The physiology and pharmacology of oxytocin in labor and in the peripartum period.

Oxytocin is a reproductive hormone implicated in the process of parturition and widely used during labor. Oxytocin is produced within the supraoptic nucleus and paraventricular nucleus of the hypothalamus and released from the posterior pituitary lobe into the circulation. Oxytocin is released in pulses with increasing frequency and amplitude in the first and second stages of labor, with a few pulses released in the third stage of labor. During labor, the fetus exerts pressure on the cervix of the uterus, which activates a feedforward reflex-the Ferguson reflex-which releases oxytocin. When myometrial contractions activate sympathetic nerves, it decreases oxytocin release. When oxytocin binds to specific myometrial oxytocin receptors, it induces myometrial contractions. High levels of circulating estrogen at term make the receptors more sensitive. In addition, oxytocin stimulates prostaglandin synthesis and release in the decidua and chorioamniotic membranes by activating a specific type of oxytocin receptor. Prostaglandins contribute to cervical ripening and uterine contractility in labor. The oxytocin system in the brain has been implicated in decreasing maternal levels of fear, pain, and stress, and oxytocin release and function during labor are stimulated by a social support. Moreover, studies suggest, but have not yet proven, that labor may be associated with long-term, behavioral and physiological adaptations in the mother and infant, possibly involving epigenetic modulation of oxytocin production and release and the oxytocin receptor. In addition, infusions of synthetic oxytocin are used to induce and augment labor. Oxytocin may be administered according to different dose regimens at increasing rates from 1 to 3 mIU/min to a maximal rate of 36 mIU/min at 15- to 40-minute intervals. The total amount of synthetic oxytocin given during labor can be 5 to 10 IU, but lower and higher amounts of oxytocin may also be given. High-dose infusions of oxytocin may shorten the duration of labor by up to 2 hours compared with no infusion of oxytocin; however, it does not lower the frequency of cesarean delivery. When synthetic oxytocin is administered, the plasma concentration of oxytocin increases in a dose-dependent way: at infusion rates of 20 to 30 mIU/min, plasma oxytocin concentration increases approximately 2- to 3-fold above the basal level. Synthetic oxytocin administered at recommended dose levels is not likely to cross the placenta or maternal blood-brain barrier. Synthetic oxytocin should be administered with caution as high levels may induce tachystole and uterine overstimulation, with potentially negative consequences for the fetus and possibly the mother. Of note, 5 to 10 IU of synthetic oxytocin is often routinely given as an intravenous or intramuscular bolus administration after delivery to induce uterine contractility, which, in turn, induces uterine separation of the placenta and prevents postpartum hemorrhage. Furthermore, it promotes the expulsion of the placenta.

Self-reported caffeine consumption miss-matched consumption measured by plasma levels of caffeine and its metabolites: results from two population-based studies.

IMPORTANCE AND OBJECTIVE: Self-reported caffeine consumption has been widely used in research while it may be subject to bias. We sought to investigate the associations between self-reported caffeine consumption and plasma levels of caffeine and its two main metabolites (paraxanthine and theophylline) in the community. METHODS: Data from two population-based studies (SKIPOGH1 and 2 (N = 1246) and CoLaus|PsyCoLaus (N = 4461)) conducted in Switzerland were used. Self-reported caffeine consumption was assessed using questionnaires. Plasma levels of caffeine and its metabolites were quantified by ultra-high performance liquid chromatography coupled to a tandem quadrupole mass spectrometer. RESULTS: In both studies, mean log plasma levels of caffeine and its two metabolites were over 6.48 (plasma levels = 652 ng/ml) when no caffeine consumption was reported. Subsequently, nonlinear associations between log plasma levels and self-reported caffeine consumption were observed in SKIPOGH, with a change of the slope at 3-5 cups of espresso per day in SKIPOGH1 but not SKIPOGH2. In CoLaus|PsyCoLaus, increased daily consumption of caffeinated beverages was associated with increased log plasma levels with a change of the slope at 3 cups. In both studies, declared caffeine consumption higher than 3-5 cups per day was not associated with higher plasma levels of caffeine and its metabolites. CONCLUSION: Self-reports of no or low caffeine consumption and consumption of more than 3-5 cups of coffee should be interpreted with caution, with possible under- or over-estimation. Quantifying plasma levels of caffeine and its metabolites may contribute to a better estimation of caffeine intake.

Variation of tafamidis plasma levels during the treatment of TTR amyloidosis patients with Glu89Gln mutation.

PURPOSE: The transthyretin kinetic stabilizer tafamidis, used as a first-line therapy of amyloidosis patients, binds selectively to the transthyretin protein structure and thus prevents its dissociation. The limited information regarding tafamidis application in Glu89Gln amyloidosis patients imposed our research team to determine and evaluate its individual mean plasma levels and their biological variation. METHODS: The present cohort study investigated Bulgarian amyloidosis patients, grouped by gender, age, and therapy duration. A total of sixty patients aged 40-75 years and therapy duration up to 9 years were included. A precise and accurate high-performance liquid chromatography method with ultraviolet detection was used for plasma concentration measurement. RESULTS: Mean plasma concentrations were 5.13 ± 2.64 µmol/L and showed low intra-individual (18.50%) and high inter-individual variability (51.43%). No significant difference was observed between tafamidis plasma levels and therapy duration with p = 0.5941 (p < 0.05 considered significant), but a significant positive correlation was found between plasma concentration, gender, and age with obtained results about p-value 0.0001 and 0.0235, respectively. CONCLUSION: The summary results of the study showed differences that may be based on some specific clinical features of the Glu89Gln mutation.

Imatinib plasma levels in patients with chronic myeloid leukaemia under routine clinical practice conditions.

INTRODUCTION: The addition of imatinib to the therapeutic arsenal for chronic myeloid leukaemia (CML) has changed the natural course of the disease, in such a way that it is now considered a chronic pathology. However, to achieve therapeutic success, it is necessary to reach adequate plasma concentrations to ensure efficacy and safety.In this study, we aimed to evaluate the plasma concentration of imatinib, analysing its influence on effectiveness and safety in patients with CML. METHODS: We performed a descriptive, multicentre study in which imatinib plasma levels from patients diagnosed with CML between 2019-2020 were analysed. An optimal therapeutic range of 750-1500 ng/mL was established for the stratification of patients, according to their minimum plasma concentrations measured at steady state (Cssmin). RESULTS: A total of 28 patients were included, of whom only 39.3% (n = 11) showed Cssmin within the therapeutic range. 100% of patients with Cssmin >750 ng/mL achieved an optimal molecular response, while only 50% of patients with Cssmin <750 ng/mL achieved an optimal molecular response (p = 0.0004). The toxicity rate was 36.4% for patients with Cssmin >1500 ng/mL and 5.9% for those with Cssmin <1500 ng/mL (p = 0.039). CONCLUSIONS: This study aimed to describe the correlation between the toxicity and effectiveness of imatinib according to its Cssmin in routine clinical practice conditions. Based on our findings, it would be certainly justified to monitor patient plasma concentrations of imatinib on a daily routine basis in our hospitals.

Imatinib plasma levels in patients with gastrointestinal stromal tumour under routine clinical practice conditions.

OBJECTIVES: Imatinib is the first therapeutic option for the treatment of unresectable or metastatic gastrointestinal stromal tumours. Previous studies have shown an improvement in patient survival rates following the use of imatinib. Nevertheless, adequate plasma concentrations of imatinib are necessary to achieve such improvement in survival and limit the toxicity of the drug. This study aims to analyse the influence of imatinib plasma concentrations on efficacy and safety in the treatment of gastrointestinal stromal tumour. MATERIALS AND METHODS: This descriptive, multicentre study analysed plasma levels of imatinib in patients diagnosed with gastrointestinal stromal tumour in the period 2019-2020. An optimal therapeutic range of 750-1500 ng/mL was established for the patient stratification based on their minimum plasma concentrations measured at the steady state. RESULTS: This study included 11 patients with metastatic disease in total, among whom only 54.5% (n = 6) had a minimum plasma concentrations measured at the steady state value within the therapeutic range. A median progression-free survival of 7.0 months was recorded for those patients with minimum plasma concentrations measured at the steady state < 750 ng/mL, while that median progression-free survival value remained unachieved for the group with minimum plasma concentrations measured at the steady state > 750 ng/mL (p = 0.005). The toxicity rate was 25% and 14.3% for patients with minimum plasma concentrations measured at the steady state > 1500 ng/mL and minimum plasma concentrations measured at the steady state ≤1500 ng/mL, respectively (p = 0.66). CONCLUSIONS: The present study aims to describe the correlation between the toxicity and effectiveness of imatinib as a function of minimum plasma concentrations measured at the steady state under routine clinical practice conditions. The results described here show the usefulness of imatinib plasma concentrations monitoring as part of the standard daily routine in our hospitals.

BDNF and Cognitive Function in Chilean Schizophrenic Patients.

Despite cognitive symptoms being very important in schizophrenia, not every schizophrenic patient has a significant cognitive deficit. The molecular mechanisms underlying the different degrees of cognitive functioning in schizophrenic patients are not sufficiently understood. We studied the relation between brain-derived neurotrophic factor (BDNF) and cognitive functioning in two groups of schizophrenic patients with different cognitive statuses. According to the Montreal Cognitive Assessment (MoCA) results, the schizophrenic patients were classified into two subgroups: normal cognition (26 or more) and cognitive deficit (25 or less). We measured their plasma BDNF levels using ELISAs. The statistical analyses were performed using Spearman's Rho and Kruskal-Wallis tests. We found a statistically significant positive correlation between the plasma BDNF levels and MoCA score (p = 0.04) in the subgroup of schizophrenic patients with a cognitive deficit (n = 29). However, this correlation was not observed in the patients with normal cognition (n = 11) and was not observed in the total patient group (n = 40). These results support a significant role for BDNF in the cognitive functioning of schizophrenics with some degree of cognitive deficit, but suggest that BDNF may not be crucial in patients with a normal cognitive status. These findings provide information about the molecular basis underlying cognitive deficits in this illness.

Therapeutic Drug Monitoring of Protein Kinase Inhibitors in the Treatment of Non-small Cell Lung Cancer.

Targeted therapy with protein kinase inhibitors (PKIs) represents one of the important treatment options for non-small cell lung cancer (NSCLC). It has contributed to improve patients' survival and quality of life significantly. These anticancer drugs are administrated orally in flat-fixed doses despite the well-known large interpatient pharmacokinetic variability and the possible need for dose individualization. To optimize and individualize dosing of PKIs, and thereby increasing the effectiveness and safety of the treatment, therapeutic drug monitoring (TDM) is the most frequently mentioned method. Unlike other areas of medicine, TDM has been rather exceptional in oncological practise since there is a little evidence or no data for concentration-effect relationships of PKIs. Therefore, the aim of this review is to summarize the pharmacokinetic characteristics of PKIs and provide the evidence supporting the use of TDM for personalised treatment of patients with NSCLC.

Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder.

BACKGROUND: Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). METHODS: This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. RESULTS: All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. CONCLUSION: These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.

Isavuconazole therapeutic drug monitoring in critically ill ICU patients: A monocentric retrospective analysis.

BACKGROUND: The broad-spectrum triazole isavuconazole is used for the treatment of invasive aspergillosis and mucormycosis. Data regarding human plasma concentrations in clinical routine of the drug are rare. OBJECTIVES: Plasma concentrations of isavuconazole were determined in critically ill ICU patients while considering different patients' characteristics. METHODS: Retrospective analysis of isavuconazole plasma concentrations were obtained as part of routine therapeutic drug monitoring (TDM) of ICU patients with invasive aspergillosis or other fungal infections treated with isavuconazole. Plasma levels 0-4 h after last dosing were defined as peak levels (Cmax ), those 20-28 h after last dosing as trough levels (Cmin ). RESULTS: Overall, 223 isavuconazole levels of 41 patients were analysed, divided into 141 peak levels and 82 trough levels. The overall median Cmax was 2.36 µg/ml (mean 2.43 µg/ml, range 0.41-7.79 µg/ml) and the overall median Cmin was 1.74 µg/ml (mean 1.77 µg/ml, range 0.24-4.96 µg/ml). In total, 31.7% of the Cmin values of the total cohort were below the plasma target concentrations of 1 µg/ml, defined as EUCAST antifungal clinical breakpoint for Aspergillus fumigatus. Both peak and trough plasma levels of isavuconazole were significantly lower among patients with a body mass index (BMI) ≥25. In addition, a significant correlation was observed between isavuconazole trough levels and sepsis-related organ failure assessment (SOFA) score. CONCLUSIONS: This study shows that isavuconazole plasma concentrations vary in critical ill ICU patients. Significantly lower isavuconazole levels were associated with elevated BMI and higher SOFA score indicating a need of isavuconazole TDM in this specific patient population.

Ibuprofen enantiomers in premature neonates with patent ductus arteriosus: Preliminary data on an unexpected pharmacokinetic profile of S(+)-ibuprofen.

S(+)-ibuprofen (S-IBU) and R(-)-ibuprofen (R-IBU) concentrations were measured in 16 neonates with patent ductus arteriosus during a cycle of therapy (three intravenous doses of 10-5-5 mg kg-1 at 24-h intervals), at the end of the first infusion and 6, 24, 48, and 72 h later. Data were analyzed with a PK model that included enantiomer elimination rate constants and the R- to S-IBU conversion rate constant. The T½ of S-IBU in the newborn was much longer than in adults (41.8 vs. ≈2 h), whereas the T½ of R-IBU appeared to be the same (2.3 h). The mean fraction of R- to S-IBU conversion was much the same as in adults (0.41 vs. ≈0.60). S-IBU concentrations measured 6 h after the first dose were higher than at the end of the infusion in 10 out of 16 cases, and in five cases, they remained higher even after 24 h. This behavior is unprecedented and may be attributable to a rapid R-to-S conversion overlapping with a slow S-IBU elimination rate. In 13 of the 16 neonates, S-IBU concentrations at 48 and/or 72 h were lower than expected, probably due to the rapid postnatal maturation of the newborn's liver metabolism.

The relationship of plasma antioxidant levels to semen parameters: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial.

PURPOSE: The understanding of the role of plasma antioxidant levels in male fertility in the USA is limited. In a secondary analysis of the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial, we sought to determine whether serum levels of vitamin E (α-tocopherol), zinc, and selenium were correlated with semen parameters and couple fertility outcomes. METHODS: This study is a secondary analysis of the MOXI clinical trial. The primary endpoints in this secondary analysis include semen parameters, and DNA fragmentation and clinical outcomes including pregnancy and live birth. Analyses were completed using Wilcoxon's rank-sum test and linear regression models. RESULTS: At baseline, the analysis included plasma labs for vitamin E (n = 131), selenium (n = 124), and zinc (n = 128). All baseline plasma values were in the normal ranges. There was no association between selenium, zinc, or vitamin E levels and semen parameters or DNA fragmentation. Baseline antioxidant levels in the male partners did not predict pregnancy or live birth among all couples. Among those randomized to placebo, baseline male antioxidant levels did not differ between those couples with live birth and those that did not conceive or have a live birth. CONCLUSIONS: Among men attending fertility centers in the USA, who have sufficient plasma antioxidant levels of zinc, selenium, or vitamin E, no association was observed between vitamins and semen parameters or clinical outcomes in couples with male infertility. Higher levels of antioxidants among men with circulating antioxidants in the normal range do not appear to confer benefit on semen parameters or male fertility.

Size matters: the importance of particle size in a newly developed injectable formulation for the treatment of schizophrenia.

One of the challenges with initiating long-acting injectable (LAI) antipsychotic regimens is achieving relevant drug levels quickly. After first injection of the LAI antipsychotic aripiprazole lauroxil (AL), the lag to reaching relevant plasma aripiprazole levels was initially addressed using supplemental oral aripiprazole for 21 days. A 1-day AL initiation regimen using a NanoCrystal® Dispersion formulation of AL (ALNCD; Aristada Initio®) combined with a single 30 mg dose of oral aripiprazole has been developed as an alternative approach. We compared the 1-day AL initiation regimen (ALNCD + 30 mg oral aripiprazole for 1 day) with the 21-day AL initiation regimen (AL + 15 mg/day of oral aripiprazole for 21 days) using kinetic modeling. Observed and modeled data demonstrate that the 1-day AL initiation regimen provides continuous aripiprazole exposure comparable to the 21-day AL initiation regimen. Each component of the 1-day AL initiation regimen (30 mg oral aripiprazole, ALNCD, and AL) contributes to aripiprazole plasma levels at different times, with oral aripiprazole predominating in the first week, then ALNCD and AL over time. In a double-blind, placebo-controlled, phase 1 study in patients with schizophrenia, the 1-day initiation regimen resulted in rapid achievement of relevant plasma aripiprazole levels comparable to those from the 21-day initiation regimen. Safety and tolerability of the 1-day regimen were consistent with the known profile of aripiprazole. Each part of the 1-day initiation regimen, together with AL, is necessary for continuous aripiprazole exposure from treatment initiation until the next regularly scheduled AL injection is administered.

The overnight reduction of amyloid ß 1-42 plasma levels is diminished by the extent of sleep fragmentation, sAPP-ß, and APOE ε4 in psychiatrists on call.

INTRODUCTION: In mice there might be an association between sleep deprivation and amyloid ß plasma levels. Hence, we examined whether amyloid plasma levels are associated with sleep duration or fragmentation in 17 psychiatrists on-call. METHODS: Amyloid ß (Aß)42, Aß40, and soluble amyloid precursor protein ß (sAPP-ß) plasma concentrations were measured at the beginning and end of 90 on-call nights, and analyzed using generalized linear models. RESULTS: In on-call nights, a 10.7% reduction of Aß42 was revealed overnight. Every single short sleep interruption diminished this reduction by 5.4%, as well as every pg/mL of sAPP-ß by 1.2%, each copy of APOE ε4 by 10.6%, and each year of professional experience by 3.0%. DISCUSSION: The extent of sleep fragmentation diminishes the physiological overnight reduction of Aß42 but not Aß40 plasma levels in the same direction as the enzyme for Aß42 production, the genetic risk factor for Alzheimer's disease (AD), and on-call experience. Might on-call duty and sleep fragmentation in general alter the risk for AD?

Maternal plasma levels of oxytocin during physiological childbirth - a systematic review with implications for uterine contractions and central actions of oxytocin.

BACKGROUND: Oxytocin is a key hormone in childbirth, and synthetic oxytocin is widely administered to induce or speed labour. Due to lack of synthetized knowledge, we conducted a systematic review of maternal plasma levels of oxytocin during physiological childbirth, and in response to infusions of synthetic oxytocin, if reported in the included studies. METHODS: An a priori protocol was designed and a systematic search was conducted in PubMed, CINAHL, and PsycINFO in October 2015. Search hits were screened on title and abstract after duplicates were removed (n = 4039), 69 articles were examined in full-text and 20 papers met inclusion criteria. As the articles differed in design and methodology used for analysis of oxytocin levels, a narrative synthesis was created and the material was categorised according to effects. RESULTS: Basal levels of oxytocin increased 3-4-fold during pregnancy. Pulses of oxytocin occurred with increasing frequency, duration, and amplitude, from late pregnancy through labour, reaching a maximum of 3 pulses/10 min towards the end of labour. There was a maximal 3- to 4-fold rise in oxytocin at birth. Oxytocin pulses also occurred in the third stage of labour associated with placental expulsion. Oxytocin peaks during labour did not correlate in time with individual uterine contractions, suggesting additional mechanisms in the control of contractions. Oxytocin levels were also raised in the cerebrospinal fluid during labour, indicating that oxytocin is released into the brain, as well as into the circulation. Oxytocin released into the brain induces beneficial adaptive effects during birth and postpartum. Oxytocin levels following infusion of synthetic oxytocin up to 10 mU/min were similar to oxytocin levels in physiological labour. Oxytocin levels doubled in response to doubling of the rate of infusion of synthetic oxytocin. CONCLUSIONS: Plasma oxytocin levels increase gradually during pregnancy, and during the first and second stages of labour, with increasing size and frequency of pulses of oxytocin. A large pulse of oxytocin occurs with birth. Oxytocin in the circulation stimulates uterine contractions and oxytocin released within the brain influences maternal physiology and behaviour during birth. Oxytocin given as an infusion does not cross into the mother's brain because of the blood brain barrier and does not influence brain function in the same way as oxytocin during normal labour does.

Vitamin C demand is increased after total knee arthroplasty: a double-blind placebo-controlled-randomized study.

PURPOSE: This study was designed to determine whether perioperative supplementation of vitamin C (VC) improves range of motion (ROM) and reduces the risk of arthrofibrosis (AF) following total knee arthroplasty (TKA). METHODS: Ninety-five patients undergoing TKA were randomized to either oral VC (1000 mg daily) or placebo for 50 days (48 VC group, 47 placebo group). The effect of VC supplementation was tested on ROM, AF, WOMAC, FJS-12, and VC plasma concentrations (VCc). VCc were analyzed in both patient groups before surgery, 4 and 7 days after surgery. RESULTS: ROM at 1 year was not different between study groups. The prevalence of AF was 5 of 48 (10.4%) in the VC group compared to 11 of 47 (23.4%) in the placebo group (p = 0.09). VCc decreased post-operatively in the placebo group (49-12 µmol/l on day 7, p < 0.001), but not in the VC group (53-57 µmol/l). Patients with a perioperative drop of VCc ≥ 30 µmol/l developed significantly more AF at 1 year compared to patients with a VCc drop of < 30 µmol/l (p = 0.007). CONCLUSIONS: TKA results in VC depletion. Perioperative VC supplementation prevents VCc drop in most patients undergoing TKA and may lower the incidence of AF. The clinical relevance of this study is that VC supplementation seems to be a cheap and safe adjunct to improve functional outcome after TKA. LEVEL OF EVIDENCE: I. TRIAL REGISTRY: The study was registered at the ISRCTN registry with study ID ISRCTN40250576.

Sex-Related Differences in Plasma Oxytocin Levels in Humans.

BACKGROUND: Increasing evidence supports a key role of Oxytocin (OT) as a modulator of social relationships in mammals. OBJECTIVE: The aim of the present study was to investigate possible sex-related differences in plasma OT levels in human beings. METHODS: Forty-five healthy men and 45 women (mean age: 34.9 ± 6.2 years), were included in the study. Plasma preparation, peptide extraction and OT radioimmunoassay were carried out according to standardized methods. RESULTS: The results showed that OT plasma levels (pg / ml, mean ± SD) were significantly higher in women than in men (4.53 ± 1.18 vs 1.53 ± 1.19, p ˂ 0.001). CONCLUSIONS: The present finding demonstrates sex-related differences in plasma OT levels in humans. It is tempting to hypothesize that such differences might be related to behaviours, attitudes, as well as susceptibility to stress response, resilience and social emotions specific of women and men.

Beta-lactams in continuous infusion for Gram-negative bacilli osteoarticular infections: an easy method for clinical use.

Continuous infusion (CI) of beta-lactams could optimize their pharmacokinetic/pharmacodynamic indices, especially in difficult-to-treat infections. PURPOSE: To validate an easy-to-use method to guide beta-lactams dosage in CI (formula). METHODS: A retrospective analysis was conducted of a prospectively collected cohort (n = 24 patients) with osteoarticular infections caused by Gram-negative bacilli (GNB) managed with beta-lactams in CI. Beta-lactams dose was calculated using a described formula (daily dose = 24 h × beta-lactam clearance × target "steady-state" concentration) to achieve concentrations above the MIC. We correlated the predicted concentration (Cpred = daily dose/24 h × beta-lactam clearance) with the patient's observed concentration (Cobs) measured by UPLC-MS/MS (Spearman's coefficient). RESULTS: The most frequent microorganism treated was P. aeruginosa (21 cases; 9 MDR). Beta-lactams in CI were ceftazidime (n = 14), aztreonam (7), and piperacillin/tazobactam (3), mainly used in combination (12 with colistin, 5 with ciprofloxacin) and administered without notable side effects. The plasma Cobs was higher overall than Cpred; the Spearman correlation between both concentrations was rho = 0.6 (IC 95%: 0.2-0.8) for all beta-lactams, and rho = 0.8 (IC 95%: 0.4-1) for those treated with ceftazidime. CONCLUSIONS: The formula may be useful in clinical practice for planning the initial dosage of beta-lactams in CI, while we await a systematic therapeutic drug monitoring. The use of beta-lactams in CI was safe.

Methadone Dose Adjustments, Plasma R-Methadone Levels and Therapeutic Outcome of Heroin Users: A Randomized Clinical Trial.

AIMS: We aimed to improve the retention in treatment and therapeutic outcome of methadone maintenance treatment (MMT) patients by adjusting the oral methadone dose in order to reach a "target" plasma R-methadone level (80-250 ng/mL). METHODS: A multicenter randomized controlled trial was organized. RESULTS: The intention-to-treat statistical analysis showed that repeated dose adjustments performed in order to obtain therapeutic plasma R-methadone levels did not improve retention in treatment of heroin-dependent patients. However, patients having plasma methadone levels in the "target range" at the beginning of the study had a better retention in treatment than controls. Furthermore, patients succeeding in keeping plasma R-methadone target levels (per protocol analysis) remained in treatment and improved their social scores better than controls. -Conclusion: Although the primary endpoint of this study was not demonstrated, a post hoc and a per protocol analysis suggested that patients in MMT with plasma R-methadone concentrations in the target range have a better therapeutic outcome than controls.

[Deficit of Magnesium and States of Hypercoagulation: Intellectual Analysis of Data Obtained From a Sample of Patients Aged 18-50 years From Medical and Preventive Facilities in Russia].

The states characterized by pronounced hypercoagulable components (deep vein thrombosis, cardio- and cerebro-vascular pathologies) are caused by multiple pathophysiological factors, including insufficient supply of magnesium (Mg) and other micronutrients. AIM: to present results of analysis of the Institute of Microelements Data Base (IMDB) performed from point of view of interrelationships of Mg deficit and hypercoagulable states in adults treated in medico-preventive facilities of Central, Northwestern, Northern, and Siberian federal districts of Russia. METHODS: The analysis was realized as analysis of data obtained in a cross-sectional study. In the cohort of patients (n=1453) formed from the IMBD adequacy of Mg supply was assessed by magnesium levels in blood plasma (Mg BP) (0.69±0.15 mmol/L) and estimates of daily Mg consumption according to dietary diaries (Mg D) (185±90 mg/day). RESULTS: Mg supply was adequate (Mg BP >0.80 mmol/L, Mg D >300 mg/day) in not more than 6 % of patients. Presence of "Hypercoagulation" label in data base was associated with greater number of chronic diseases (2.3±2.1 and 0.83±0.8 with and without this label, respectively, р=0.0006) and elevated risk of the presence on 4 comorbid pathologies (odds ratio [OR] 18, 95 % confidence interval [CI] 10-25, р=0.0006). Mg deficit (Mg BP.

Clinical and interferon-modulating efficacy of a combination of rectal and topical dosage forms of interferon-α2b in acute respiratory infections.

AIM: The aim of the study was to evaluate the clinical and interferon-modulating efficacy of a combination of rectal and topical dosage forms of IFN-α2b with antioxidants in the treatment of acute respiratory infections (ARIs) in comparison with other variants of antiviral therapy. MATERIALS AND METHODS: A total of 90 servicemen aged 19.2±0.9 years with uncomplicated forms of ARI were hospitalized not later than 48 hours after the onset of the disease. Patients were randomized into 3 groups of 30 people each. In the first group, patients received rectal suppositories containing IFN-α2b (1 million IU) and antioxidants (alpha-tocopherol acetate and ascorbic acid) twice a day for 5 days. In the second group, patients received intranasally a gel formulation containing IFN-α2b (36 000 IU/1 g) and antioxidants 3 times a day in addition to the above suppositories. In the third group, patients were prescribed umifenovir (reference drug) at dose of 200 mg 4 times a day for 5 days. The dynamics of regression of clinical manifestations of ARI in different groups, changes in concentrations of IFN-α and IFN-γ in blood plasma, as well as spontaneous and induced production of these cytokines by blood cells ex vivo were evaluated. After that, the patients were observed for another 3 months to register repeated cases of hospitalization for ARI. RESULTS: Marked tendency to accelerate the regression of symptoms of intoxication and fever was observed when intranasal dosage form of IFN-α2b was administered to patients receiving the rectal form of this cytokine. The combination of rectal and topical dosage forms of IFN-α2b with antioxidants was more effective than monotherapy with the rectal suppositories in preventing repeated hospitalization for ARI. The above combination caused the most complete correction of induced production of IFN-α by blood cells ex vivo at its initial deviation from the norm. CONCLUSION: The obtained data indicate the expediency of using the combination of rectal and topical dosage forms of IFN-α2b with antioxidants for treatment of ARI.