Therapeutic drug monitoring of antibiotic agents: evaluation of predictive performance.

BACKGROUND: The precision of the population pharmacokinetic model used in therapeutic drug monitoring (TDM) is essential for successful dosage optimisation. OBJECTIVE: To evaluate the predictive performance of pharmacokinetic models used in our hospital and to evaluate the possible impact of demographic characteristics or renal function on TDM accuracy. METHODS: We compared a posteriori an adjusted concentration-time curve profile based on the first measured drug concentration with the second measured drug concentration. Linear regression models were used to compare predicted and observed drug serum concentrations, and to evaluate potential relationships between predictive performance and patients´ demographic/clinical features. Predictive performance of TDM was expressed using accuracy, precision, sensitivity and specificity. RESULTS: One hundred and fifty-two patients were enrolled in the study. All pharmacokinetic models showed good predictive performance expressed by the coefficient of determination (r2) of 0.5642, 0.7263, 0.9001 and 0.9454 for continuous vancomycin, intermittent vancomycin, amikacin and gentamicin, respectively. Accuracy was 93.3%, 91.2%, 113.9% and 130.9% for continuous vancomycin, intermittent vancomycin, amikacin and gentamicin, respectively. Demographic characteristics or renal functions had no substantial impact on the accuracy of TDM. CONCLUSION: We found the predictive performance of both aminoglycosides and vancomycin pharmacokinetic models to be satisfactory.

Impact of ABCB1 and CYP2D6 polymorphisms on tamoxifen treatment outcomes and adverse events in breast cancer patients.

PURPOSE: This study was designed to evaluate the effect of CYP2D6 and ABCB1 polymorphisms and co-medication on the outcomes and adverse events (AEs) of tamoxifen therapy. METHODS: In total, 258 women (187 postmenopausal and 71 premenopausal) with hormone positive breast carcinoma were retrospectively evaluated. CYP2D6 polymorphisms were evaluated with AmpliChip (Roche), and polymorphisms of ATP-binding cassettes B1 (P-glycoprotein) (ABCB1) rs2032582 and rs1045642 with restriction fragment length polymorphisms polymerase chain reaction (RFLP-PCR). RESULTS: CYP2D6 polymorphisms or co-medication affecting CYP2D6 activity demonstrated no statistically significant effect on the efficacy of tamoxifen therapy or AE incidence. There was only a trend towards shortening the time to event (TTE) in CYP2D6-poor metabolisers. ABCB1 polymorphism rs2032582 was not associated with clinical outcomes, while a trend towards an increase in TTE, in variant allele carriers, was noted. The ABCB1 polymorphism rs1045642 demonstrated statistical significance, albeit only in premenopausal patients, i.e. the effect of two variant alleles on the TTE extension was demonstrated only in the premenopausal group (p=0.0012, HR 0.69; 95% CI 0.21-2.31), and statistical significance (p=0.0106) only for gynaecological/vasomotor AEs (p=0.0221, HR=1.0588), with no evidence of any influence on the incidence and onset of venous complications (i.e. deep venous thrombosis or pulmonary embolism). CONCLUSIONS: Although no conclusive statistical association between the examined polymorphisms and the outcome or incidence of AEs in tamoxifen therapy was found, the impact of ABCB1 polymorphisms warrants further research. The importance of finding predictive pharmacogenomic biomarkers is a major challenge for individualization and pharmaco-economic rationalization of therapy. The latest international guidelines support this notion.

Neonatal effect of remifentanil in general anaesthesia for caesarean section: a randomized trial.

BACKGROUND: Remifentanil has been suggested for its short duration of action to replace standard opioids for induction of general anaesthesia in caesarean section. While the stabilizing effect of remifentanil on maternal circulation has been confirmed, its effect on postnatal adaptation remains unclear, as currently published studies are not powered sufficiently to detect any clinical effect of remifentanil on the newborn. METHODS: Using a double-blinded randomized design, a total of 151 parturients undergoing caesarean delivery under general anaesthesia were randomized into two groups--76 patients received a bolus of remifentanil prior to induction, while 75 patients were assigned to the control group. Remifentanil 1 µg/kg was administered 30 seconds before the standard induction of general anaesthesia. The primary outcome measure was an assessment of neonatal adaptation using the Apgar score, while secondary outcomes included the need for respiratory support after delivery and differences in umbilical blood gas analysis (Astrup). RESULTS: The incidence of lower Apgar scores between 0 and 7 was significantly higher in the remifentanil group at one minute (25% vs. 9.3% of newborns, p = 0.017); whilst at five minutes and later no Apgar score differences were observed. There was no difference in the need for moderate (nasal CPAP) or intensive (intubation) respiratory support, but significantly more neonates in the remifentanil group required tactile stimulation for breathing support (21% vs. 7% of newborns, p = 0.017). There was no difference in the parameters from umbilical cord blood gas analysis between the groups. CONCLUSION: At a dose of 1 µg/kg, remifentanil prior to induction of general anaesthesia increases the risk of neonatal respiratory depression during first minutes after caesarean delivery but duration of clinical symptoms is short. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01550640.

Active pharmaceutical ingredients available as substances for extemporaneous preparation in veterinary medicine in the Czech Republic.

UNLABELLED: In veterinary medicine, extemporaneously prepared drugs can be also used in therapy. In the recent four years the selection of suitable compounds for extemporaneous (magistral) preparation has been expanded and new possibilities for the creation of formulas have appeared. The paper reports on the substances available for compounding that can be used in veterinary medicine, in the pharmacotherapeutic classes antibiotics, antimycotics, antiseptics, corticosteroids, emollients and epithelizing agents, anti-inflammatory drugs, local anesthetics, decongestives, beta-blockers and calcium channel blockers, antiemetics and prokinetics, sedatives and hypnotics. The emphasis has been placed on newly available substances. Examples of suitable magistral formulas are presented that can replace mass-produced drug products which are not readily obtainable. The aim of the paper is to inform pharmacists and veterinarians about new possibilities of drug compounding. KEYWORDS: compounded preparations extemporaneous preparation compounding of drugs possibilities magistral formulas in veterinary medicine.

Pharmacogenetics of chronic pain and its treatment.

This paper reviews the impact of genetic variability of drug metabolizing enzymes, transporters, receptors, and pathways involved in chronic pain perception on the efficacy and safety of analgesics and other drugs used for chronic pain treatment. Several candidate genes have been identified in the literature, while there is usually only limited clinical evidence substantiating for the penetration of the testing for these candidate biomarkers into the clinical practice. Further, the pain-perception regulation and modulation are still not fully understood, and thus more complex knowledge of genetic and epigenetic background for analgesia will be needed prior to the clinical use of the candidate genetic biomarkers.

[Magistral prepared lidocaine-gel for topical aplication on skin]. / Lidokainový gel pro pouzití na kuzi magistraliter pripravený.

Due to a limited availability of industrially manufactured products containing local anesthetics for skin application and an increased demand for lidocaine-containing gel applicable prior to a product containing capsaicin for neuropathic pain treatment, it is necessary to prepare a topical semi-solid preparation containing the local anesthetic in pharmacies. Our aim was to create a mixed system of a hydrophilic gel with the emulsified drug, using excipients to decrease the lidocaine melting point, thereby creating a eutectic mixture with a high concentration of lidocaine in the oil phase. Based on bibliographic data, thymol creating a binary eutectic system containing lidocaine has been chosen. After addition of other excipients, an emulsion system was prepared and the drug was stabilized in the oil phase by a mixed nonionic emulsifier and carbomera. For the optimal anesthetic effects, the pH value should be adjusted; trometamol has been chosen as a suitable basic reacting excipient. Based on the addition of different amounts of trometamol, pH values of individual emulgels have been measured and the final composition of lidocaine emulgel has been created. A recipe for a 5 % lidocaine emulgel with the pH value of 9.1 has been created, based on the gel-forming substance carbomera with an emulsion of the oil phase containing a eutectic mixture of lidocaine and thymol, with an addition of ethanol and propylenglycol, stabilized by a mixed nonionic emulsifier. The advantage is the absence of other local anesthetics.