonvulsant therapeutic drug monitoring in epileptic populations. However, one study did show better rates of seizure control rates in patients monitored in the first 6 months of their epileptic disorder; but not if the monitoring began later than this.Under conditions of contemporary practice, monitoring appears to be most advantageous under the following conditions: (i) while seizure control is being established in a patient; (ii) if seizures are no longer being controlled by therapy; (iii) if adverse effects that are possibly treatment-related occur; (iv) if a concomitant illness develops; (v) if there is a change in a patient's physiological state, e.g. pregnancy; and (vi) prior to the withdrawal of therapy.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Bone infection has long been a formidable foe of orthopaedic surgeons. The standard method of treating osteomyelitis generally consists of irrigation and debridement supplemented by pre- and postoperative antibiotics and intraoperative antimicrobial solutions. In the 1970s, Buchholz introduced the concept of local antibacterial therapy in the form of antibiotic impregnated bone cement to treated infected arthroplasties. From this, antibiotic impregnated beads were developed to treat local infections of bone and soft tissue. The advantage of these beads compared with parenteral therapy is that they deliver a high concentration of antibacterial locally while avoiding high systemic concentrations, thus avoiding adverse effects that are often associated with parenteral antibacterial therapy.Additionally, methylmethacrylate bone cement does not significantly affect the immune response of the body. This makes the use of antibiotic-impregnated polymethylmethacrylate (PMMA) beads highly effective either as an alternative to, or in conjunction with, systemic antibiotic treatment of infected arthroplasties, and localised bone and soft tissue infection. This article explores the indications for the use of local therapy as well as any advantages or disadvantages it may have over systemic antibacterial treatment. Additionally, there are important pharmacokinetic considerations for the optimal use of antibacterial agents in the treatment of osteomyelitis.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

More than 7 years after the introduction of zidovudine for treatment of HIV infection, little use has been made of the pharmacokinetic properties of this or any of the subsequently approved antiretroviral agents to optimise therapy. This is partly because of the limits of technologies developed to measure clinically relevant forms and concentrations of these drugs, and partly because the clinical community has been slow to recognise the potential benefits of pharmacokinetic optimisation of nucleoside analogue therapy in any disease. Nonetheless, for some of these agents, progress in understanding the relationship between pharmacokinetics and pharmacodynamics has been made.With zidovudine, for example, even though plasma concentrations have little clinical utility, evidence suggests that concentrations of active phosphorylated forms of zidovudine inside target cells are related to disease progression and toxicity. Furthermore, a decreased ability to phosphorylate zidovudine might be a prerequisite for the emergence of zidovudine-resistant HIV strains. Measurements of phosphorylated zidovudine inside cells similarly suggest that 100mg of oral zidovudine every 8 hours approximates the optimal initial dosage regimen in asymptomatic patients. Increased plasma didanosine concentrations have been associated with several measures of clinical improvement in patients, and may be associated with an increased risk of toxicity as well.For zalcitabine and stavudine, however, the picture is much less clear. Their pharmacokinetic and pharmacodynamic relationships have not been studied in patients. Furthermore, there is insufficient data on the effects of age, gender, race and concurrent underlying conditions on the pharmacokinetics ofallof these agents. Mounting evidence suggests that monitoring of these compounds could lead to individually optimised intervention strategies. Given the marginal benefits of therapy with these agents, their proven toxic effects and the lack of proven alternatives, it is critical that the clinical community strive to make the most effective use of these agents in the treatment of their patients.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS