Anna Wiela-Hojeńska

Therapeutic drug monitoring of amikacin in septic patients.

IntroductionUse of higher than standard doses of amikacin (AMK) has been proposed during sepsis, especially to treat less susceptible bacterial strains. However, few data are available on drug concentrations during prolonged therapy and on potential adverse events related to this strategy.MethodsSixty-three critically ill patients who required AMK administration for the treatment of severe infection were included in this study. After a loading dose (LD, 18 to 30 mg/kg), the daily regimen was adapted using therapeutic drug monitoring (TDM) of both peak (Cpeak) and trough (Cmin) concentrations. Target concentrations had to give a ratio of at least 8 between Cpeak and the minimal inhibitory concentration (MIC) of the isolated pathogen. A Cmin >5 mg/L was considered as potentially nephrotoxic. We recorded clinical and microbiological responses, the development of acute kidney injury (AKI) during therapy and ICU mortality.ResultsThe median AMK LD was 1500 (750 to 2400) mg, which resulted in a Cpeak/MIC ≥8 in 40 (63%) patients. Increasing the dose in the 23 patients with a Cpeak/MIC <8 resulted in optimal Cpeak/MIC in 15 of these patients (79%). In 23 patients (37%), Cmin was >5mg/L after the LD, notably in the presence of altered renal function at the onset of therapy, needing prolongation of drug administration. Overall, only 11 patients (17%) required no dose or interval adjustment during AMK therapy. Clinical cure (32/37 (86%) vs. 16/23 (70%), P = 0.18)) and microbiological eradication (29/35 (83%) vs. 14/23 (61%), P = 0.07) were higher in patients with an initial optimal Cpeak/MIC than in the other patients. The proportion of patients with clinical cure significantly improved as the Cpeak/MIC increased (P = 0.006). Also, increased time to optimal Cpeak was associated with worse microbiological and clinical results. AKI was identified in 15 patients (24%) during AMK therapy; 12 of these patients already had altered renal function before drug administration. Survivors (n = 47) had similar initial Cpeak/MIC ratios but lower Cmin values compared to nonsurvivors.ConclusionsTDM resulted in adjustment of AMK therapy in most of our septic patients. Early achievement of an optimal Cpeak/MIC ratio may have an impact on clinical and microbiological responses, but not on outcome. In patients with impaired renal function prior to treatment, AMK therapy may be associated with a further decline in renal function.

Optimization of lidocaine application in tumescent local anesthesia

Tumescent local anesthesia is based upon the infusion of large volumes of neutralized anesthetic solutions, mainly lidocaine, at very low concentrations. This results in the paralysis of sensory nerve endings and minute nerve twigs, leading to a reduction in pain. The aim of this study was to assess the safety of lidocaine application in tumescent local anesthesia on different regions of patients bodies. Measures of safety included the analysis of lidocaine concentrations and its pharmacokinetic parameters. In total, 48 patients were infused with tumescent anesthesia in the hypogastrium, buttocks and thighs, axillae, breasts, trunk, and face and neck areas. Lidocaine was infused in doses ranging from 5.2-40 mg/kg b.w., and in concentrations of 0.05% (hypogastrium, buttocks, thighs) or 0.1-0.15% (axillae, breasts, trunk, face, neck), using a total amount of 300-3200 mg. As the peak lidocaine concentration did not exceed 5 microg/ml (commonly known as the toxic threshold), the results of our study indicate that the doses used (not exceeding 40 mg/kg b.w.) are completely safe for patients undergoing tumescent anesthesia in different body areas. The observation of statistically significant correlations between both the dose and the total amount of lidocaine administered and its peak plasma concentration, together with the lack of correlations between the dose and the amount and the time taken to reach peak concentration, allows the safety of each anesthetic dose to be predicted. An analysis of the heterogeneous dynamics of lidocaine plasma concentration changes in tumescent anesthesia in different body areas indicates that both the rates and the degrees of absorption and elimination depend on the area of infiltration; this is in turn related to the vascularization of any given area. The study of lidocaine concentration and pharmacokinetic parameters also showed that there may potentially be a higher risk of a large anesthetic concentration developing within a short period of time during anesthesia of the upper parts of the body. During tumescent anesthesia, significantly higher plasma concentrations of lidocaine were observed in the face and neck than in the hypogastrium, buttocks and thighs, axillae, breast and trunk 0.5 to 4 h after its infusion. This indicates the need for carefully conducted patient observations immediately after infiltration into the aforementioned areas.

Influence of anticancer therapy on oxidation phenotype and acetylation phenotype in patients with acute myeloblastic leukemia

The aim of this study was to determine whether antineoplastic cytostatic therapy induces changes in the oxidation or acetylation phenotypes in patients with acute myeloblastic leukemia (AML). The investigations involved 22 patients with AML undergoing chemotherapy with daunorubicin, cytosine arabinoside, etoposide and mitoxantrone. The oxidation phenotype prior to therapy and after termination of induction was examined in all 22 patients and was examined in 10 patients after termination of the first consolidation cycle. The acetylation phenotype was examined prior to therapy and after termination of induction in 21 patients and after termination of the first remission consolidation cycle in 9 patients. The oxidation phenotype was determined by means of the method by Eichelbaum and Gross. The acetylation phenotype was determined using Varleys modification of the Bratton-Marshall method. Anticancer therapy affected the oxidation phenotype, causing decreased activity of the cytochrome P450 isoenzyme CYP2D6. This decrease suggests that daunorubicin, cytosine arabinoside, etoposide and mitoxantrone may impair the metabolism of other active substances metabolized by this isoenzyme, which should be taken into consideration in planning the dosage scheme in individual patients and considering interactions between drugs. Evaluation of the effect of administered cytostatic drugs on acetylation phenotype revealed no statistically significant decrease in the rate of sulfadimidine acetylation.

Genetic polymorphism of ABCB1 gene (C3435T) in patients with inflammatory bowel diseases. Is there any gender dependency

BACKGROUND In recent years, an increasing incidence of inflammatory bowel disease (IBD) has been reported, mainly as Crohns disease (CD) and ulcerative colitis (UC). The individual susceptibility, the diseases course and response to the applied therapy is likely due to genetic factors such as ABCB1 gene mutations, exemplified by C3435T polymorphism. The aim of the study was to evaluate the distribution of C3435T polymorphism regarding the gender in IBD patients and control subjects from Lower Silesia region and its possible association with IBD susceptibility. METHODS The research was conducted in groups of 61 IBD patients and 101 healthy subjects from the Lower Silesia region. Polymorphism of C3435T was determined using PCR-RFLP method. RESULTS Frequency distributions of C3435T genotype and of 3435T or 3435C gene alleles of IBD, CD or UC patients were compared to control group; each treated as a whole or split further by gender. The statistically significant correlation was discovered between gender and C3435T genotype both for IBD and CD patients, with 3435CT heterozygote prevailing in IBD and CD males. Odds ratio calculations revealed statistically significant difference for the 3435CT genotype between control and: IBD group considered as a whole; IBD males; CD males; and for 3435TT variant between control and IBD males. Conclusions. The 3435CT genotype could be a risk factor for IBD and CD in men. The 3435TT genotype in males seems to be associated with the lower chance of IBD presence.

Comparison of clinical pharmacology of voriconazole and posaconazole

Despite greater knowledge and possibilities in pharmacotherapy, fungal infections remain a challenge for clinicians. As the population of immunocompromised patients and those treated for their hematologic ailments increases, the number of fungal infections grows too. This is why there is still a quest for new antifungal drugs as well as for optimization of pharmacotherapy with already registered pharmaceutics. Voriconazole and posaconazole are broad-spectrum, new generation, triazole antifungal agents. The drugs are used in the pharmacotherapy of invasive aspergillosis, Candida and Fusarium infections. Voriconazole is also used in infections caused by Scedosporium. Posaconazole is used in the treatment of coccidioidomycosis and chromoblastomycosis. Besides some similarities, the two mentioned drugs also show differences in therapeutic indications, pharmacokinetics (mainly absorption and metabolism), frequency and severity of adverse drug reactions, drug–drug interactions and dosage. As both of the drugs are used in the treatment of invasive fungal infections in adults and children, detailed knowledge of the clinical pharmacology of antifungal agents is the main factor in pharmacotherapy optimization in treatment of fungal infections. The goal of the article is to present and compare the clinical pharmacology of voriconazole and posaconazole as well as to point out the indications and contraindications of using the drugs, determine factors influencing their pharmacotherapy, and provide information that might be helpful in the treatment of fungal infections.

CYP2D6 basic genotyping as a potential tool to improve antiemetic efficacy of ondansetron in prophylaxis of postoperative nausea and vomiting

BACKGROUND Postoperative nausea and vomiting (PONV) is a common complication after anesthesia and surgery. Ondansetron is one of the most widely used drugs in the prophylaxis of PONV and is extensively metabolized in humans. In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P450 enzymes. The cytochrome P450 (human hepatic cytochrome [CYP]) 2D6 inhibitor quinidine reduced in vitro hydroxylation of ondansetron, which indicates the important role of CYP2D6 in ondansetron metabolism. Genotyping these alleles allows the prediction of the extensive metabolizer (EM) and poor metabolizer (PM) phenotypes with approx. 90-96% accuracy. OBJECTIVES The aim of our study was to evaluate whether the pharmacological prevention of PONV with ondansetron depends on the most common CYP2D6 alleles (CYP2D6*1, *3, *4, *5, and NxN [multiplication gene]). MATERIAL AND METHODS Genotyping for the defective CYP2D6*3, CYP2D6*4 and CYP2D6*5 alleles among 93 surgical female patients was performed by polymerase chain reaction amplification and restriction fragment length polymorphism (PCR-RFLP). RESULTS The genetically defined EMs and ultrarapid metabolizers (UMs) of CYP2D6 had a statistically significant (p < 0.02) higher frequency of nausea and vomiting after strumectomy (33.3%) than intermediate metabolizers (IMs) (10.3%) and PMs (0%). The relative risk (odds ratio [OR]) of PONV occurrence was 5 times higher for EMs/UMs than IMs/PMs. CONCLUSIONS Our results suggest that PONV treatment with ondansetron could be improved by basic, widely available and inexpensive PCR-RFLP genetic tests.