Basic & clinical pharmacology & toxicology
-
Basic Clin. Pharmacol. Toxicol. · May 2012
Randomized Controlled TrialLoading dose required to achieve rapid therapeutic teicoplanin trough plasma concentration in patients with multidrug-resistant gram-positive infections.
Teicoplanin is an antibiotic drug prescribed for the treatment of multidrug-resistant Gram-positive infections. However, there is currently no consensus as to the optimal teicoplanin loading dose. The objective of this study was to compare plasma concentrations of teicoplanin in patients with multidrug-resistant Gram-positive infections after the administration of two different loading doses. ⋯ In addition, more patients in group B achieved therapeutic concentrations from days 2 through 12. In conclusion, despite limitations in drawing definitive conclusions because of a relatively small sample size and variability in renal impairment among patients, our findings suggest that a teicoplanin loading dose of 12 mg/kg body-weight results in a safe and rapid attainment of therapeutic trough plasma concentrations. This regimen may enhance treatment efficacy.
-
Basic Clin. Pharmacol. Toxicol. · Apr 2012
No antidotal effect of intravenous lipid emulsion in experimental amitriptyline intoxication despite significant entrapment of amitriptyline.
Intravenous lipid emulsion has been used in the resuscitative treatment of intoxications caused by local anaesthetics and tricyclic antidepressants with seemingly beneficial results. We studied the effect of intravenous lipid emulsion on the plasma concentration of amitriptyline and haemodynamic recovery in a pig model of amitriptyline intoxication. Twenty pigs were anaesthetized (1% isoflurane in 21% O(2)) and given amitriptyline 15 mg/kg intravenously for 15 min. ⋯ However, five pigs in the Lipid group and two pigs in the Control group died. In conclusion, a marked entrapment of amitriptyline by intravenous lipid emulsion was observed but this did not improve the pigs' haemodynamic recovery from severe amitriptyline intoxication. Care should be exercised in the antidotal use of lipid emulsion until controlled human studies indicate its efficacy and safety.
-
Basic Clin. Pharmacol. Toxicol. · Mar 2012
ReviewPharmacokinetic-pharmacodynamic modelling of opioids in healthy human volunteers. a minireview.
Pain is characterized by its multi-dimensional nature, explaining in part why the pharmacokinetic/pharmacodynamic (PK/PD) relationships are not straightforward for analgesics. The first part of this MiniReview gives an overview of PK, PD and PK/PD models, as well as of population approach used in analgesic studies. The second part updates the state-of-the-art in the PK/PD relationship of opioids, focusing on data obtained on experimental human pain models, a useful tool to characterize the PD of analgesics. ⋯ The studies assessing the PK/PD of fentanyl and its derivatives showed a short t(1/2) k(e0) for analgesia, between 0.2 and 9 min., reflecting a short onset of effect. In conclusion, depending on the speed of transfer between the plasma and the effect site as well as the participation of active metabolites, the time-course of the analgesic effects can be close to the plasma concentrations (alfentanil and derivates) or observed with a prolonged delay (codeine, buprenorphine, morphine). These PK/PD data can be used to better characterize the differences between opioids, and partly explain the important observed variability among opioids in experimental conditions and should be systematically evaluated during drug development to better predict their selection in specific clinical conditions.
-
Basic Clin. Pharmacol. Toxicol. · Mar 2012
Lithium attenuates peripheral neuropathy induced by paclitaxel in rats.
As a cancer chemotherapeutic agent, paclitaxel (Taxol® ) causes dose-related peripheral neuropathy in human beings. The mechanisms underlying this toxicity are currently unknown, and there are no validated treatments for its prevention or control. To assess whether lithium as a pre-treatment and at subtherapeutic dose could prevent the peripheral neuropathy produced by it, rats were treated with paclitaxel (2 mg/kg i.p. every other day for a total of 16 times) and/or lithium chloride (300 mg/l) via water supply. ⋯ The same results were observed in histopathological examinations; however, dorsal root ganglion neurons did not significantly change in the paclitaxel-treated groups. These results suggest that lithium, at subtherapeutic doses, can prevent both motor and sensory components of paclitaxel neuropathy in rats. Thus, lithium at these doses, as an inexpensive and relatively safe salt, may be useful clinically in preventing the neuropathy induced by paclitaxel treatment.
-
Basic Clin. Pharmacol. Toxicol. · Dec 2011
Clinical TrialEffect of age on systemic exposure and haematological toxicity of carboplatin in advanced non-small cell lung cancer patients.
The aim of this study was to evaluate systemic exposure to carboplatin and its haematological toxicity in patients with advanced non-small cell lung cancer both older and younger than 70 years when the target area under the curve (AUC) in elderly patients was reduced by 20%. For this purpose, a population pharmacokinetic model was developed and the haematological toxicity of the drug was assessed. A total of 33 patients received carboplatin on day 1 and gemcitabine (1250 mg/m(2) ) on days 1 and 8. ⋯ No significant differences were observed between the two groups with respect to rates of grade 3+ anaemia, neutropenia or thrombocytopenia. In clinical practice, a target AUC of 4 mg/min./mL carboplatin is applied to patients aged 70 and over, but the actual systemic exposure to the drug is higher. This supports a target AUC of 4 mg/min./mL carboplatin for patients older than 70 years when the dose is calculated by means of the Calvert-Crokcoft-Gault formula.