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Low-density lipoprotein apheresis (LDL-A) is a blood purification therapy used to treat refractory ulcers in patients with arteriosclerosis obliterans. We describe a case of vancomycin treatment in a patient undergoing maintenance hemodialysis and LDL-A therapy and assess its impact on serum vancomycin concentration. The patient underwent LDL-A twice a week (Mondays and Fridays) and maintenance dialysis three times a week (Tuesdays, Thursdays, and Saturdays) for diabetic nephropathy associated with type 1 diabetes mellitus. Following the wound culture results, vancomycin was initiated with a 1.75 g administration post-dialysis. Serum vancomycin levels before and after LDL-A, measured on the subsequent day, exhibited only slight fluctuations within the intermeasurement variability range. Despite continuing vancomycin administration at the standard dose in patients undergoing hemodialysis, the serum concentration remained consistent, suggesting a minimal impact of LDL-A on vancomycin pharmacokinetics. [ABSTRACT FROM AUTHOR]

It is found that there are great differences in the efficacy of quetiapine at the same dose in many patients with bipolar disorders. Therefore, therapeutic drug monitoring (TDM) is a valuable tool for guiding treatment with quetiapine. The aims of this study were to assess the relationship between serum concentration and clinical response of quetiapine in adolescents and adults with bipolar disorders in acute stage. The study design was prospective and observational. Within the naturalistic setting of a routine TDM service at the First Affiliated Hospital, Zhejiang University School of Medicine. Psychiatric symptoms were assessed using the HAMD (Hamilton Depression Scale), YRMS (Young manic rating scale) and CUDOS-M (Clinically Useful Depression Outcome Scale-Mixed Subscale). The decline of HAMD and YMRS scores was were used to assess clinical outcome of bipolar disorders respectively. 169 inpatients (23.7 % male, 76.3 % female) were enrolled in the study. We found that there was a strong correlation between quetiapine serum concentrations and clinical outcomes (r s = 0.702, p < 0.001). While, quetiapine daily dose was not correlated with clinical outcome. We found that when the quetiapine serum level is >146.85 ng/ml in depression episodes patients could obtain a satisfactory treatment effect after 2 weeks of hospitalization. We found a significant positive relationship between serum concentration and clinical outcome, and also determined the serum concentration of quetiapine for the treatment of bipolar depression. • This is the first study about the relationship between TDM of quetiapine and clinical treatment response in BD. • The main finding is that there is a correlation between TDM of quetiapine and clinical outcome in bipolar disorders. [ABSTRACT FROM AUTHOR]

• Tigecycline treatment causes a significant decrease in fibrinogen levels. • Tigecycline exposure is highly predictive of hypofibrinogenemia. • Serum concentration at the 6 hours after the dosing (C 1/2) ≥ 0.645 mg/l with best predictive performance may be the optimal toxicity threshold. This study aimed to determine the thresholds of serum concentration as a predictor of tigecycline (TGC)-induced hypofibrinogenemia (HF) in critically ill patients. A retrospective cohort study was conducted in intensive care unit patients treated with TGC. The clinical data and serum concentration were extracted from the patients' electronic medical records. Patients were divided into an HF group and a normal group according to fibrinogen value. The receiver operating characteristic curves and logistic regression were used to derive serum concentration thresholds and quantify the association between exposure thresholds and HF while adjusting for confounders. In total, 100 patients were included. The receiver operating characteristic curves analysis showed that TGC concentration parameters were strongly predictive of HF. Adjusting for duration of TGC, serum concentration at the 6 hours after the dosing (C 1/2) ≥ 0.645 mg/l, area under the concentration-time curve over a 24-hour period (AUC 0-24) ≥ 20.76 mg·h/l, and serum concentration of 30 minutes before next dose (C min) ≥ 0.455 mg/l were associated with a three- to five-fold increased risk of TGC-induced HF in logistic regression. The findings from this study provide evidence that TGC exposure is highly predictive of HF, with an approximately three- to five-fold increased risk. Serum concentration at the 6 hours after the dosing (C 1/2) ≥ 0.645 mg/l with best area under the receiver operating characteristic curve and negative predictive value appears to be the most appropriate toxicity threshold. [Display omitted] [ABSTRACT FROM AUTHOR]

While the revised 2020 consensus guideline recommends the use of area under the concentration–time curve (AUC)-guided vancomycin monitoring, collecting multiple vancomycin serum samples to calculate the AUC may cause clinical complications. The aim of the present retrospective study was to evaluate whether AUC-guided vancomycin monitoring, in which AUC was calculated based on a single trough concentration, is a better predictor of nephrotoxicity than trough-guided monitoring in patients receiving vancomycin therapy. A single-center, retrospective cohort study was conducted at the 614-bed Gifu University Hospital in Japan. Patients who received intravenous vancomycin for a documented or suspected infection and had their serum vancomycin trough concentration monitored between October 1, 2016 and September 30, 2020 were enrolled in the present study. Multivariate Cox proportional hazard analysis indicated that AUC (>600 μg•h/mL) was a significant risk factor for the incidence of acute kidney injury (AKI), while trough concentration (≥15 μg/mL) was not. Moreover, the AUC (>600 μg•h/mL) showed higher specificity and similar sensitivity to the trough concentration (≥15 μg/mL). Kaplan-Meier plots of the cumulative incidence of the AKI-free rate in patients indicated that the onset of AKI was significantly longer in patients with AUC ≤600 μg•h/mL than in patients with AUC >600 μg•h/mL (HR, 16.1; 95% CI, 6.3–41.2; p < 0.001). AUC based on a single trough concentration was a better predictor of nephrotoxicity than trough concentration. [ABSTRACT FROM AUTHOR]

Low-dose amitriptyline (AMT) is an effective treatment for diarrhea-dominant irritable bowel syndrome (IBS-D). Its efficacy depends upon its serum concentration and the patient's CYP2C19 genotype. To identify the association between serum AMT and nortriptyline (NT) concentration and CYP2C19 polymorphism and the clinical response in IBS-D patients. Ninety IBS-D patients were treated of AMT for 6 weeks. Efficacy was evaluated by the results of the Adequate Relief question each week and an IBS severity scoring system (IBS-SSS) at 0, 3, and 6 weeks. CYP2C19 genotyping was performed by direct sequencing. AMT and NT steady-state serum concentrations were detected by high-performance liquid chromatography. The CYP2C19 polymorphism exhibited a significant influence on the NT serum concentration but did not predict the clinical efficacy of AMT for treating IBS-D. The NT steady-state and dose-corrected serum concentrations were significantly correlated with an improvement in the IBS-SSS score after 6 weeks, whereas the AMT serum concentration was not correlated with clinical improvement. The cut-off NT steady-state serum concentration of 2.91 ng/ml may help distinguish responders from non-responders. NT serum concentration but not CYP2C19 polymorphism may be correlated with the clinical efficacy of AMT for treating IBS-D, and such a response may occur at the upper NT threshold of 2.91 ng/ml. [ABSTRACT FROM AUTHOR]

Association between clinical effect and serum concentration of amiodarone (AMI) and its active metabolite desethylamidarone (DEA) in patients after surgical ablation (SA) of atrial fibrillation (AF) has not yet been studied. We wanted to find a correlation between AMI and DEA serum concentration and maintaining sinus rhythm (SR) after SA of AF. Sixty eight patients with AF who had undergone surgical ablation between 2014 and 2017 were included in a single-centre, prospective, observational study. Maintaining of SR was evaluated by standard 12-lead ECG and 24-hour Holter ECG monitoring at months 1, 3, 6 and 12 following surgery. Therapeutic monitoring of AMI and DEA concentrations was done to optimize therapy and adverse effects were followed up. We have noticed a high success rate in maintaining of SR (overall 83%). The median of serum concentration of AMI was 0.81 mg/L (range 0.16–2.35 mg/L) and DEA 0.70 mg/l (range 0.19–2.63 mg/L). No significant differences were found in the serum concentratration of AMI, DEA or DEA/AMI concentratration ratios between patients with SR and persistent supraventricular tachyarrhythmia except on the second outpatient visit. We observed significant correlation between serum concentration of DEA and thyroid-stimulating hormone elevation. We confirmed the efficacy of AMI and DEA at the measured serum concentrations. However, analysis of these concentrations alone cannot replace assessment of the clinical response for treatment. Establishment of individual AMI (and DEA) concentrations at which the optimal therapeutic response is achieved seems to be advantageous. Therapeutic monitoring of AMI and DEA is helpful in personalised pharmacotherapy after SA of AF. [ABSTRACT FROM AUTHOR]

In December 2021, the U.S. Food and Drug Administration (FDA) granted emergency authorization for Paxlovid® as an antiviral treatment for COVID-19. Paxlovid® is composed of two tablets, nirmatrelvir and ritonavir. Dose adjustment is necessary in cases of renal insufficiency. The aim of present study is to establish a LC–HRMS method for simultaneous determination of nirmatrelvir/ritonavir in human serum for therapeutic drug monitoring. Internal standard saquinavir was added in 25 μL human serum samples, and then the samples were precipitated with methanol. The analytes were separated by gradient elution on a C18 column, using a mobile phase of 0.1 % formic acid-water and methanol, at a flow rate of 0.4 mL/min. The injection volume was 2 μL, and the analysis time was 5 min. The determination of the analytes was performed by electrospray ionization in positive mode by full mass monitoring. The detected ions of nirmatrelvir, ritonavir and saquinavir were m/z 500.24792, 721.32004 and 671.39155, respectively. The linear concentration range for nirmatrelvir was 78.13–20000 ng mL−1, for ritonavir was 15.63–4000 ng mL−1 (r2＞0.9900). The accuracy ranged from 87.45 %∼104.63 %, and the intra-day and inter-day precision RSD was <15 %. The recovery of nirmatrelvir ranged from 98.72 %∼109.83 %, and that of ritonavir was 95.41∼112.36 %. The matrix effect of nirmatrelvir was 88.31∼97.73 %, and that of ritonavir was 85.17∼103.05 %. This method was used to measure the trough concentrations of nirmatrelvir/ritonavir in 17 patients. The trough concentration of nirmatrelvir was 1331.7–8352.5 ng/mL, and that of ritonavir was 53.4–1325.5 ng mL−1, with large individual differences. The method is simple, sensitive, specific, and reproducible, and can be used for monitoring the blood concentration and pharmacokinetic study of nirmatrelvir/ritonavir in COVID-19 patients. • This is a rapid LC–HRMS method for detection of nirmatrelvir/ritonavir in serum. • The nirmatrelvir trough concentration was 1331.7–8352.5 ng/mL in COVID-19 patients. • The trough concentration of ritonavir was 53.4–1325.5 ng/mL in COVID-19 patients. • This method can be used for pharmacokinetic study in COVID-19 patients furtherly. [ABSTRACT FROM AUTHOR]

Purpose: Perampanel (PER) is a selective, non-competitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor. In Japan, PER is approved for patients with epilepsy who are at least 12 years old for the adjunctive treatment of primary generalised tonic-clonic seizures and partial-onset seizures (with or without secondary generalization). We surveyed the efficacy, adverse effects, and serum concentrations of PER, focusing especially on patients younger than 12 years of age.Methods: We retrospectively surveyed the clinical information of patients treated with PER and assessed the efficacy at 6 months after treatment initiation. We compared efficacy, adverse effects, and serum concentration in patients younger or older than 12 years of age. Responders were defined as those who experienced a ≥50% seizure reduction.Results: Eighty-four patients were enrolled. The average age of the younger group was 7.1 ± 3.3 (standard deviation) years compared to 16.4 ± 3.7 years in the older group. The responder rate was 42.9% (36/84). The responder rate did not differ between the two age groups (<12 years, 20/44, 45.4%; >12 years, 16/40, 40.0%; p = 0.78). The younger age group had a significantly lower concentration-to-dose (CD) ratio than the older age group (<12 years, 1849.8 ± 2209.3; >12 years, 3076.3 ± 3352.2, p = 0.02). Treatment-emergent adverse events (TEAEs) were observed in 22.6% (19/84) of patients, with the most common being somnolence (8/84, 9.5%).Conclusion: PER may be an alternative to treat seizures in paediatric drug-resistant epilepsy. Serum concentrations of PER might be lower in patients younger than 12 years than in older patients. [ABSTRACT FROM AUTHOR]

Major Depressive Disorder (MDD) is associated with a high rate of inadequate treatment response, which is mainly due to the large inter-individual genetic variability in pharmacokinetic and pharmacodynamic targets of antidepressant drugs. Little is still known about the exact association between plasma level of first-line antidepressants and clinical response. This is particularly true for duloxetine, a dual serotonin and norepinephrine reuptake inhibitor recommended as first-line treatment for MDD. The aim of this study was to investigate the association between serum concentration of duloxetine (SCD) and antidepressant response (AR). 66 MDD patients treated with duloxetine 60 mg/day monotherapy were recruited in an outpatient setting and followed for three months. Hamilton Depression Rating Scale - 21 (HAMD-21) was administrated at baseline, at month 1, and at month 3 to assess AR. SCD was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCD and AR. SCD showed a high inter-individual variability in our sample, despite the duloxetine fixed oral dosage. We found a strong association between SCD and AR following a bell-shaped function at month 1 and at month 3. Nonetheless, within the recommended SCD range of 30–120 ng/mL a more linear correlation between SCD and AR was observed. Our results suggest that for duloxetine the association between SCD and AR likely follows a bell-shaped quadratic function with poor AR at subtherapeutic SCD and progressive decrease of AR at higher SCD. The maximum antidepressant efficacy seems to require SCD values next to the highest recommended SCD (30–120 ng/mL), probably because of the optimal saturation of both serotonin and norepinephrine transporters. Thus, taking into account the observed high interindividual variability of SCD, our findings suggest that for MDD patients treated with duloxetine, SCD could be a useful tool to guide the treatment by optimizing the oral dosage in order to increase the AR rate. • Response to duloxetine (DLX) may be modulated by its serum concentration (SC). • DLX SC shows a wide inter-individual variability despite similar oral dose. • A strong association between DLX SC and response was found. • A bell-shaped function correlates DLX SC and response. • The monitoring of DLX SC may help to optimize antidepressant efficacy. [ABSTRACT FROM AUTHOR]

Purpose To investigate the change in zonisamide (ZNS) serum concentration and its consequences in pregnant women with epilepsy. Methods Six hospitals in Norway and Denmark screened their records for women who had been using ZNS during pregnancy. Absolute serum concentrations as well as concentration/dose (CD)-ratios were compared to non-pregnant values. Descriptive data on seizure control and obstetrical data were also collected. Results 144 serum concentrations from 23 pregnancies in 15 individual women with epilepsy were included (six on monotherapy). The mean ZNS serum concentration fell to a minimum of 58.6 ± 15.1%, while the C/D-ratio fell to as low as 55.1 ± 15.3% of the non-pregnant-value. The lowest values were seen in gestational months six to nine, and the individual nadir varied considerably (range: 24–81% of the non-pregnant value). Four out of ten previously seizure-free patients experienced breakthrough seizures. Gestational age, weight at birth and head circumference of the newborns were within the reference ranges. Conclusions ZNS serum concentrations may fall by over 40% during pregnancy, with large interindividual variability. In some patients, this may lead to worsened seizure control. These findings are in line with reports on other AEDs and suggest that regular therapeutic drug monitoring and dose adjustments may be useful. [ABSTRACT FROM AUTHOR]

This study investigated the association of two levels of targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) with administered doses of sedative and analgesic drugs, serum concentrations, and the effect on time to awakening. This substudy of the TTM2-trial was conducted at three centers in Sweden, with patients randomized to either hypothermia or normothermia. Deep sedation was mandatory during the 40-hour intervention. Blood samples were collected at the end of TTM and end of protocolized fever prevention (72 hours). Samples were analysed for concentrations of propofol, midazolam, clonidine, dexmedetomidine, morphine, oxycodone, ketamine and esketamine. Cumulative doses of administered sedative and analgesic drugs were recorded. Seventy-one patients were alive at 40 hours and had received the TTM-intervention according to protocol. 33 patients were treated at hypothermia and 38 at normothermia. There were no differences between cumulative doses and concentration and of sedatives/analgesics between the intervention groups at any timepoint. Time until awakening was 53 hours in the hypothermia group compared to 46 hours in the normothermia group (p = 0.09). This study of OHCA patients treated at normothermia versus hypothermia found no significant differences in dosing or concentration of sedatives or analgesic drugs in blood samples drawn at the end of the TTM intervention, or at end of protocolized fever prevention, nor the time to awakening. [ABSTRACT FROM AUTHOR]

Major Depression Disorder (MDD) has a highly variable treatment response due to the large inter-individual variation in the pharmacokinetics and pharmacodynamics of drug treatments. In detail the correlation between plasma level and efficacy has been much debated. Among first-line drugs for MDD, one of the most used is escitalopram. In the present study we investigated the association between serum concentration of escitalopram (SCE) and antidepressant response (AR). 70 MDD patients treated with escitalopram monotherapy were recruited and followed for three months. Hamilton Depression Rating Scale - 21 (HAMD-21) was administrated at baseline, month 1, and month 3 to assess AR. SCE was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCE and AR. We found an association between SCE and AR both at month 1 ( p <0.001) and month 3 ( p =0.0003), which persists also excluding 3 patients with SCE equal to 0. Interestingly, by excluding patients with SCE < 20 ng/mL, i.e. with a SCE lower than the putative therapeutic threshold, these associations disappeared. The curvilinear function AR = a + (SCE-SCE 2 ) explained a higher proportion of variance compared to the linear other models ( p <0.001). Our results suggest that for escitalopram the association between SCE and AR likely follows a nearly-asymptotic function, with poor AR at sub-therapeutic SCE and stable AR response at therapeutic SCE. Thus, when a patient reaches the therapeutic SCE range, further increase of escitalopram dosage seems to be useless, although further studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFASs) are ubiquitous contaminants found worldwide, including in South Korea. As a result, they are frequently detected in Koreans. However, there is limited representative data and information on potential sources in Korea. Therefore, we measured the serum concentrations of ten PFASs in nationally representative samples of the Korean population (n=1874, 18-69 years) and evaluated the factors associated with their exposure. Serum PFOS, PFDA, PFOA, and PFNA were detected in nearly all participants (83.1-99.9%). However, serum PFPA, PFHxA, and PFHpA were almost undetected (<0.5% of participants). PFOS had the highest population-weighted geometric mean of 10.23ng/mL (95% CI: 9.99-10.47), which was followed by PFOA with 2.85ng/mL (95% CI: 2.73-2.97) and PFDA with 2.17ng/mL (95% CI: 2.12-2.23). PFNA, PFDA, PFHxS, PFOA, and PFOS concentrations were higher in males (p<0.001) and older adults (p<0.001). PFNA was higher in those who used wax, polish, and water-resistant materials (adjusted proportional change=1.14; 95% CI: 1.08-1.22), and those who ate cooked fish (1.16; 95% CI: 1.03-1.31) compared to those who ate nearly no fish. PFDA was higher in those who used herbicides and pesticides (1.05; 95% CI: 1.02-1.09), those who drank beverages in a plastic bag on a daily basis (1.10; 95% CI: 1.03-1.19), and those who ate raw fish (1.15; 95% CI: 1.03-1.29) or cooked fish (1.13; 95% CI: 1.05-1.23) compared to those who ate nearly no fish. PFHxS was higher in those who used traditional Korean health supplement foods (1.08; 95% CI: 1.01-1.15). PFOA was higher in those who used plastic wrap in a microwave daily or weekly (1.08; 95% CI: 1.00-1.16), and those who used disposable paper cups (1.07; 95% CI: 1.01-1.13). PFOS was lower in underweight participants (0.84; 95%CI: 0.75-0.93) compared to those who were obese, and higher in those who exercised regularly (1.08; 95% CI: 1.03-1.14) or irregularly (1.06, 95% CI: 1.01-1.12) compared to those who did not exercise. Subjects who used severely damaged Teflon appliances had lower concentrations of PFOA (0.78, 95% CI: 0.65-0.95), while regular use of Gore-Tex goods was related to higher PFNA (1.15, 95% CI: 1.03-1.28) and PFDA (1.11; 95% CI: 1.02-1.20) levels. These findings suggest that most Koreans are frequently exposed to PFASs, and that serum concentrations of PFASs vary with age, sex, and exposure factors. [ABSTRACT FROM AUTHOR]

Background Switching patients from a branded antiepileptic drug (AED) to a generic is often challenging. Several studies have shown that considerable proportions of patients report deteriorated seizure control or increased adverse effects, enforcing a switchback to the original drug. Since tolerability and seizure control usually correlate with AED serum concentrations, we examined the fluctuation of levetiracetam (LEV) serum concentrations in patients with epilepsy before and after generic substitution. Methods This was an 18-week, naturalistic, open, prospective, two-center study. After a baseline period of 10 weeks, 33 outpatients on stable treatment with branded LEV (Keppra ® ) either continued with this product or were switched overnight to a generic LEV preparation (1A Pharma) for an eight-week study period. Throughout the study, patients were monitored with bi-weekly LEV serum concentration measurements and seizure diaries. Results 16 out of 33 patients were switched to a generic LEV product. No switchbacks were seen. LEV dose, LEV serum concentrations, fluctuation index and concentration/dose-ratio (C/D-ratio) were not significantly different within-group (baseline vs. study period) or between-group. Large within-subject variability in serum concentrations was seen in both groups. None of the patients that were seizure-free before inclusion experienced seizures while on the generic LEV product. Conclusions Our results show equal fluctuation of LEV serum concentrations with branded LEV and the generic LEV. Most importantly, within-subject variability was much larger than the small, non-significant differences between brands. [ABSTRACT FROM AUTHOR]

Purpose Our aim was to investigate the association between self-report measure and serum concentration fluctuation of immunosuppressive medication (IM) in renal transplant recipients in China and examine the relationship between post-transplantation time and IM adherence. Methods Renal transplant recipients at least 3 months post transplantation were recruited from a follow-up outpatient clinic. Both self-reported Morisky Medication Adherence Scale and serum concentration of IM (cyclosporine trough level and tacrolimus trough level) were used to measure drug adherence. Findings Two hundred and nine patients were recruited in the study. The majority of the patients received grafts from deceased donors (70.3%), were male (63.2%), and were married (83.3%). The nonadherence to IM was 31.7%, as measured by the Morisky Medication Adherence Scale. A statistically significant association between self-reported adherence and serum concentration fluctuation of tacrolimus trough level was identified ( P < 0.001), but not for cyclosporine ( P = 0.997). Serum concentration fluctuation of tacrolimus trough levels and self-report adherence of IM were associated with transplantation time ( P < 0.001 and P = 0.003, respectively). Implications The Morisky Medication Adherence Scale appears valid in measuring drug adherence when compared with serum concentration fluctuation. Both self-report questionnaire and serum concentration fluctuation of tacrolimus changed with different post-transplantation time. These 2 measurements could be integrated into routine clinical practice for renal transplant recipients. [ABSTRACT FROM AUTHOR]

To evaluate the current methods of surgical antimicrobial prophylaxis from the viewpoint of pharmacokinetics for patients undergo urologic surgery, this study was designed to measure the serum concentrations of two different prophylactic antimicrobial agents in different types of urologic surgery. This prospective study included 39 patients with prostate cancer, renal pelvic cancer, ureteral cancer or renal cancer treated by radical surgery from August 2005 to March 2006. Blood samples were taken intraoperatively at 30 min and 180 min after the beginning of the first administration. The half-life of the beta phase of cefazolin is 2.46 h and that of piperacillin is 0.7 h according to their manufacturers. The average serum concentration of cefazolin at 30 min was 144 μg/mL in the prostatectomy group and 175 μg/mL in the nephrectomy group. At 180 min, the average concentration of cefazolin was 37 μg/mL in prostatectomy group and 59 μg/mL in the nephrectomy group. The average concentration of piperacillin at 30 min was 134 μg/mL in the prostatectomy group and 137 μg/mL in the nephrectomy group. At 180 min, the average concentration of piperacillin was 10 μg/mL in the prostatectomy group and 22 μg/mL in the nephrectomy group. Thus, the concentration at 180 min after the beginning of infusion was different according to the half-life of each antimicrobial agent. Therefore, up-to-date guidelines for surgical antimicrobial prophylaxis that deal with additional types of intraoperative prophylaxis should be consulted if the operation exceeds two half-lives of the prophylactic antimicrobial agents used in real-life clinical practice. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to develop and validate a HPLC-MS/MS assay to determine total and unbound concentrations of temocillin in serum samples. Design and methods Methanolic protein precipitation and ultrafiltration were used for total and unbound concentration extraction, respectively. Extract was injected into a LC-MS/MS system. Reversed phase chromatography was performed on a phenyl grafted column in gradient mode. Temocillin and internal standard (ticarcillin) were identified in positive electrospray ionization mode using ion transitions of m/z 415.34 > 339.1 and 385.31 > 160.3, respectively. Results Temocillin total and unbound concentration quantification assays were linear over concentrations ranging from 1 to 500 mg/L and from 0.5 to 300 mg/L, respectively. Both assays presented acceptable intra and inter-assay precision and accuracy < 13.9%. Limits of quantification and detection were of 1 and 0.10 mg/L, and 0.5 and 0.05 mg/L for total and unbound concentration respectively. Total temocillin concentration recovery ranged from 85.80 to 99.40%. Temocillin ion suppression effect was < 36.2 % in both assays. Conclusion The method described is fast, sensitive and selective, with no interferences. This method may be used for both pharmacokinetic studies and therapeutic drug monitoring purposes. [ABSTRACT FROM AUTHOR]

Purpose: High initial serum concentrations increase the risk of cutaneous adverse reactions. Genetic variants of the main metabolizing isoenzyme, uridine diphosphate glucuronosyltransferase (UGT) 1A4 influence the elimination of lamotrigine (LTG). Our aim was to investigate the potential association between the two best studied variants, *2 (P24T) and *3 (L48V), and the occurrence non-bullous skin reactions from LTG.Method: The study included 29 patients of Caucasian ethnicity with a history of non-bullous skin reactions from LTG. 184 subjects tolerant to LTG for at least three months were used as controls. UGT1A4 genotyping was performed in all patients and controls by sequencing of the first part of exon 1. Six controls were excluded due to rare genetic variants.Results: Two of 29 subjects (7%) with rash from LTG were heterozygous for UGT1A4 *2, compared to 23 of 178 (13%) tolerant controls (p=0.54). Four of 29 subjects (14%) with rash from LTG were heterozygous for UGT1A4 *3 compared to 25 of 178 (14%) tolerant controls (p=0.97).Conclusion: It is unlikely that heterozygosity of the UGT1A4 genetic variants *2(P24T) or *3(L48V) influences the risk of non-bullous skin reactions in patients treated with LTG. [ABSTRACT FROM AUTHOR]

Abstract: We examined clinical characteristics including serum olanzapine concentrations for acute schizophrenia patients who required above conventional doses. We performed a rater-blinded, randomized clinical trial in 12 psychiatric emergency sites. Eligible patients were 18–64 years old and met diagnostic criteria for schizophrenia, acute schizophrenia-like psychotic disorder, or schizoaffective disorder. A total of 42 patients were randomly assigned by means of sealed envelopes to receive risperidone (3–12mg/day; n=20) and olanzapine (10–40mg/day; n=22), with follow-up at 8 weeks. The Negative score of the Positive and Negative Syndrome Scale was significantly higher in patients who required high doses than in patients who responded to conventional doses. Serum olanzapine concentrations at the time of oral 20mg/day could be obtained from 5 out of 7 patients who subsequently required high-dose olanzapine. All values were more than 30ng/mL after 11–16h from dosing to sample collection, and the mean value was 47.876 (S.D. 21.546) ng/mL. Such concentrations are appropriate with respect to a therapeutic range of 20–50ng/mL. The present study has shown evidence that the reason for requiring high-dose olanzapine cannot be explained by pharmacokinetics in the treatment of acute-phase schizophrenia. [Copyright &y& Elsevier]

Abstract: We report the case of an immunosuppressed patient with Strongyloides disseminated infection who was successfully treated with the veterinary parenteral form of ivermectin. A kidney transplant recipient developed disseminated infection with Strongyloides stercoralis. Because oral treatment with ivermectin was not possible, subcutaneous ivermectin (75µg/kg/day, then 200µg/kg/day) was given for 9 days, with clinical improvement and disappearance of all larvae. Serum ivermectin concentrations were between 15.6ng/mL and 19.7ng/mL during the 9 days of therapy; however, drug accumulation (plasma levels >40ng/mL) 48h after discontinuation of therapy was associated with the development with encephalopathy. We also review all cases of human disseminated Strongyloides infection treated with parenteral ivermectin. [Copyright &y& Elsevier]

Abstract: Background: Methadone and buprenorphine are widely used in the treatment of opioid addiction. Some study results suggest that methadone can be associated with QT interval prolongation and torsades de pointes ventricular arrhythmias, whereas no such risk has been observed for buprenorphine. The aim of this study is to determine the risk of corrected QT interval (QTc) increase among patients treated with these medications in an opioid maintenance treatment (OMT) programme, and to study possible associations between QTc changes and serum concentrations of methadone or buprenorphine. Methods: Eighty patients enrolled in the OMT programme were followed after start of treatment with methadone (n =45) or buprenorphine (n =35). QTc interval was assessed by electrocardiography (ECG) at baseline and after 1 month (n =79) and 6 months (n =66) in the OMT programme. Blood samples were obtained for the analysis of serum concentrations of buprenorphine, (R)-methadone, (S)-methadone and total methadone. Results: No patients had QTc prolongation (defined as a QTc value above 450ms) at baseline or after 1 or 6 months. When analysed in a linear mixed effects model, QTc was not associated with the serum concentrations of buprenorphine or methadone. However, low serum potassium levels increased QTc significantly. Conclusions: These results support and extend previous findings that treatment with methadone in modest doses (i.e. below 100mg/d) is not associated with clinically significant QTc increases, and that buprenorphine in commonly used doses is a suitable alternative to methadone with regard to the risk of QTc prolongation. [Copyright &y& Elsevier]

Objective: This randomized controlled trial examined serum and macular (in vivo measured macular pigment optical density [MPOD]) responses to supplemental lutein and zeaxanthin in Chinese subjects with early age-related macular degeneration. Methods: One hundred and eight patients with early age-related macular degeneration older than 50 y were randomized to low lutein (LL; 10 mg/d), high lutein (HL; 20 mg/d), lutein plus zeaxanthin (LZ; each 10 mg/d), or placebo during a 48-wk intervention. Serum concentrations were quantified by C30 high-performance liquid chromatography (at baseline and 4, 12, 24, and 48 wk), and MPOD was measured by analysis of autofluorescence images (at baseline and 24 and 48 wk). Results: Serum lutein levels in the LL, LZ, and HL groups increased significantly in the first 4 wk and then increased 4.24-, 4.66-, and 6.23-fold during the trial, respectively (all P < 0.001). The serum lutein level in the HL group was significantly higher than that in the LL or LZ group at 48 wk (P < 0.05). Similarly, the serum zeaxanthin concentration in the LZ group increased 3.11-fold at 48 wk. MPOD increased smoothly in all treated groups, and the increase from baseline was greatest in the HL group at 24 and 48 wk (both P < 0.05). MPOD and serum lutein levels increased linearly with the dosage and their increasing rates were statistically correlated (all P < 0.05). No notable changes were detected in the placebo group for MPOD and serum concentrations. Conclusion: Xanthophyll supplementation significantly increased serum concentrations and MPOD in patients with early age-related macular degeneration, and a higher lutein supplementation (20 mg/d) might be more effective in increasing these two biochemical markers in Chinese patients without significant side effects. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Transforming growth factor-beta 1(TGF-β1) is a regulatory protein, involved in bone fracture healing. Circulating TGF-β1 levels have been reported to be a predictor of delayed bone healing and non-union, suggesting active relationship between tissue and circulating TGF-β1 in fracture healing. The purpose of this study was to analyse TGF-β1 local and serum concentrations in fracture healing to further contribute to the understanding of molecular regulation of fracture healing. Patients and methods: Serum samples of 113 patients with long bone fractures were collected over a period of 6 months following a standardised time schedule. TGF-β1 serum concentrations were measured using ELISA. Patients were assigned to 2 groups: Group 1 contained 103 patients with physiological healing. Group 2 contained 10 patients with impaired healing. Patients in both groups were matched. One patient of the group 2 had to be excluded because of missing match partner. In addition, fracture haematoma from 11 patients of group 1 was obtained to analyse local TGF-β1 concentrations. 33 volunteers donated serum which served as control. Results: TGF-β1 serum concentrations increased during the early healing period and were significantly higher in patients with physiological healing compared to controls (P =0.04). Thereafter, it decreased continuously between weeks 2 and 8 and fell again after week 8. TGF-β1 serum concentrations in patients with physiological healing were significantly higher at week 24 compared to controls (P =0.05). In non-unions, serum concentrations differed significantly from those of controls at week 6 (P =0.01). No significant difference in between patients with physiological and impaired fracture healing was observed. Fracture haematoma contained significantly higher TGF-β1 concentrations than peripheral serum of the patients (P =0.017). Conclusion: Elevated levels of TGF-β1 in haematoma and in serum after bone fracture especially during the entire healing process indicate its importance for fracture healing. [Copyright &y& Elsevier]

Background: Patients with psoriasis tend to be overweight, and the efficacy of fixed-dose biologics may be compromised by high body weight. Objective: We sought to determine whether the optimal dose of ustekinumab is affected by weight in patients with psoriasis. Methods: Patients were randomized in two phase III trials (PHOENIX 1 and 2) to receive 45 mg or 90 mg of ustekinumab every 12 weeks (n = 1331) or placebo with crossover to ustekinumab at week 12 (n = 665). Efficacy and serum ustekinumab concentrations were to be evaluated by 10-kg increments of body weight at week 28 (steady-state trough level). Results: Mean baseline weight was 93.9 and 91.0 kg in PHOENIX 1 and 2, respectively. Based on the analyses by 10-kg increments, a cutoff of 100 kg was determined to best differentiate the dose response. The proportion of patients with at least 75% improvement from baseline in Psoriasis Area and Severity Index score was 74.2% for 90 mg and 54.6% for 45 mg in heavier patients (>100 kg), but the proportion with a response of at least 75% improvement from baseline in Psoriasis Area and Severity Index score was similar between doses (80.8% vs 76.9%) in lighter patients (≤100 kg). Serum ustekinumab concentrations were also affected by weight, with lower serum concentrations observed in heavier patients at each dose. Safety was not affected by weight. Limitations: Low numbers of patients at the extremes of body weight may limit the analyses of these subgroups. Conclusion: Results of weight-based analyses of clinical and pharmacokinetic data indicate that fixed dosing of ustekinumab based on weight is appropriate for the treatment of patients with psoriasis. [ABSTRACT FROM AUTHOR]

Abstract: Background: An easy and specific enzyme-linked immunoassay (ELISA) for the determination of metallothinein-1 (MT-1) and 2 (MT-2) simultaneously in serum and other biological specimens in humans and experimental animals has not been developed yet. Methods: We developed a competitive ELISA, a specific polyclonal antibody against rat MT-2. The epitope mapping of the antibody was conducted using MTs in mouse, rat, rabbit, human and the fragment peptides of human MT-2. MT1/2 and MT-3 knock-out mice and cadmium treated mice were used for the evaluation of the ELISA. Pretreatment method of serum was examined to deplete blocking factors for this assay. Results: The antibody used for this ELISA had the same cross-reactivity with MT in humans and experimental animals. NH2 terminal peptide of MT with acetylated methionine was proved to be the epitope of this antibody. The reactivity of this ELISA system with liver, kidney and brain in MT1/2 knock-out mice was significantly low, but was normal in MT-3 knock-out mouse. The lowest detection limit of this ELISA was 0.6ng/ml and the added MT-1 was fully recovered from serum. The mean MT concentration in our preliminary study was 23±4.6ng/ml in human serum. Cadmium treatment to mice induced significantly higher amount of MT in serum, liver, kidney and spleen as reported previously by different established methods. Conclusion: The proposed competitive ELISA is an easy and specific method for practical use, determining total MT-1 and -2 simultaneously in serum and other biological specimens of human and experimental animals. [Copyright &y& Elsevier]

Abstract: Introduction: Vancomycin is still the cornerstone of antibiotic therapy for patients with suspected or proven invasive methicillin resistant Staphylococcus aureus infections. However, clinical and pharmacodynamic studies underline that appropriate doses depend on the infection site, the patient''s weight, his renal function, and the bacterial susceptibility. Objective and method: In this prospective study made in a Paris teaching hospital, our two goals were to describe the modalities of infusion and serum concentration obtained during therapy, in our pediatrics and adults population. Results: In our hospital, vancomycin was administered every eight hours in 83 % (97/102) of the cases and the doses used were 30mg/kg per day in 67 % of cases (68/102). Serum trough levels reached 15mcg/ml and 20mcg/ml in 36 % and 18 % of cases respectively. Moreover, despite adequate doses, trough levels of 15mcg/ml were obtained in only 40 % of cases. Conclusion: Vancomycin infusion use could be optimized, by defining optimal serum concentrations and monitoring made by a mobile team of infectious diseases specialists. [Copyright &y& Elsevier]

Summary: Purpose: To prospectively analyse the pharmacokinetics of lamotrigine (LTG) during pregnancy and lactation in a consecutive series of epileptic pregnant women. Methods: Nine women on LTG-monotherapy were studied during pregnancy, delivery and lactation, until a mean of 3 weeks postpartum. Maternal blood samples were available from all trimesters as well as umbilical cord blood samples of the newborn 24 and/or 48h postpartum. In 4 cases we additionally determined the LTG-concentration in breast milk. Results: The median LTG-clearance was elevated by 197% during the first trimester, 236% and 248% during the second and third trimester respectively. A maximum of 264% was reached at delivery. An average LTG-dose increase by 250% had to be undertaken in order to obtain therapeutic serum levels. In puerperium LTG-clearance decreased again to reach the initial concentrations approximately at the third week postpartum. The median LTG-concentration ratio of the umbilical cord blood to maternal serum was 1.01 (range: 0.56–1.42), while the median LTG-concentration ratio of breast milk to maternal serum was 0.59 (range: 0.35–0.86). Discussion: Our study confirms the therapeutic relevant changes of LTG-clearance during pregnancy and lactation in women on LTG-monotherapy. Since LTG crosses the placenta, a close monitoring of both mother and newborn is indispensable. [Copyright &y& Elsevier]

Abstract: Background: Cancer that originates in the bone, termed primary bone cancer, is rare. Osteosarcoma (OS) occurs primarily in growing bone tissue and is more prevalent in children and adolescents. OS in adults is rare, with 3 to 5 cases per million population per year worldwide. There are limited data on treatment-related prognosis and adverse reactions in adults reported in the literature. Objectives: The aims of this study were to investigate factors that influence serum methotrexate (MTX) concentrations used in chemotherapy in Chinese adult patients with OS, and to determine the correlations (based on age, sex, and dosage), if any, between MTX and prognosis, in terms of disease-free survival (DFS) and overall survival (OAS), and tolerability. Methods: Adult patients aged ≥30 years with OS received ≥3 courses (2 courses before surgery and 3–4 courses postsurgery) of high-dose MTX (6 or 8 g/m2) combined chemotherapy. The regimen consisted of day 1: MTX + folinic acid (herein referred to as citrovorum factor rescue); day 8: cisplatin; days 21 to 25: ifosfamide + mesna; and day 21: doxorubicin. Serum MTX concentrations were assessed immediately after the end of infusion (baseline) and at 24 and 48 hours using high-performance liquid chromatography. Changes in serum MTX concentrations, factors that influence serum MTX concentrations, and the relationship between serum MTX concentrations and prognosis and tolerability (determined by adverse reactions) were analyzed. Patients received a second course of treatment after a 3-week period. Results: Ninety patients (58 men, 32 women; age range, 30–67 years) with OS were included in the study. A total of 532 courses of combined chemotherapy were administered. The serum MTX concentrations ranged widely at baseline (244.31–929.68 mol/L, Cmin and Cmax, respectively) and at 24 hours (0.73–28.24 mol/L, respectively), suggesting that the serum MTX concentrations varied significantly between different individuals and within the same individual at different time points. The serum MTX concentrations in ~23% of cases (122/532) determined at 24 and/or 48 hours were numerically higher than the safety values (according to Nirenberg''s reference: irreversible damage if MTX concentration was >10 umol/L and > 1 umol/L at 24 and 48 hours, respectively). No correlation was found between high serum MTX concentration at baseline and high serum MTX concentration at 24 hours (r = 0.401). The prevalences of the 3 most common adverse reactions in these patients were depressed white blood cell count (44.03%), dental ulcer (23.0%), and rash (18.0%). However, in the remaining 410 courses in which serum MTX concentrations were lower than the safety values, these prevalences were 14.6%, 3–9%, and 2.4%, respectively. Neither age nor sex was significantly associated with MTX Cmax, but dosage was (P < 0.05). Patients with a serum MTX Cmax concentration >500 μmol/L at baseline had a significantly longer DFS rate than those with ≤500 umol/L (P = 0.040). There were no significant between-group differences in the OAS rates. conclusions: In these Chinese patients with OS, serum MTX concentrations measured at different time points were varied. The findings suggest that adverse reactions occurred in patients whose serum MTX concentrations at 24 and/or 48 hours were higher than the safety values. The dosage appeared to have influenced MTX Cmax, while sex and age did not, and the Cmax was significantly related to DFS but not OAS. [Copyright &y& Elsevier]

Abstract: Malignant diseases are often complicated by malnutrition, and nutritional support is often indicated. Nutritional support should be evaluated primarily by improved clinical outcome. During nutritional support as artificial nutrition, monitoring is of paramount importance. Several biochemical markers are frequently used to monitor nutritional status. Most widely used are serum levels of albumin, transferrin, and transthyretin which are subnormal in malnutrition. Unfortunately, monitoring nutritional support by biochemical indices in malignant disease is complicated by the pathophysiology of cancer related malnutrition. Systemic inflammation is central in this context as it perturbs most of the traditional biochemical indices, and is inversely correlated to survival. In addition, systemic inflammation explains variations in body composition. Thus, the most important biochemical index to be measured in malignant disease is the assessment of systemic inflammatory response, preferably by high-resolution CRP, and if normal, common biochemical indices such as albumin, transferrin or transthyretin might be used. Preferentially, indices with high turnover should be used. IGF-1 is an index well suited for assessing nutrition support in conventional malnutrition, but its use in malignant disease is still unproved. If APPR is prevalent, methods detecting changes in body composition, performance or physical activity might offer better options to evaluate nutritional support. [Copyright &y& Elsevier]

Abstract: Studies were carried out on 5-aminolevulinic acid (ALA)-induced protoporphyrin (PpIX) synthesis in mice peritoneal macrophages and two human oral squamous cell carcinoma (OSCC) cell lines NT8e and 4451. Cells were treated with 200μg/ml ALA for 15h and PpIX accumulation was monitored by spectrofluorometry and phototoxicity to red light (630±20nm) was measured by MTT assay. PpIX accumulation was higher in macrophages as compared to OSCC cells under both normal serum concentration (10%) and conditions of serum depletion. The results on phototoxicity measurements correlated well with the levels of PpIX accumulation in both macrophages and cancer cells. While red light caused 20% phototoxicity in macrophages, no phototoxicity was seen in 4451 cells at 10% serum. Decrease in serum concentration to 5% and 1% led to higher phototoxicity corresponding to 40% and 70% in macrophages and 10% and 15% in 4451 cells. Similar results were obtained in NT8e cell line. Propidium iodide staining followed by fluorescence microscopic observations on photodynamically treated co-culture of murine or human macrophages and cancer cells showed selective damage to macrophages. These results suggest that in OSCC, macrophages would contribute more to tumor PpIX level than tumor cells themselves and PDT may lead to selective killing of macrophages at the site of treatment. Since macrophages are responsible for production and secretion of various tumor growth mediators, the effect of selective macrophage killing on the outcome of PDT would be significant. [Copyright &y& Elsevier]

Abstract: Objective: Increasing research suggested that Cimicifugae rhizoma might be protective against osteoporosis. In this study, we investigated the effects of three cycloartane-type triterpenoids isolated from Cimicifugae rhizoma, cimicidol-3-O-β-d-xyloside (1), cimicidanol-3-O-β-d-xyloside (2) and acetylacteol-3-O-β-d-xyloside (3) on bone resorption in vitro and bone loss in ovariectomized (OVX) mice. Methods: The activities of the tested compounds on bone resorption were evaluated using three assays, neonatal mouse parietal bone organ culture, osteoclast-like cells (OCLs) formation and pit formation. The effects on bone mineral density (BMD) and uterine weight were examined using OVX mice. Using LC–MS/MS method, the serum concentrations of the triterpenoids were measured in mice serum collected at 0.5, 1, 3, 6 and 12h following its oral administration. Results: All of the tested compounds exerted the inhibitory effects on bone resorption in bone organ culture, suppressed both of the formation and the resorbing activity of OCLs. Furthermore, a synergistic effect was observed among those compounds. In vivo studies revealed that compounds 1–3 and the mixture of compounds 1–3 prevented the bone loss in OVX mice without affecting uterine weight, and each compound was detected in the mice serum after single oral administration. Conclusions: The triterpenoids exerted the inhibitory effects on osteoclastic bone resorption through the suppression of both OCLs formation and the resorbing activity of OCLs, and also showed a significant protective effect on BMD in OVX mice. The present results might provide a new pharmacological potential for the treatment of osteoporosis. [Copyright &y& Elsevier]

Abstract: A novel formulation of curcumin in combination with the phospholipids was developed to overcome the limitation of absorption and to investigate the protective effect of curcumin–phospholipid complex on carbon tetrachloride induced acute liver damage in rats. The antioxidant activity of curcumin–phospholipid complex (equivalent of curcumin 100 and 200mg/kg body weight) and free curcumin (100 and 200mg/kg body weight) was evaluated by measuring various enzymes in oxidative stress condition. Curcumin–phospholipid complex significantly protected the liver by restoring the enzyme levels of liver glutathione system and that of superoxide dismutase, catalase and thiobarbituric acid reactive substances with respect to carbon tetrachloride treated group (P <0.05 and <0.01). The complex provided better protection to rat liver than free curcumin at same doses. Serum concentration of curcumin obtained from the complex (equivalent to 1.0g/kg of curcumin) was higher (C max 1.2μg/ml) than pure curcumin (1.0g/kg) (C max 0.5μg/ml) and the complex maintained effective concentration of curcumin for a longer period of time in rat serum. The result proved that curcumin–phospholipid complex has better hepatoprotective activity, owe to its superior antioxidant property, than free curcumin at the same dose level. [Copyright &y& Elsevier]

Abstract: Schizophrenic outpatients (n =102) whose condition had stabilized with clozapine (CLZ) therapy and were being maintained on CLZ were followed for 1 year. Clinical status and concentrations of serum clozapine (CLZ) and its metabolite norclozapine (NCLZ) were evaluated periodically or when relapse occurred. Relapse was defined as a significant exacerbation of psychotic symptoms or hospitalization. Thirty-three patients relapsed and 69 did not. Relapse patients displayed significantly lower serum concentrations of CLZ and a sum of CLZ and NCLZ at endpoint than non-relapses (CLZ: 162 ng/ml vs. 237 ng/ml, p <0.001; CLZ+NCLZ: 225 ng/ml vs. 301 ng/ml, p <0.001). When all subjects were pooled together, a significant inverse correlation was observed between percent increase in the total score on the Brief Psychiatric Rating Scale (BPRS) from baseline and serum levels of CLZ alone (r=0.404, p <0.001) and the sum of CLZ and NCLZ (r=0.364, p <0.001). Relapses and non-relapses were well separated by a threshold CLZ serum concentration of 200 ng/ml with a sensitivity of 73% and a specificity of 80%. The threshold value represented about a 40% lower serum CLZ level than concentration achieved in acute treatment. Survival analysis showed a similarity of the relapse risk over time defined by the CLZ serum threshold and by symptomatic criteria. These results suggest that effective relapse prevention may require maintenance of patients at CLZ serum concentrations above 200 ng/ml and above 60% of the acute-phase level during long-term maintenance treatment of schizophrenia. [Copyright &y& Elsevier]

Vancomycin serum concentrations were determined for 1737 patients treated with either 2 × 1 g of vancomycin or 4 × 500 mg daily (780 patients), according to current nomograms, or by continuous infusion (957 patients) with a loading dose (1 g) and a total of 2–6 g daily. Trough serum concentrations were determined after 36–48 h. Adequate serum levels for the treatment of a normal methicillin-resistant Staphylococcus aureus (MRSA) and a glycopeptide-intermediate S. aureus (GISA) were observed in 81% and 20.9% of patients, respectively. The data support theoretical arguments that higher and more sustained serum levels of vancomycin, obtained by continuous infusion, may enhance clinical efficacy. [ABSTRACT FROM AUTHOR]

Abstract: This work was performed within a commercial nuclear transfer program to investigate different methods for synchronizing donor cell cycle stage, for harvesting donor cells, and for fusion and activation of reconstructed caprine embryos. Primary fetal cells isolated from day 35 to day 40 fetuses were co-transfected with DNA fragments encoding both the heavy and light immunoglobulin chains of three different monoclonal antibodies and neomycin resistance. Four neomycin resistant cell lines for each antibody were selected, expanded, and aliquots were both cryopreserved for later use as karyoplast donors or used for further genetic characterization. Transfected fetal cells were cultured in 0.5% FBS to synchronize G0/G1 cell cycle stage cells, then re-fed with 10% FBS prior to use to allow donor cells to re-enter the cell cycle. Alternatively, transfected fetal cells were grown to confluence in 10% FBS to induce contact inhibition to synchronize G0/G1 cell cycle stage cells. Adherent monolayers of transfected fetal donor cells were harvested by either partial or complete trypsinization. Donor cells were simultaneously fused and activated with enulceated in vivo produced ovulated oocytes from superovulated does. Half of the fused couplets received an additional electrical activation pulse and non-fused couplets were re-fused. Four live offspring were produced from 587 embryos generated from cell lines cultured in 0.5% FBS, while one live offspring was produced from 315 embryos generated from cell lines cultured in 10% FBS (0.7% versus 0.3% embryos transferred, respectively, P > 0.05). Five offspring were produced from 633 embryos generated from cell lines harvested by partial trypsinization (0.8% embryos transferred), and no offspring were produced from 269 embryos generated from cell lines harvested by complete trypsinization. Four live offspring were produced from 447 embryos generated from re-fused couplets, and one live offspring was produced from 230 embryos generated from fused couplets that received an additional electrical activation pulse (0.9% versus 0.4% embryos transferred, respectively, P > 0.05). These results suggest that low-serum culture of transfected goat fetal cells and harvest by partial trypsinization may be more efficient methods for generating transgenic goats by somatic cell nuclear transfer. In addition, re-fusion of non-fused couplet or an additional activation step was successful for producing live offspring. [Copyright &y& Elsevier]

Escitalopram mediates the serotonin re-uptake inhibitory and antidepressant effect of citalopram racemate. However, recent studies have shown that R-citalopram inhibits the escitalopram-induced increase of extracellular 5-HT levels in the frontal cortex of rats. Here, we investigated the inhibitory effect of R-citalopram on the escitalopram-induced increase of 5-HT neurotransmission at the behavioural [potentiation of 5-hydroxytryptophan (5-HTP)-induced behavioural changes in mice and rats] and functional (increase in serum corticosterone in rats) levels. The effect of escitalopram was inhibited by R-citalopram in all three models, and R-citalopram, given alone, was inactive. The effects were more pronounced using an escitalopram to R-citalopram ratio of 1:4 than ratios of 1:2 and 1:1, suggesting a dose-dependent effect. The ED50-value of escitalopram in mouse 5-HTP potentiation studies corresponded to a serum concentration of approximately 50 ng/ml, which can be considered to be in the range of clinically relevant serum concentrations.In conclusion, R-citalopram inhibited the escitalopram-induced increase of 5-HT activity in functional, as well as behavioural, animal models. The mechanism involved in this interaction is currently unknown, but may be related to an improved clinical effect seen with escitalopram in comparison with citalopram. [Copyright &y& Elsevier]

The β-amyloid peptide, the major component of the senile plaques that characterize Alzheimer’s disease, is generated from a set of alternatively spliced β-amyloid precursor proteins (APPs), which are proteolytically cleaved by the action of a set of enzymes referred to generically as secretases. The major processing pathway involves the proteolytic cleavage of APP by α-secretase and results in the release of soluble non-amyloidogenic full-length amino terminal fragments (sAPP), which appear to be involved in neurotrophic events. A reduced production of these neuroprotective sAPP would contribute, together with deposition of the β-amyloid peptide, to the neurodegenerative processes that lead to the cellular death in Alzheimer’s disease. In the present work, we describe a dramatic reduction of sAPP content in medium conditioned by neuronal cells grown under low-serum conditions, when compared with the levels released in the presence of 10% serum. The inhibitory effect on sAPP release appears to be quite specific since that reduction occurs without major changes in cell proliferation, expression of APP-mRNA or intracellular APP levels. Under low-serum conditions, cells showed a more differentiated morphology and no apoptotic signs were observed. Since the α-secretase has been described as a membrane anchored protein, our results suggest that the serum contains an essential factor(s) involved in the α-secretase activity. [Copyright &y& Elsevier]

Data from the 1-year, phase II trial of oral ibandronate for treatment of postmenopausal osteoporosis are presented (n = 180). Participants were at least 10 years past menopause and had osteopenia defined as a forearm bone mineral density at least 1.5 SD below the premenopausal mean value. Doses were 0.25, 0.50, 1.0, 2.5, or 5.0 mg daily oral ibandronate or placebo. A total of 116 women treated with ibandronate completed the study. Blood samples for pharmacokinetic analyses were drawn 20 min, 40 min, 60 min, 2 h, 4 h, and 6 h after the first and last administration of the study drug. An enzyme-linked immunosorbent assay was used to determine the concentration of ibandronic acid (BM 21.0955) in serum (Enzymun-Test System ES 600). The assay is based on streptavidine technology to fix the capture antibody to the wall of the tube. Standards were prepared for each participant using individual drug-free serum. The serum concentration-time curves of ibandronate, expressed as the area under the curve over the sampling period (AUC0–6h), revealed a highly significant dose-response relationship, p < 0.0001, and linear pharmacokinetic behavior. An initial half-life (T1/2λ1) in serum representing distribution and early elimination was 1.3 hours. Steady-state AUC (AUC0–6h ss) increased by a factor of 2.5, which is consistent with an apparent elimination half-life of 32.6 h and a dosing interval of 24 h. There was an exponential association between AUC0–6h ss and the change from baseline at month 12 in the bone markers (n = 116): r = −0.37 (serum total osteocalcin), r = −0.65 (urine C-telopeptides of type I collagen), and r = −0.65 (serum C-telopeptides of type I collagen), all p < 0.0001. All bone markers were maximally depressed at values of AUC0–6h ss of about 3 ng h/mL. AUC0–6h ss furthermore revealed a logarithmic association with change from baseline at month 12 in spine BMD, r = 0.39, p < 0.0001. In conclusion, the serum concentration of ibandronate was determined validly by the enzyme-linked immunosorbent assay. The data are the first to show highly significant associations between pharmacokinetic parameters of a bisphosphonate and the clinical response in bone mass and bone turnover. [ABSTRACT FROM AUTHOR]

Purpose: The present study aimed to compare the serum LTG levels during the early-/mid-follicular (low estradiol) and mid-luteal (high estradiol) phases of the physiologic menstrual cycle.Method: In a cross-sectional study, 20 women with epilepsy were recruited. Participants had been on monotherapy with LTG for at least two months. All the subjects had normal menstrual cycles. Blood samples for each patient were taken whilst fasting during the early-/mid-follicular (Days 3-5) and mid-luteal phases (Days 20-24). All samples were analyzed in batched assays. A comparison of the serum LTG levels was carried out using the Mann-Whitney U test Data were analyzed with the SPSS program, version 16 (SPSS Inc., Chicago, IL), p-values below 0.05 were considered significant.Results: The mean serum LTG levels for the early-/mid-follicular and mid-luteal phases were 4.28±2.76 mg/ml (SD) and 3.86±2.06 mg/ml (SD), respectively. There was no statistically significant difference in serum LTG level between the (low estradiol) early-/mid-follicular and (high estradiol) mid-luteal phases in our patients (p-value=0.23).Conclusion: The serum level of LTG does not alter significantly during the menstrual cycle. [ABSTRACT FROM AUTHOR]

• In most ICIs, an exposure-response (E-R) relationship has been used to describe the safety and efficacy of ICIs, which occurred by unique pharmacokinetics (PK) and pharmacodynamics (PD). • To improve the curative effects, it is necessary to understand the E-R which expediently detected by trough serum concentration of these drugs. In this review, we summarized the studies of exposure in immunotherapy, exploring the possible effect of serum concentration on efficacy and safety of ICIs. Immune checkpoint inhibitors (ICIs) have been demonstrated an effective treatment in multiple tumor type, which restore the immune response to against cancer cell. Currently, approved ICIs include anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4); anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) monoclonal antibodies (mAbs). In most these drugs, unique pharmacokinetic (PK) and pharmacodynamics (PD) have shown significant influence on clinical outcomes, which occurred by target-mediated drug concentration and time-varying drug clearance. An exposure-response (E-R) relationship has been used to describe the safety and efficacy of ICIs, and shown a plateaued E-R and time dependent changes in exposure. Using an enzyme linked immunosorbent assay (ELISA) or LC-MS/MS method to measure the peak concentration, trough concentration or area under the curve (AUC) of ICIs to assess the drug exposure. There are lots of covariates that have an influence on exposure, such as sex, clearance, body weight and tumor burden. In this review, we pooled data from studies of concentration or other pharmacokinetics parameter of mAbs to assess E-R in efficacy and safety. [ABSTRACT FROM AUTHOR]

Many different forms of hormonal contraception are used by millions of women worldwide. These contraceptives differ in the dose and type of synthetic progestogenic compound (progestin) used, as well as the route of administration and whether or not they contain estrogenic compounds. There is an increasing awareness that different forms of contraception and different progestins have different side-effect profiles, in particular their cardiovascular effects, effects on reproductive cancers and susceptibility to infectious diseases. There is a need to develop new methods to suit different needs and with minimal risks, especially in under-resourced areas. This requires a better understanding of the pharmacokinetics, metabolism, serum and tissue concentrations of progestins used in contraception as well as the biological activities of progestins and their metabolites via steroid receptors. Here we review the current knowledge on these topics and identify the research gaps. We show that there is a paucity of research on most of these topics for most progestins. We find that major impediments to clear conclusions on these topics include a lack of standardized methodologies, comparisons between non-parallel clinical studies and variability of data on serum concentrations between and within studies. The latter is most likely due, at least in part, to differences in intrinsic characteristics of participants. The review highlights the importance of insight on these topics in order to provide the best contraceptive options to women with minimal risks. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: The effects of heat treatment and concentration of fish serum (FS) on cell growth in a suspension culture of recombinant Chinese hamster ovary (CHO) 1-15500 (ATCC CRL-9606) cells were investigated. An increase in FS concentration from 1% to 4% markedly increased cell density. On the other hand, heat treatment of FS showed nearly no effect on cell density. [Copyright &y& Elsevier]

Abstract: Introduction: As the susceptibility of staphylococcal strains to glycopeptides rises, it is becoming necessary to increase vancomycin dosages. Objective: To evaluate an administration protocol for vancomycin using continuous infusion with a loading dose of 30mg/kg followed by 30mg/kg per 24h in intensive care patients presenting creatinine clearance (CLc) greater than 50. Results: A total of 22 patients were included in the study. Serum vancomycin concentrations after 24h (C24h) ranged from 25 to 30mg/l in seven of 14 patients with CLc less than 120ml/min (50 %), compared with three patients (21 %) with C24h greater than 35mg/l and four patients (29 %) with C24h less than 25 mg/l. However, C24h was less than 20mg/l for the eight patients with CLc greater or equal to 120ml/min. Bacteriological data was available for eight of the 14 patients with CLc less than 120ml/min, and in these eight patients, the C24h/MIC was greater or equal to 8; seven of these patients had an AUC/MIC greater or equal to 350. Conclusion: Assay of serum vancomycin concentrations after 24h of treatment is necessary to enable rapid adjustment of vancomycin concentration in order to improve therapeutic efficacy or avoid nephrotoxicity. [Copyright &y& Elsevier]

The efficacy of antibody-based therapeutics depends on their pharmacokinetics. The pharmacokinetic and exposure response profiles of ustekinumab, a monoclonal antibody against interleukin 12/interleukin 23, are known in patients with Crohn's disease, yet there are few data from patients with ulcerative colitis. We characterized ustekinumab's pharmacokinetics, exposure response, and optimal serum concentrations in patients with ulcerative colitis. We collected data from 2 phase 3 trials (1 induction and 1 maintenance), in which patients with moderate to severe ulcerative colitis received an intravenous induction dose of ustekinumab (130 mg, n = 320; or approximately 6 mg/kg, n = 322). Responders were assigned randomly to groups that received subcutaneous maintenance ustekinumab (90 mg) every 8 weeks (n = 176) or 12 weeks (n = 172), or placebo (n = 175). We evaluated the association between ustekinumab concentration and efficacy, serum based on clinical effects (Mayo score), histologic features, and inflammation (measurement of C-reactive protein, fecal calprotectin, and fecal lactoferrin), as well as safety (infections, serious infections, and serious adverse events), during induction and maintenance therapy. Optimal serum concentrations of ustekinumab were identified using receiver operating characteristic curve analyses. In patients with ulcerative colitis, dose-proportional serum concentrations of ustekinumab, unaffected by prior biologic or concomitant immunomodulator therapy, reached steady state by the second maintenance dose; the median trough concentration for dosing every 8 weeks was approximately 3-fold that of dosing every 12 weeks. Serum concentrations were associated with clinical and histologic features of efficacy and normalization of inflammation markers. The week-8 concentration threshold for induction of response was 3.7 μg/mL. A steady-state trough serum concentration of 1.3 μg/mL or higher was associated with a higher rate of clinical remission compared with patients who had lower serum concentrations. Serum concentrations of ustekinumab were not associated with infections, serious infections, or serious adverse events. In an analysis of data from 2 phase 3 trials of patients with ulcerative colitis, we found that serum concentrations of ustekinumab were proportional to dose, unaffected by prior biologic or concomitant immunomodulator therapies, associated with clinical and histologic efficacy and markers of inflammation, and were not associated with safety events at doses evaluated. Ustekinumab pharmacokinetics are consistent between patients with Crohn's disease vs ulcerative colitis. [ABSTRACT FROM AUTHOR]

There is increasing concern regarding human exposure to bisphenol analogues (BPs) due to their widespread use and potentially adverse effects. Nevertheless, information on the occurrence of BPs in pregnant women is limited. In this study, BPs were detected in 181 serum samples from pregnant Chinese women. Ten BPs, including bisphenol S (BPS), bisphenol F (BPF), bisphenol AF (BPAF), bisphenol B (BPB), bisphenol P (BPP), bisphenol Z (BPZ), bisphenol AP (BPAP), tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), and tetrachlorobisphenol A (TCBPA), were positively identified and quantified in serum samples with total BP concentrations (sum of bisphenols: ∑BPs) of 0‐144 ng/mL. Concentrations of the two frequently detected compounds, TBBPS and BPS, were 0.593 and 0.113 ng/mL, respectively. The results were also compared with the geographic distributions of the BPs. To our knowledge, this is the first time that TBBPS and TCBPA have been detected in serum samples of pregnant women. These findings suggest that additional studies are urgently needed to identify the risk of maternal and fetal exposure to these compounds. Unlabelled Image • Ten BPs were detected in serum samples from pregnant Chinese women. • TBBPS and BPS were frequently detected compounds. • The results were compared with the geographic distributions of the BPs. • This is the first report of TBBPS and TCBPA detection in serum of pregnant women. [ABSTRACT FROM AUTHOR]

The increasing availability of e-cigarettes is a potential toxicological concern. E-cigarettes appeared on the Polish market in 2006, and since 2009 they have been widely available with a new source of nicotine, the so-called e-liquid. In this paper two cases of suicidal oral and intravenous poisonings with the e-liquid are described. The clinical courses of these poisonings are presented. Nicotine and cotinine concentrations in the patient's blood were determined using high performance liquid chromatography with diode array detection. In the course of intoxication patient No. 1, classic symptoms of acute nicotine poisoning without convulsions were observed. Nicotine and cotinine concentrations measured in serum were 0.096 and 4.4mg/L, respectively. The case of patient No. 2, admission with no typical symptoms of nicotine poisoning was identified, except unconsciousness and slow respiration. Nicotine and cotinine concentrations in the serum at the time of No. 2 admissions were determined to be 0.8 and 1.3mg/L, respectively. With the increasing number of e-liquid poisonings cases, it should be aware that these products can be a readily available source of poison. [ABSTRACT FROM AUTHOR]