The effects of oral co- and pre-administration of Sho-seiryu-to extract powder (TJ-19, 1 g/kg), a widely used Kampo (traditional Chinese herbal) medicine, on the pharmacokinetics of an anti-epileptic drug, carbamazepine (CBZ), and its active metabolite (carbamazepine-10,11-epoxide, CBZ-E) after oral administration of CBZ (50 mg/kg) were examined in male rats. The simultaneous administration of TJ-19 significantly lengthened the time to reach the peak plasma concentration (Tmax), but did not influence the peak plasma concentration, area under the plasma concentration-time curve or terminal elimination half-life (t1/2). Each parameter for CBZ or CBZ-E with a single pretreatment with TJ-19 was not significantly different from that with the vehicle. Tmax and the elimination rate constant for CBZ were significantly increased by 1-week repeated pretreatment with TJ-19, by 83% (p<0.01) and 88% (p<0.001), respectively. t1/2 and the mean residence time from zero to infinity (MRT0-infinity) in the TJ-19 pretreatment group were significantly shortened, by 52 and 34% (p<0.005), respectively. No significant difference in the bound fraction of each drug at two concentrations (1 and 10 microg/ml) was observed between the control and TJ-19 pretreatment groups. These results indicate that simultaneous oral administration of TJ-19 delays the oral absorption of CBZ, while 1-week repeated pretreatment with TJ-19 accelerates the metabolism of CBZ in rats, without affecting the protein binding of CBZ.
What is known and objective Daptomycin‐induced creatinine phosphokinase (CPK) elevation is reported to be associated with its trough level (Ctrough; breakpoint of 24.3 μg/mL). However, even with high‐dose treatment (ie, > 8 mg/kg), the safety of daptomycin treatment is widely demonstrated with low or no significant incidence of CPK elevation or other adverse effects, despite the possibility of Ctrough above 24.3 μg/mL. Therefore, we questioned the clinical significance of Ctrough levels of 24.3 μg/mL. In this study, we retrospectively evaluated the significance of Ctrough in the clinical setting, in addition to completing a retrospective safety assessment of daptomycin utilizing electronic health records. Methods Patients who had received daptomycin treatment for > 4 days from July 2011 to June 2015 were enrolled. Serum daptomycin levels, including Ctrough and peak (Cpeak), were measured by high‐performance liquid chromatography equipped with a photodiode array. To evaluate the safety, patients’ characteristics and relevant laboratory test values were reviewed retrospectively using an electronic medical record system. Results and discussion A total of 52 therapeutic cases for 46 patients were identified; of these, Ctrough and Cpeak levels were measured in 27 and 28 cases, respectively, and 6 patients received multiple courses of daptomycin treatment. The median age of the 52 patients was 68 years (range: 19‐88 years), and 14 patients initially had an estimated creatinine clearance of less than 30 mL/min. Seven cases indicated a Ctrough of above 24.3 μg/mL; however, none of these presented CPK elevation, which meets with the study definition for abnormality. Furthermore, of the two patients with abnormal CPK elevations, only one patient had a measured Ctrough (of 10.9 μg/mL). Their CPK abnormalities were temporal and did not result in treatment discontinuation. The other four patients discontinued daptomycin treatment due to suspicions of adverse effects. Of the discontinued patients, two had measured Ctrough levels; these were 8.6 and 8.1 μg/mL. All patients with abnormal CPK elevation or treatment discontinuation exhibited Ctrough levels lower than 24.3 μg/mL. In this study, two patients receiving high‐dose daptomycin (ie, 9.4 and 10.0 mg/kg) had observed Ctrough levels similar to patients who received doses of daptomycin < 9 mg/kg. What is new and conclusions The safety of daptomycin treatment was suggested in this study. Ctrough level of 24.3 μg/mL was not suggested as a significant clinical index for the incidence of CPK elevation, adverse effects or treatment discontinuation. Thus, acceptable tolerability towards higher Ctrough levels than 24.3 μg/mL was also suggested, though further studies are required. On the other hand, low levels of daptomycin in blood were unexpectedly observed in two cases, despite the high‐dose treatments. Accordingly, the monitoring of serum daptomycin levels may also be useful to assess cases in which subtherapeutic levels were achieved.
Intravenous lipid emulsion (ILE) therapy has been recognized as an effective treatment for calcium channel antagonist (CCA)-induced intoxication. 1 However, the proper time and use of ILE therapy remain debatable. 2 Herein, we report a case in which only a single bolus (1.5 mL/kg) of ILE therapy (20% Intralipid ® ) was administered for intoxication with multiple drugs, including amlodipine, and discuss the preferred implementation of ILE therapy. | DE TAIL S OF THE C A S EA 73-year-old man was admitted to our hospital. Trauma could not be confirmed. However, as summarized in Table S1, the patient presented with impaired awareness, slightly decreased heart rate, decreased core body temperature and decreased blood pressure (see AbstractWhat is known and objective: Amlodipine overdose is common; however, the dose and timing of intravenous lipid emulsion (ILE) therapy as a management strategy remain debatable. Case description:A 73-year-old man received a single bolus (1.5 mL/kg) of ILE therapy following massive ingestion of multiple drugs, including amlodipine. After approximately 20 hours of ILE therapy, the serum amlodipine level that had decreased from 90.2 to 49.9 ng/mL increased to 70.8 ng/mL. What is new and conclusion:A single bolus (1.5 mL/kg) of ILE therapy is probably insufficient to completely capture and partition serum amlodipine following amlodipine overdose. K E Y W O R D Samlodipine, calcium channel antagonist, emergency, intravenous lipid emulsion therapy, liquid chromatography-mass spectrometry
BackgroundThe implementation of a protocol has been associated with improvements in the processes of care in clinical settings. Although stress ulcer prophylaxis is recommended for critically ill patients at high risk, there is currently no consensus on its use. Therefore, we herein developed a protocol for stress ulcer prophylaxis, and evaluated therapeutic outcomes in a before-after study.MethodsThe protocol was developed by considering the effectiveness, disadvantages (including adverse events) and cost of each agent based on previous findings. Patients who were admitted to the 8-bed emergency intensive care unit (ICU) of our hospital for more than 24 h during the year before and after implementation of the study were eligible. Each investigation item was evaluated retrospectively.ResultsThere were 211 and 238 study patients before and after implementation of the protocol, respectively. The baseline characteristics of patients on/during ICU admission were similar in the two groups. The proportion of medicated patients was 79.6 % before and 84.5 % after protocol implementation. Before implementation of the protocol, 4.3 % of patients developed clinically important gastrointestinal bleeding, and this incidence decreased significantly to 0.8 % after its implementation (P = 0.019). The frequency at which medication was discontinued due to adverse events was slightly lower after implementation of the protocol. No significant differences were observed in the costs of stress ulcer prophylactic agents or mortality in the ICU.ConclusionsThe results of the present study indicated that the development and implementation of a protocol for stress ulcer prophylaxis, for which there are currently no criteria, improved a main outcome, clinically important gastrointestinal bleeding.
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