Subtherapeutic Range Research Articles

Enhancing Therapeutic Drug Monitoring in Inflammatory Bowel Disease: A Comparative Analysis of Rapid Point-of-Care Infliximab, Adalimumab and Anti-Drug Antibodies' Determination against ELISA.

The introduction of point-of-care (POC) assays into clinical practice in patients with inflammatory disease enables on-demand therapeutic decision making. The aim of this study was to compare the POC test Quantum blue (Bühlmann Laboratories) for infliximab (IFX), adalimumab (ADL), and its anti-drug antibodies with the traditional ELISA assay (Promonitor). A total of 200 serum samples were analyzed. Samples were classified into the following three different groups; sub-therapeutic range (IFX < 3 μg/mL and ADL < 5 μg/mL); therapeutic range (IFX: 3-7 μg/mL and ADL: 5-12 μg/mL) and supra-therapeutic range (IFX levels > 7 μg/mL and ADL levels > 12 μg/mL). Significant higher values were measured using the POC test (p < 0.001) for IFX results but no differences in ADL trough levels were observed (p = 0.3101). Spearman's correlation indicated a good correlation between the two assays (rs = 0.88 for ADL and rs = 0.93 for IFX), and McNemar's test revealed significant differences (p = 0.016) when classifying IFX samples between therapeutic and supra-therapeutic ranges but no significant differences were found among the other ranges for either IFX or ADL. These results show that we should be cautious when using these rapid measurement methods, and new targets should probably be defined for IFX when using this new analytical method.

Drug-level change and optimal dose adjustment of tacrolimus with the use of rifabutin for treating mycobacterial disease in solid organ transplant recipients.

Little is known about the change in drug level and the need for dose adjustment of calcineurin inhibitor when it is used with rifabutin in solid organ transplant (SOT) recipients. We aimed to analyze whether the drug level of tacrolimus significantly reduced after the use of rifabutin and to assess optimal adjustment of tacrolimus dose in SOT recipients. Of the SOT recipients in a tertiary referral center in South Korea in 2000-2019, 50 patients who maintained an unchanged dose of tacrolimus after the use of rifabutin for treating mycobacterial disease were enrolled. Their medical records were reviewed retrospectively. The mean age of the patients was 53.9±11.5years. The most commonly transplanted organ was the liver (66.0%). The most common indication of rifabutin use was for treating active tuberculosis (78.0%). After rifabutin initiation, the trough level of tacrolimus decreased significantly to the subtherapeutic range in 38 (76.0%) patients. The drug levels of these 38 patients dropped from 7.2 to 3.8ng/ml (p<.001) after rifabutin treatment. In these patients, the median 1.5-fold increase in the tacrolimus dose was required to restore the drug level to the within-therapeutic range. These findings indicate that careful tacrolimus drug-level monitoring and dose adjustment are necessary for most SOT recipients when rifabutin is administered for the treatment of mycobacterial disease.

Magnitudes of Risk Factors of Venous Thromboembolism and Quality of Anticoagulant Therapy in Ethiopia: A Systematic Review.

BackgroundVenous thromboembolism is one of the major public health problems in the world. Though several studies were conducted to estimate common risk factors of venous thromboembolism and quality of anticoagulant therapy in Ethiopia, it is difficult to estimate the overall burdens of risk factors and quality of anticoagulant use because of the lack of a nationwide study.ObjectiveTo assess magnitudes of risk factors of venous thromboembolism and quality of anticoagulant therapy in Ethiopia.Materials and MethodsElectronic searching using PubMed, EMBASE, Science Direct, Cochrane Database, Scopus, Hinari, Sci-Hub, African Journals Online Library, and Free-text Web Searches using Google Scholar was conducted from September, 15 to October 27, 2021. Each of the original studies was identified by Mesh terms and Boolean search technique using full title, various keywords and was assessed using the Joanna Briggs Institute Critical Appraisal Checklist. The data were extracted using a format prepared in Microsoft Excel and exported to STATA 14.0 for the outcome analyses.ResultsThe database search delivered a total of 2118 studies. After articles were removed by duplications, titles, reading the abstract, and assessed for eligibility criteria, 12 articles were found suitable for the systematic review. Prolonged immobilization (41.30%) was the most commonly observed risk factor of venous thrombosis followed by acute infection (40.25%). The proportion of therapeutic range (INR = 2–3), sub-therapeutic range (INR <2), and supra-therapeutic range (INR >3) were 32.15%, 47.58%, and 17.62%, respectively. One hundred and thirty-eight patients (11.4%) have developed minor or major bleeding complications.ConclusionProlonged immobilization and acute infection were the main risk factors for venous thromboembolism. The quality of anticoagulant therapy in Ethiopia was poor and bleeding complications were high. A strong effort is needed to improve the quality of anticoagulation and close monitoring of patients’ international normalized ratio is required to improve treatment outcomes.

Therapeutic drug monitoring in epilepsy: Can drug levels reliably measure drug adherence?

Background: Drug adherence is often assessed from patients' reports and confifirmed with therapeutic drug monitoring. The study investigated the relationship between reports of drug adherence and drug levels of carbamazepine among adult patients on carbamazepine monotherapy. Methods: 84 consecutively consenting patients who had been on carbamazepine monotherapy for seizure control were recruited from the Neurology Clinic, LUTH, Idi-Araba, Lagos for the study. Adherence in the past month was assessed using a standard proforma. Drug levels were taken in the trough phase (just before the next dose of carbamazepine) and analyzed using high performance liquid chromatography. Results: Among the population studied, full adherence was reported in 45.2% of the participants while the remainder had missed one or more doses in the past month. Serum drug levels were found to be signifificantly higher in patient who reported full adherence compared to non-adherent patients (p&lt;0.05). When levels were compared to the reference range of carbamazepine, 15.8% of the patient who reported good adherence had blood levels in the subtherapeutic range, while 21.7% who reported poor adherence had blood levels in the subtherapeutic range (p&gt;0.05). Conclusion: Adherence is associated with higher drug levels, but both adherent and nonadherent patients had a similar likelihood of having serum drug blood levels in the subtherapeutic range. This calls for caution in the interpretation of drug levels as it relates to adherence. Further studies on standardization of therapeutic drug measurement to develop predictive tools for adherence are recommended.

Omeprazole-induced galactorrhea in kidney transplant patients\u2014a case report

BackgroundOmeprazole belongs to the pharmacological classifications of proton pump inhibitors and is a widely used medicine. All proton pump inhibitors have a common mechanism of action and are prodrugs that require activation in an acidic environment. Omeprazole is extensively metabolized in the liver by cytochrome 2C19 and cytochrome 3A4, which are responsible for drug interactions. Omeprazole-induced galactorrhea is a rare adverse event of drug metabolism and is often underreported.Case presentationThis is a case of a 26-year-old unmarried Asian (Bhutanese) female who underwent kidney transplant and was administered standard antirejection medication (tacrolimus, prednisolone, and leflunomide) along with an antihypertensive agent. She came to the emergency department with complaints of nausea, vomiting, abdominal pain, chronic gastritis, anemia, hypertension, and loss of appetite. The tacrolimus trough level was in the subtherapeutic range at admission. The tacrolimus dose was adjusted, and oral omeprazole was administered. After 3 days, she experienced milk production from her left breast, which according to the patient was her second incidence after omeprazole ingestion.ConclusionCausality assessment using Naranjo’s algorithm and recovering from galactorrhea after stopping omeprazole and omeprazole rechallenge with the reappearance of galactorrhea confirmed omeprazole as the causative agent. Tacrolimus interferes with omeprazole metabolism and increases tacrolimus levels in the blood. Caution needs to be taken when omeprazole is administered with other drugs that interfere with metabolizing enzymes.

The PHARMACOM-EPI Framework for Integrating Pharmacometric Modelling Into Pharmacoepidemiological Research Using Real-World Data: Application to Assess Death Associated With Valproate.

In pharmacoepidemiology, it is usually expected that the observed association should be directly or indirectly related to the pharmacological effects of the drug/s under investigation. Pharmacological effects are, in turn, strongly connected to the pharmacokinetic and pharmacodynamic properties of a drug, which can be characterized and investigated using pharmacometric models. Recently, the use of pharmacometrics has been proposed to provide pharmacological substantiation of pharmacoepidemiological findings derived from real-world data. However, validated frameworks suggesting how to combine these two disciplines for the aforementioned purpose are missing. Therefore, we propose PHARMACOM-EPI, a framework that provides a structured approach on how to identify, characterize, and apply pharmacometric models with practical details on how to choose software, format dataset, handle missing covariates/dosing data, how to perform the external evaluation of pharmacometric models in real-world data, and how to provide pharmacological substantiation of pharmacoepidemiological findings. PHARMACOM-EPI was tested in a proof-of-concept study to pharmacologically substantiate death associated with valproate use in the Danish population aged ≥65years. Pharmacological substantiation of death during a follow-up period of 1year showed that in all individuals who died (n=169) individual predictions were within the subtherapeutic range compared with 52.8% of those who did not die (n=1,084). Of individuals who died, 66.3% (n=112) had a cause of death possibly related to valproate and 33.7% (n=57) with well-defined cause of death unlikely related to valproate. This proof-of-concept study showed that PHARMACOM-EPI was able to provide pharmacological substantiation for death associated with valproate use in the study population.

A Multicenter Retrospective Study of Vancomycin Dosing by Weight Measures in Children.

Vancomycin carries risks of treatment failure and emergent resistance with underexposure and renal toxicity with overexposure. Children with overweight or obesity may have altered pharmacokinetics. We aimed to examine how body weight metrics influence vancomycin serum concentrations and to evaluate alternative dosing strategies. This was a multicenter retrospective cohort study across 3 large, academic hospitals. Patients aged 2 to 18 years old who received ≥3 doses of intravenous vancomycin were included. Weight metrics included total body weight, adjusted body weight, ideal body weight, body surface area, and allometric weight. Outcomes included vancomycin concentration and ratios of area under the curve (AUC) to minimum inhibitory concentration (MIC). Regression analyses were used to examine which body-weight identifier predicted outcomes. Of the 1099 children, 45% were girls, mean age was 9.0 (SD = 5.4) years, 14% had overweight, and 17% had obesity. Seventy-five percent of children had vancomycin concentrations in the subtherapeutic range by trough <10 µg/mL, and 63% had a ratio of AUC to MIC <400 μg-hr/mL. Three percent had a supratherapeutic initial trough >20 µg/mL or ratio of AUC to MIC >600 μg-hr/mL. Serum vancomycin concentrations were higher in children with overweight or obesity compared with children who were at a normal weight or underweight; the mean ratio of AUC to MIC also trended higher in the groups with overweight or obesity. Most children received vancomycin regimens that produced suboptimal trough levels. Children with overweight or obesity experienced higher vancomycin trough levels than children of normal weight despite receiving lower total body weight dosing. Using the ratio of AUC to MIC was a better measure of drug exposure.

Effect of serum isoniazid level on treatment outcomes among tuberculosis patients with slow response – A retrospective cohort study

BackgroundIn this study, we investigate the effects of low serum TB drug level on treatment outcome among TB patients with slow response in South Korea, where the prevalence of rapid acetylator is relatively high. MethodsAmong the pulmonary TB patients whose treatment outcomes were reported between 2014 and 2018 at Incheon St. Mary hospital, those who underwent TDM because of delayed culture conversion or reversion were included. Primary outcome was microbiological failure defined as (1) positive sputum culture after 120 days of treatment, or (2) culture-confirmed relapse within one year after treatment completion. Patients with culture conversion within 120 days and no relapse were classified as the final conversion group. Clinical characteristics and serum drug concentration at 2 h after administration (C2hr) were compared between those two groups. ResultsA total of 55 pulmonary TB patients were included. Prevalence of subtherapeutic range of C2hr for isoniazid and rifampin was 78.2% and 21.8%, respectively. With one year of follow-up, 21 cases were classified as the microbiological failure group, and 34 cases as the final conversion group. In a multivariable logistic regression model for predicting microbiological failure, C2hr of isoniazid was the most significant predictor after adjusting for the effects of age and sex (adjusted odds ratio, 0.29; p = 0.009). In a tree-based classification model, C2hr of isoniazid with cutoff level 2.5 μg/ml was the most important variable for predicting microbiological failure. ConclusionsLow serum isoniazid level was related to poor treatment outcomes among the TB patients with slow response.

Determination of Voriconazole Plasma Concentration by HPLC Technique and Evaluating Its Association with Clinical Outcome and Adverse Effects in Patients with Invasive Aspergillosis.

Purpose Invasive aspergillosis is a prevalent fungal disease, especially in Asian countries with a high mortality rate. Voriconazole (VRZ) is the first choice for invasive aspergillosis treatment. Plasma concentration of this drug is unpredictable and varies among individuals. This variability is influenced by many factors leading to clinical implication. Therapeutic drug monitoring (TDM) may have a crucial role in the patients' treatment process. The HPLC method provides sufficient specificity and sensitivity for plasma VRZ concentration determination for TDM purposes of this drug. Methods Patients who initiated oral or intravenous VRZ for invasive aspergillosis were enrolled in this study. Demographic characteristics and clinical data, outcome, and adverse effects were documented. For each patient, the plasma sample was collected under steady-state condition and analyzed using a validated HPLC method. Results A total of 22 measurements were performed. Fifty percent of patients were out of the therapeutic range. From them, 27.27% and 22.73% were in subtherapeutic and supratherapeutic ranges (<1 μg/mL and >5.5 μg/mL), respectively. There was a significant correlation between VRZ plasma concentration and treatment outcomes (P=0.022). Treatment failure was five times higher than treatment success in those in the subtherapeutic range. Adverse effects were observed more frequently in patients with supratherapeutic concentrations compared to those with non-supratherapeutic levels. Furthermore, the mortality rate in patients experiencing treatment failure was 2.17 times higher than those with treatment success. Conclusions TDM of VRZ plays an important role in better evaluation of efficacy and toxicity during treatment. Therefore, determination of the drug level may be of clinical significance.

Rapid and Simple Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC) Method for Simultaneous Quantifications of Triazole Antifungals in Human Serum.

To develop and validate a one-step, rapid and simple reversed-phase high-performance liquid chromatography (HPLC)-based protocol for the simultaneous measurement of voriconazole (VCZ), posaconazole (POSA), itraconazole (ITC) in serum/plasma. Calibration standards (CS) and quality control samples were prepared in drug-free serum by spiking with the triazoles at different concentrations. HPLC was performed with C18 column, isocratic mobile phase after extraction with cold acetonitrile. The standardized method was tested in 2693 patients' serum/plasma samples. Linearity of CS for ITC, VCZ and POSA was proportional to the nominal concentration (correlation coefficient > 0.999). Limit of detection (mg/L) for ITC, VCZ and POSA was 0.25, 0.25 and 0.125, respectively. The lower limit of quantification (mg/L) for ITC, VCZ and POSA was 0.5, 0.5 and 0.25, respectively. Precision and accuracy were in acceptable range with 100% average percentage recovery. No interferences from endogenous substances and other antimicrobial compounds were noted. In clinical samples, the therapeutic range achieved for VCZ was 39.9%. Whereas, 61.1% and 44% of samples with ITC and POSA, respectively, were in the sub-therapeutic range. We developed a rapid and simple HPLC method to quantify common triazoles in a single chromatographic run allowing simultaneous measurement of different antifungals in a small volume of serum/plasma. Thus, therapeutic drug monitoring requests can be processed in one run without changing the protocol parameters, column or column conditioning thereby improving turnaround time.

Therapeutic drug monitoring of olanzapine: Easy and reliable method for clinical correlation

AIM:The current work establishes an easy, reliable technique for the estimation of serum Olanzapine concentration which correlates it clinically.SUBJECTS AND METHODS:The work was agreed in 61 schizophrenic patients who were on olanzapine. Serum drug amount was estimated by normal-phase high-performance liquid chromatography and brief psychiatry rating scale was used to determine disease progression.RESULTS:Samples provided 61 patients, 40 were under sub-therapeutic range, 18 were under therapeutic range and 3 were above the therapeutic range.CONCLUSION:Therapeutic drug monitoring must be a part of clinical practice in psychiatric hospitals for optimizing the dose of an individual patient along with the correlation of serum concentration with the clinical assessment scales.

Does fasting during Ramadan influence the therapeutic effect of warfarin?

The changes in the therapeutic effect of warfarin during Ramadan fasting are controversial. Hence, we carried out the present study to assess if there are any alterations in the anticoagulation response to warfarin and identify the associated risk factors. Patients receiving warfarin for at least 1year were included in the present study. Their demographic details, warfarin doses, prothrombin time-international normalized ratio (PT-INR) values and concomitant diseases/drugs were retrieved. The dates of Ramadan periods for the calendar years were obtained, and these periods were considered as Ramadan periods. One month before the start dates of Ramadan was considered as pre-Ramadan, and 1month later than the last dates was considered as post-Ramadan periods. Warfarin sensitivity index (WSI), PT-INR category and time spent in therapeutic range (TTR) were assessed. National Institute of Clinical Health Excellence (NICE) criteria for anticoagulation status were adhered to where TTR (%) <65 was considered as poor anticoagulation. One hundred and eighty-three patients were recruited. No significant differences were observed in warfarin doses between the study participants between pre-Ramadan, Ramadan and post-Ramadan periods. Significantly more numbers of PT-INR tests were carried out during Ramadan compared with pre- and post-Ramadan periods. A higher WSI was akin to PT-INR, and lower intra-individual variability was observed in middle-aged and older adults in the post-Ramadan period. Significantly fewer patients had their PT-INR in the therapeutic range and more in the subtherapeutic range during Ramadan periods. Greater proportion of patients had PT-INR in the supratherapeutic range during post-Ramadan periods, particularly the elderly. Although 38.3% had poor anticoagulation status overall, 92.4% met the NICE criteria for poor anticoagulation during the 3months (pre-Ramadan, Ramadan and post-Ramadan periods). Ramadan fasting influences the therapeutic effect of warfarin in terms of lowered TTR (%), reduced proportion of patients achieving therapeutic PT-INR and increased risk of poor anticoagulation control. Greater caution is required during the post-Ramadan period, particularly in the elderly category as they are more prone for over-anticoagulation and consequently the risk of bleeding.

ASSESSMENT OF TIME IN THERAPEUTIC RANGE WITH WARFARIN THERAPY IN PHARMACIST VERSUS USUAL CARE GROUP: A RETROSPECTIVE COHORT STUDY

Objective: Anticoagulation management with warfarin is a familiar challenge seen in primary care settings. A greater time in the therapeutic range (TTR) has shown improved health benefits in patients treated with warfarin for atrial fibrillation. The aim of this study was to assess the level of anticoagulation control achieved with warfarin therapy measured by TTR.&#x0D; Methods: Patients attending anticoagulation service at a medical center were included in this retrospective cohort study. Patients with at least two international normalized ratio (INR) values not more than 4 weeks apart were included and placed in a usual care group or a pharmacist care group based on the care received. Anticoagulation control was measured by calculating TTR according to Roosendaal’s linear interpolation method. A TTR of &gt;70% was considered high-quality and &gt;60% was considered moderate coagulation control. The data were analyzed for descriptive statistics, associations, and for identifying predictors of TTR. A p value of &lt;0.05 was considered statistically significant.&#x0D; Results: Mean age of patients was 58±9 years; 57% were male; 48% were White Caucasian, and 43% had a CHADS2 score of ≥3. Patients in the pharmacist group had a high TTR (67.6% vs. 43.4%, p&lt;0.0001) and an INR in a significantly lower sub-therapeutic range than the usual care group (5.6% vs. 14.8%; p&lt;0.0001). Half of the patients in the pharmacist group were able to achieve a TTR threshold of 60% and greater compared to less than one-third among the usual care group. Age and pharmacist care were found to be great predictors of TTR after adjusting for gender, ethnicity, and CHADS2 score (p&lt;0.001).&#x0D; Conclusion: Our findings confirmed that pharmacist led anticoagulation care positively improved patients’ TTR with warfarin.

Risk of perioperative bleeding complications in rhegmatogenous retinal detachment surgery: a retrospective single-center study.

The goal of this study was to analyze the incidence of perioperative bleeding complications in rhegmatogenous retinal detachment. The handling of perioperative anticoagulation during vitreoretinal surgery remains controversial, since the risk of bleeding complications by its continuation has to be balanced against the risk of progression of retinal detachment and the risk of thromboembolic events when anticoagulation is interrupted. Nevertheless, only few studies have investigated the risk of perioperative bleeding complications in an emergency such as retinal detachment surgery. We therefore examined the rate of all perioperative hemorrhages and separately the rate of only severe bleedings during vitrectomy, scleral buckling with or without drainage of subretinal fluid (SRD), or combined procedures due to retinal detachment in patients undergoing different types of perioperative anticoagulation including acetylsalicylic acetate (ASA), clopidogrel, heparin, low molecular weight heparin, and phenprocoumon. This retrospective single-center study included 893 patients with primary rhegmatogenous retinal detachment, n = 192 on anticoagulation and n = 701 serving as control without anticoagulation. Our analysis revealed no significantly increased rate of perioperative hemorrhages under anticoagulation with ASA 100mg (all, 11.4%; severe, 5.0%) or phenprocoumon (all, 11.6%; severe, 2.3%) compared with controls (all, 13.0%; severe, 5.4%). However, frequencies of bleeding complications varied markedly regarding the type of surgical procedure: Scleral buckling plus SRD showed the highest rates of hemorrhages (all, 18.9%; severe, 9.1%) with significant difference (P < 0.001) compared with scleral buckling without SRD (all, 3.8%; severe, 0.6%) and vitrectomy (all, 9.2%; severe, 1.5%), respectively. Furthermore, subretinal bleeding was the most common type of perioperative hemorrhage. The data suggest not to stop ASA therapy prior to vitreoretinal surgery. Furthermore, we found no evidence of an increased risk for perioperative bleedings in patients under anticoagulation with vitamin-k antagonists with an INR within the sub-therapeutic range. SRD during scleral buckling procedure should be avoided as possible and regardless of any type of anticoagulation.

Comparison of prothrombin time and international normalized ratio values using point-of-care system with a standardized laboratory method in patients on long-term oral anticoagulation – A prospective study

Background: In our country, methods of prothrombin time (PT) and international normalized ratio (INR) testing have not been standardized across various centers. Often, we find disparity in INR values from different laboratories, posing a challenge to make an appropriate clinical decision. Objective: The objective of the study was to compare and correlate the PT/INR values using a point-of-care (POC) system with standardized laboratory (SL) testing and to evaluate the efficiency of the POC system in monitoring patients. Methods: We have prospectively compared PT/INR values between a commercially available POC, CoaguChek XS System, Roche, and SL testing in 205 patients and 353 samples from July 2017 to April 2018. Results: The overall strong correlation between POC PT/INR values and simultaneous standard laboratory values was noted. The overall coefficient of correlation among the two groups was 0.919 (P = 0.001) for INR values. In INR range of 2–3.5, the values correlated well with a coefficient of correlation, 0.756 (P = 0.001). In INR range 4. Conclusions: In this comparison study, statistical analysis yielded a good correlation between POC PT/INR values and SL values in therapeutic and subtherapeutic range. POC testing is a good alternative to SL testing. If widely available, POC testing may enable patient self-testing and self-monitoring. In our experience, POC testing had added benefits in emergency settings. However, clinicians and laboratory professionals should be aware of the occasional disagreement between POC INR and standard laboratory INR values.

The Effect of Valproic Acid on Olanzapine Serum Concentration: A Study Including 2791 Patients Treated With Olanzapine Tablets or Long-Acting Injections.

The combination of olanzapine and valproic acid (VPA) is regularly prescribed in the treatment of bipolar or schizoaffective disorders. The VPA has been shown to reduce olanzapine concentration, but the mechanism behind this interaction remains unknown. We aimed to investigate the effect of VPA on olanzapine concentration during oral versus long-acting injectable (LAI) formulation in a real-life setting. From a therapeutic drug monitoring service, prescribed doses and serum concentrations from 2791 olanzapine-treated patients (9433 measurements) were included. The number of patients on olanzapine-LAI treatment was 328, whereas 2463 were using oral olanzapine. The frequency of patients comedicated with VPA was 9.4% for olanzapine tablets and 5.8% for olanzapine-LAI. The VPA had no effect on olanzapine dose-adjusted concentrations in LAI users (1.6 vs 1.7 [ng/mL]/[mg/d]; P = 0.38), whereas in the oral group the dose-adjusted olanzapine concentration was lower in VPA users (2.2 vs 2.7 [ng/mL]/[mg/d]; P < 0.001). For smokers in the oral olanzapine group using VPA, 8.7% of the measurements were in the subtherapeutic range (<10 ng/mL) compared with 6.0% in nonusers (P = 0.003). These findings show that the VPA-olanzapine interaction involves a presystemic mechanism and is therefore restricted to oral olanzapine treatment. For oral treatment of olanzapine, comedication with VPA implies a risk of insufficient effect, which may be of clinical relevance in smokers in particular. Thus, it is important to be aware of the interaction potential with VPA during oral olanzapine use, whereas for LAI-treated patients fewer precautions are required from a pharmacokinetic point of view.

Abstract TP528: Differences in Stroke Severity According to the Prior Medication in Patients With Non-Valvular Atrial Fibrillation

Introduction: Atrial fibrillation is one of the most common rhythmic disorders in general population and a major risk factor of ischemic stroke. We investigated whether there was any difference in initial stroke severity and short term outcome in patients with acute ischemic stroke and known non-valvular atrial fibrillation according to their prior medication status. Methods: We retrospectively reviewed patients with acute ischemic stroke and non-valvular atrial fibrillation who admitted at six hospitals from 2013 to 2016. We selected patients with known non-valvular atrial fibrillation before admission and a CHA 2 DS 2 -VASc score of ≥2. We categorized their prior medication status as follows: 1) no antithrombotics, 2) only antiplatelet, 3) warfarin with a subtherapeutic range, 4) warfarin with a therapeutic range, 5) under-dosed novel oral anti-coagulant (NOAC), and 6) standard-dosed NOAC. We compared the initial NIHSS score and 3 month modified Rankin Scale (mRS) between the groups. Results: Total 741 patients were enrolled for analysis. Patients were categorized as follows: 177 no antithrombotics, 296 only antiplatelet, 169 warfarin with a subtherapeutic range, 36 warfarin with a therapeutic range, 25 under-dosed NOAC, and 38 standard-dosed NOAC. Median NIHSS score was lowest in patients with standard-dosed NOAC (3, interquartile range [IQR] 1-7) compared to no antithrombotics (7, IQR 2-17), only antiplatelet (4, IQR 1-12.75), warfarin with a subtherapeutic range (6, IQR 2-15), warfarin with a therapeutic range (3.5 IQR 1-7), and under-dosed NOAC (7, IQR 2-16). Proportions of the patients with good functional outcome (mRS 0-2) are as follows; 45.5% no antithrombotics, 60.4% only antiplatelet, 56.5% warfarin with subtherapeutic range, 62.1% warfarin with therapeutic range, 40.9% under-dosed NOAC, and 64.7% standard-dosed NOAC. Conclusions: Large portion of non-valvular atrial fibrillation patients do not receive proper anticoagulation, although they have higher risk of embolization. Therapeutic anticoagulation reduces the initial severity of neurologic deficit in patient with ischemic stroke.

Результаты проведения терапевтического лекарственного мониторинга галоперидола у пациентов с алкогольными психозами и шизофренией

The purpose of the study: was to conduct therapeutic drug monitoring in two groups of patients with different nosology (schizophrenia and alcoholic psychosis) taking haloperidol (HAL) in different drug forms, evaluate the distribution of HAL concentrations relative to the therapeutic range, compare the concentration-dose ratio data and make recommendations for personalized pharmacotherapy patients of these groups. Material and methods: Dur ing this study, clinical , pathological and psychometr ic approaches were used. The concentration of haloperidol was determined by high-performance liquid chromatography in combination with mass-spectrometry. Group A — male patients whose age were 30,02 ± 6,9 years; group B also included male patients whose age were 40,54 ± 9,34 years. Group B was divided into subgroups, where some patients took tablet form of GAL, whereas others received therapy in the form of infusions. The exclusion criterion was overweight and the presence of infectious diseases (HIV, hepatitis, liver disease). Inclusion criteria were a signed voluntary informed consent, clinical diagnosis and the absence of somatic diseases. Concomitant therapy in groupsA and B was different. Results: In group A, indicators of measured concentrations were in the subtherapeutic range — 18,2%, therapeutic — 54,5%, conditionally toxic range — 27,3%. In group B — for the infusion form of HAL in the subtherapeutic range were 51,6% of the measured concentrations, in the therapeutic range — 48,4%, in the conditionally toxic — 0,0%; for the tablet form, the distri-bution was as follows — 69,2% in the subtherapeutic range, 30,8% in the therapeutic range, in the conditionally toxic range no concentration indicators were recorded. Conclusion: This study has shown a significant difference between normalized concentrations when comparing indicators from the group of patients with schizophrenia to the patients from the group B, who took the tablet form. That observation allows usto conclude that significant effect on the biotransformation of GAL can have a comedic effect from inducer of the C3A4 isoform of the cytochrome R450 — carbamazepine, while the concomitant therapy in the group A included atypical antipsychotics that did not affect this enzyme.

Mutations in the NOD2 gene are associated with a specific phenotype and lower anti-tumor necrosis factor trough levels in Crohn's disease.

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene mutations are known to be an important risk factor in the pathogenesis of Crohn's disease (CD). Specific disease phenotypes are associated with the presence of NOD2 gene mutation. One treatment option is to use an anti-tumor necrosis factor (TNF)-α agent. Therapeutic drug monitoring (TDM) is usually performed in cases of a loss of response. Our aim was to explore whether NOD2 gene mutations have an effect on the disease phenotype, vitamin D levels, and on TDM in CD patients. This was a retrospective genotype-phenotype association study on NOD2 gene mutations in 161 patients with CD. Altogether 55 (34.2%) patients carried at least one mutant allele of NOD2. NOD2 gene mutations were associated with ileocecal disease, ileocecal resection, stricturing and perianal disease, and patients with NOD2 gene mutation had significantly less frequent colonic disease and received an ostomy less frequently. TDM in patients with NOD2 gene mutation showed more frequent anti-TNF trough levels in the subtherapeutic range and lower anti-TNF trough levels than in NOD2 wild-type (WT) patients. CD patients with NOD2 gene mutation have a specific clinical phenotype and they may require higher doses of anti-TNF agents to achieve sufficient anti-TNF trough levels. They may therefore benefit from a proactive TDM than a reactive approach. This could be another step in the direction of personalized medicine.

S69. A CASE STUDY OF CLOZAPINE AND COGNITION: FRIEND OR FOE?

BackgroundCognitive dysfunction is as a hallmark feature of schizophrenia. Antipsychotic medication is effective for treating the positive symptoms of psychosis, but their potential for therapeutic effects on cognition continues to divide researchers.Improvements in clinical symptoms can occur independently of cognitive functioning, whereby typical antipsychotics improve different clinical domains, but have little or no efficacy for improving primary cognitive functions. However, it has been suggested that the second-generation antipsychotic clozapine can improve cognition in schizophrenia. Unusual cases, such as remitted patients who decide to stop taking clozapine, thus represent a unique opportunity to understand the effect of antipsychotic medication on cognition, as described in the case study below.MethodsA 38-year old man suffered severe psychotic episodes at age 19, leading to a diagnosis of treatment-resistant schizophrenia. Clozapine was initiated at age 21, with excellent treatment response and complete remission of positive, negative and depressive symptoms. For the following 16 years, he had a full-time paid job, lived independently and had an ample social circle. For the last five years, he was stable and compliant taking 175 mg of clozapine, with clozapine levels in sub-therapeutic range (between 0.17 and 0.26 mg/L). He had no metabolic syndrome and no oversedation, but complained of hypersalivation and persistent memory problems. He decided, against advice, that medication was no longer needed and requested support for waning off clozapine.A five-month program was subsequently implemented, with 25 mg reductions of clozapine every six weeks. Four enhanced assessments were scheduled after two weeks on stable doses of 125, 75, 25 and 0 mg, respectively, which included the Brief Assessment of Cognition in Schizophrenia (BACS) and the Clinical Global Impression-Schizophrenia scale (CGI-SCH).ResultsAt each level of clozapine dose, the patient continued to be stable. However, the patient showed impaired cognitive performance at the highest dose of clozapine titration (see T-scores from Table and figure), with improvements then shown at each level of dose reduction (75 and 25 mg). The final assessment was done after 6 weeks of not taking medication. At this time, he was admitted to hospital for psychotic relapse. Unfortunately, the patient refused to re-initiate clozapine and has remained floridly psychotic for 18 months.Our case suggests that cognitive impairment is dose-dependent with clozapine. As presented, the t-score of the patient at 125 mg was worse than normative data reported for healthy controls (z-score=0.50) and patients with schizophrenia treated with other first-or second generation antipsychotics (z-score=-1.42). However, cognitive performance of the patient was most notably impaired when medication-free.DiscussionThe longterm effects of high-dose antipsychotic medication on cognition in patients with schizophrenia are largely unknown. It is also possible that changes in cognitive states are either domain-specific with clozapine. Nonetheless, daily antipsychotic dose and polypharmacy have been shown to predict poor cognitive functioning.The present case is also a reminder that the appropriate long-term maintenance dose of clozapine is poorly understood. As this case suggests, the current recommended therapeutic levels of clozapine (0.35 to 0.50 mg/L) might be unnecessarily high for patients in full remission. Controlled studies are therefore needed to evaluate the potential for cognitive improvements in schizophrenia as a function of reduced clozapine dose, to ensure the optimal delivery needed not just for good clinical but also good cognitive outcome.