ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Remifentanil is a novel, short-acting μ-receptor opioid agonist currently in the late stages of development. A member of the 4-anilidopiperidine class, it is unique among the currently marketed agents because of its ester structure. Remifentanil undergoes widespread extrahepatic metabolism by blood and tissue nonspecific esterases, resulting in an extremely rapid clearance of approximately 3 L/min (180 L/h). Like the other members of this class of drugs, remifentanil is lipophilic and is widely distributed in body tissues with a steady-state volume of distribution of approximately 30L.Because of its unique metabolic pathway (among this group of drugs) and rapid clearance, remifentanil represents a new pharmacokinetic class of opioid. Unlike the other fentanyl congeners, termination of the therapeutic effect of remifentanil mostly depends on metabolic clearance rather than on redistribution. The context-sensitive half-time [defined as the time necessary to achieve a 50% decrease in blood (or plasma) concentration after termination of a variable-length, continuous infusion targeted to maintain a steady-state concentration, where the ‘context’ is the duration of the infusion] is strikingly short for remifentanil, and this is perhaps the most compelling evidence of the pharmacokinetic singularity of the drug. Determined by computer simulation, the context-sensitive half-time of remifentanil is approximately 3 minutes, and is independent of infusion duration.Pharmacodynamically, remifentanil is similar to the other fentanyl congeners. The drug produces physiological changes consistent with potent μ-receptor agonist activity, including analgesia and sedation. Its adverse effect profile (like that of the other drugs of this class) includes ventilatory depression, nausea, vomiting, muscular rigidity, bradycardia and pruritus. Because it does not release histamine upon injection, remifentanil has fewer haemodynamic adverse effects than morphine. The therapeutic potency of remifentanil is somewhat less than that of fentanyl, with an effective concentration (producing 50% of maximal effect, as measured by electroencephalography) of approximately 15 to 20 μg/L. Speed of onset of effect is very rapid and is similar to that of alfentanil, which is reflected in a t½ke0(a parameter used to characterise the delay between peak blood drug concentration and peak pharmacodynamic effect utilising a theoretical effect compartment) of approximately 1 to 2 minutes.Remifentanil is likely to be a welcome addition to the anaesthesia drug formulary. Anaesthetists have long recognised the need for a short-acting opioid with a predictable pharmacokinetic profile. Because the length of surgical procedures is often unpredictable, and because the level of surgical stimulation against which the depth of anaesthesia must be balanced is highly variable and dynamic, the advantages of predictably short-acting agents are obvious.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Ondansetron is a potent and highly selective serotonin 5-HT3-receptor antagonist which has demonstrated important antiemetic activity and good tolerability in the prevention of chemotherapy-induced nausea and vomiting.Ondansetron is completely and rapidly absorbed from the gastrointestinal tract after oral administration, and does not accumulate with repeated oral administration. Owing to hepatic first-pass metabolism, its bioavailability is only about 60% compared with ondansetron administered by infusion over 15 minutes. Bioavailability is slightly increased when administered after a standard meal, and is not influenced by coadministration of antacids; a slightly enhanced bioavailability has been observed in patients with cancer. Since the time to reach peak concentration is 0.5 to 2 hours after oral ingestion, the drug should be administered at least 30 minutes before chemotherapy. Possible alternative ways of administration of ondansetron include intramuscular, subcutaneous and rectal administration, and oral controlled-release formulations.Ondansetron is widely distributed (volume of distribution approximately 160L) and binds moderately (70 to 76%) to plasma proteins; the elimination half-life averages approximately 3.8 ± 1 hours. Clearance occurs by hepatic metabolism (95%) rather than renal excretion. Metabolites do not play a role in the activity of the drug, and there is no evidence of genetic polymorphic metabolism.Although aging is associated with decreased clearance and increased bioavailability, dosage adjustments are not required for the elderly, and may be necessary only in patients with severe hepatic impairment. Chemotherapeutic agents do not seem to modify the pharmacokinetics of ondansetron.There remains the question of whether control of emesis is related to systemic availability of ondansetron and, in consequence, the optimal dose and schedule of ondansetron is still to be identified with certainty.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Pharmacological treatment of patients with Alzheimer's disease is becoming more important, as evidenced by the number of drugs being developed in different countries. It has been shown in the majority of clinical trials that cholinesterase inhibitors, such as tacrine (tetrahydroaminoacridine), are able to induce beneficial effects in cognition and memory.Tacrine, like most of the other oral antidementia agents, is rapidly absorbed from the gastrointestinal tract. It is excreted mainly through the kidney, with a terminal elimination half-life of about 3 hours. Tacrine has nonlinear pharmacokinetics and there are large interindividual differences in pharmacokinetic parameters after oral, intravenous and rectal administration. A positive relationship between cognitive changes and plasma tacrine concentrations has been recently described. Similarly, velnacrine exhibits evidence of nonlinearity in some pharmacokinetic parameters, but renal excretion is a minor route of elimination for this drug. Pharmacokinetic data pertaining to eptastigmine, a third cholinesterase inhibitor, is more limited. However, the drug is rapidly distributed to the tissues after oral administration and readily enters the central nervous system, where it can be expected to effectively inhibit acetylcholinesterase in the brain for a prolonged period.Pharmacokinetic data for the nootropic agents are more limited. However, of the 3 agents reviewed only pramiracetam penetrates the central nervous system (CNS) poorly. Indeed, oxiracetam crosses the blood-brain barrier and persists for longer in the CNS than in the serum.Selegiline (deprenyl), a neuroprotective agent, is readily absorbed from gastrointestinal tract. It is metabolised mainly in the liver, and to a minimal extent in the lung or kidneys. The steady-state concentrations of metabolites inthe cerebrospinal fluid (CSF) and serum are very similar, reflecting their easy penetration into the CNS. Idebenone, another neuroprotective agent, likewise is rapidly absorbed and achieves peak concentrations in the brain comparable to those in plasma. Similarly, CSF concentrations of metabolites of ST 200 (acetyl-L-carnitine) parallel those in plasma, suggesting that they easily cross the blood-brain-barrier.Gangliosides (GM1) can be given intramuscularly or subcutaneously, but the latter route of administration provides a concentration 50% higher both in the serum and the ganglioside fraction. However, because of its longer elimination, the intramuscular route is the best form of administration when the brain is the target organ for the treatment.Absorption of nimodipine is quite rapid. The pharmacokinetics of nimodipine during multiple-dose treatment have not been studied extensively; however, the drug does not appear to accumulate during repeated administration of standard doses. Nimodipine has linear pharmacokinetics and is subject to interindividual variability. It is primarily excreted in the urine, but 32% of the dose is excreted in the faeces, possibly as a consequence of biliary excretion.To achieve adequate drug concentrations in the brain, different methods have been devised, both invasive (implantable drug infusion pumps and polymer drugdelivery systems, neural transplantation, etc.) and noninvasive (prodrugs microencapsulated within biocompatible polymers that can protect the drug from degradation, etc.) methods. These methods may provide more effective drug delivery into the CNS, and pharmacokinetic data should be determined when these methods of drug delivery are being assessed in clinical trials.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

The eye provides an interesting study in contrasts: it is a delicate structure with a transparent anterior wall as thin as 0.5mm; yet this structure in combination with the ocular adnexa provides a resilient physicochemical barrier. The lids, tears and lacrimal apparatus work in concert to continuously protect the cornea and conjunctiva with a stable tear film, which also serves as the primary refracting surface. This elaborate defence system simultaneously prevents ready intraocular access of pharmaceutical agents. Additionally, the trilaminate structure of the cornea has variable permeability to chemical agents, thereby further limiting the passage of highly hydrophobic and hydrophilic moieties.Presenting topical pharmaceutical agents to the eye via different delivery systems allows clinicians to directly affect the profile of drug bioavailability and, ultimately, bioactivity. While achieving optimum bioavailability is therapeutically important, one must simultaneously limit the occurrence of drug-induced adverse effects, both systemic and local. Utilising the different pharmacokinetic properties of drug delivery systems permits clinicians to maximise their therapeutic plans for addressing specific clinical situations while minimising the potential for adverse drug effects.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS