Clin Pharmacokinet
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Morphine, morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G) and normorphine were analysed with high performance liquid chromatography in plasma and urine, collected over 72 h after administration of single intravenous 5 mg and oral 20 mg doses of morphine to 7 healthy volunteers. Systemic plasma clearance of morphine was on average 21.1 +/- 3.4 ml/min/kg (1.27 +/- 0.20 L/h/kg), volume of distribution was 2.9 +/- 0.8 L/kg and oral bioavailability was 29.2 +/- 7.2%. Clearance of morphine to form M3G and M6G comprised 57.3% and 10.4%, respectively, and renal clearance comprised 10.9% of total systemic plasma clearance; hence, more than one-fifth of a dose (20.8%) remained as unidentified residual clearance. ⋯ The terminal half-life of normorphine was 23.9 +/- 10.1 h after oral administration. Comparison of oral with intravenous excretion curves showed that a greater part of morphine and metabolites were excreted during the slowly declining phase after the oral dose than the intravenous dose, which is highly suggestive of enterohepatic cycling. The renal clearance of M6G and morphine was seen to exceed creatinine clearance, possibly due to an active secretion process.
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The opioid analgesic agents exhibit relatively large pharmacokinetic differences between drugs, and there is substantial pharmacokinetic and pharmacodynamic variability across subjects or patients with each agent. The advent of patient-controlled analgesic administration techniques and their widespread use in contemporary pain management, especially in postsurgical and cancer patients, has decreased the unfortunate impact of interpatient variability on achieving the optimal balance between pain relief and opioid adverse effect intensity. ⋯ Finally, physicochemical and pharmacokinetic characteristics of these agents are important determinants of the speed of onset of effects, duration of action and spinal selectivity of epidurally and intrathecally administered analgesics. Thus, effective patient-controlled analgesia depends on an understanding of the differential pharmacokinetics of opioids self-administered by a variety of possible modes.
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Review Clinical Trial
Intrathecal drug administration. Present use and future trends.
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Neuromuscular blocking agents provide muscle relaxation for a great variety of surgical procedures with light planes of general anaesthesia. Besides having a significant impact in the development of anaesthesia and surgery, these agents continue to play an important role as pharmacological tools in the elucidation of the physiological and pharmacological regulation of neuromuscular transmission and the morphofunctional organisation of the neuromuscular junction. In the daily practice of anaesthesia, muscle relaxants are considered to be safe drugs with predictable, straightforward pharmacological actions. ⋯ Biotransformation plays an important role in the total elimination of recently introduced compounds. Consequently, knowledge of the disposition pharmacokinetics, excretion and biotransformation of this class of drugs is indispensable for their rational choice for various surgical procedures. In this review, the known pharmacokinetics of standard compounds (introduced before 1980) are briefly summarised and new information generated by the development of vecuronium, rocuronium, pipecuronium (steroidal agents) and atracurium, mivacurium, doxacurium (benzylisoquinolinium esters) is discussed in more detail.
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Carboplatin [diammine(1,1-cyclobutanedicarboxylato)platinum(II)] is one of the most promising second generation platinum compounds. Its greater chemical stability in comparison with cisplatin accounts for its lower reactivity with nucleophilic sites of DNA, and may therefore be related to the higher dose necessary to obtain an antitumour effect similar to that of cisplatin. The lower reactivity with proteins may be related to the observed reduction in nephrotoxicity. ⋯ The low bioavailability (4 to 12%) and the gastrointestinal side effects observed did not warrant further studies with oral administration. In contrast to results from animal studies, the modulation of carboplatin-induced myelosuppression by diethyldithiocarbamate (DDTC) was not clinically successful. Valuable alternatives may be the combination with WR2721 or colony-stimulating factors.