Midazolam plasma concentration after anesthesia premedication in clinical routine - an observational study : Midazolam plasma concentration after anesthesia premedication.

BACKGROUND: Midazolam is commonly used as a pre-anesthesia anxiolytic. It`s elimination may not be fast enough for short procedures. In orally premedicated patients we obtained midazolam plasma concentrations at the end of surgical procedures and compared those to concentrations at anesthesia induction. METHODS: The study was conducted prospectively with consent of the local ethics committee (Ethikkomission Kanton Thurgau, Switzerland) and carried out with written informed consent of each patient. Female patients aged 20 to 60 years undergoing elective procedures with general anesthesia were included, and were divided in two groups according to the planned surgical time: group S (<30 min) and group L (90-120 min), respectively. All patients received 7.5 mg Midazolam po as premedication. Blood samples were drawn at anesthesia induction, and at the end of surgery. Data were compared with t-test (independent samples; significance level p <0.05). RESULTS: Twenty-five patients per group were included. Four patients were excluded from analysis, since midazolam was not detectable in any samples. Time of premedication to the 1st blood sample was not statistically different between groups, neither were Midazolam plasma levels at this time point (p = 0.94). None of the patients from group L (n = 24), but five patients in group S (n = 22) did have a higher plasma level of Midazolam at the end of the case compared to the beginning. CONCLUSIONS: The elimination half-life of oral Midazolam can lead to higher plasma levels at the end of a short procedure compared to those at induction of anesthesia. TRIAL REGISTRATION: German Clinical Trials Register (Deutsches Register Klinischer Studien), DRKS00005429 ; date of registration 3rd January 2014.

Germline TYMS genotype is highly predictive in patients with metastatic gastrointestinal malignancies receiving capecitabine-based chemotherapy.

PURPOSE: This work was initiated to extend data on the effect of pharmacogenetics and chemotherapy pharmacokinetics (PK) on clinical outcome in patients with gastrointestinal malignancies. METHODS: We assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, GSTM1, GSTT1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2 and UGT2B7) in 64 patients with metastatic colorectal cancer (CRC) receiving capecitabine/oxaliplatin and 76 patients with advanced gastroesophageal cancer (GEC) receiving epirubicin/cisplatin/capecitabine, respectively. Plasma concentrations of anticancer drugs were measured for up to 24 h, and results were submitted to population PK analysis. We calculated the association between gene polymorphisms, chemotherapy exposure, tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests. RESULTS: Patients with a low clearance of 5FU were at increased risk of neutropenia (P < 0.05) and hand-foot syndrome (P = 0.002). DPYD T85C, T1896C and A2846T mutant variants were associated with diarrhea (P < 0.05) and HFS (P < 0.02), and IVS14+1G>A additionally with diarrhea (P < 0.001). The TYMS 2R/3G, 3C/3G or 3G/3G promoter variants were associated with worse PFS in the CRC (HR = 2.0, P < 0.01) and GEC group (HR = 5.4, P < 0.001) and worse OS in the GEC group (HR = 4.7, P < 0.001). The GSTP1 A313G mutant variant was associated with a higher PFS (HR = 0.55, P = 0.001) and OS (HR = 0.60, P = 0.002) in the CRC group. CONCLUSIONS: Germline polymorphisms of DPYD, TYMS and GSTP1 have a significant effect on toxicity and clinical outcome in patients receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. These data should further be validated in prospective clinical studies.