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Introduction Survival in PAH is strongly associated with adaptation of the RV to pressure overload. Purpose To investigate acute hemodynamic reactions during infusion of the stable thromboxane A2 (TXA2) analogue U46619 in a porcine model. Materials and methods The study comprised 9 male Landrace pigs (32.7±3.8 kg) under GA. After heparinization, PAH was induced by continuous and stepwise increasing infusion of U46619 (10 mg/ml; Tocris, USA) according to a pre-specified protocol. The target mPAP was 40 mmHg. Hemodynamics was assessed, cardiac output (CO) was calculated using the Fick equation before and during U46619 infusion. Results U46619 infusion at a previously published rate 0.1, 0.2 μg kg–1 min–1 in pig 1 resulted in rapid hemodynamic deterioration. Two-time reduced U46619 dose infusione resulted in a target mPAP but severe mBP drop in 1, 3, 4 pigs and required cathecholamine support. The U46619 dosage was reduced up to ¼ (0.025, 0.05, 0.075, 0.1, 0.12, 0.15, 0.175 μg kg–1 min–1). In animals on 1/4 dosage U46619 infusion, heart rate (HR), mBP, mPAP, RAP and PVR reliably increased and BP was stable (Table 1). There was a positive correlation between the mPAP and heart rate (HR) on U46619 infusion (r=0.66; t=2.38; p=0.048) and between CO and mBP (r=0.66; t=2.36; p=0.04). Low CO was associated with high PVR (r=−0.98; t=−14.3; p Conclusions High dose U46619 infusion was associated with acute RV decompensation due to pressure overload accompanied with systemic BP drop and low CO. Lower dosages of U46619 infusion were characterized by stable target mean PAP. HR acceleration and mean systemic BP are of compensation mechanisms for cardiac output maintenance in PAH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): RFBR grant 18-315-20050

Introduction : Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, uncommon dermatological reactions usually associated with drug use. They are characterized by damage and detachment of the epidermis, with involvement of mucous membranes. Usually the onset of symptoms 4-28 days after the start of the medication. In the present case, the adverse reaction occurred after the increase in the dose of carbamazepine. Although this association has been poorly described in the literature, it is important that health personnel know about this, since the timely withdrawal of the causative agent has prognostic importance. Methods and results : This article describe the case of a 79-year-old patient with frontotemporal dementia, treated with carbamazepine and subsequently with dose adjustment at 8 days presented SJS with rapid progression to TEN. Conclusions : The identification of the causative agent is vital in patients with toxicodermas and a medication previously tolerated by the patient should not be ruled out as an etiological agent.

Aprocitentan is an orally active dual endothelin receptor antagonist currently in development for treatment of difficult-to-control (resistant) hypertension. In phase 1 and 2 studies, aprocitentan has been characterized predominantly in Caucasian subjects. In this bridging, double-blind study, 20 healthy Japanese and Caucasian male and female subjects received 25 mg of aprocitentan or placebo once daily for 10 days and were monitored until 216 hours after the last dosing. The pharmacokinetics of aprocitentan were similar between ethnicities. At steady state, maximum plasma concentration was reached at 4 and 3 hours, and elimination half-life was 49.1 and 48.8 hours for Japanese and Caucasian subjects, respectively. The accumulation index was around 3 for both populations. Geometric means ratios for maximum plasma concentration and area under the plasma concentration-time curve during 1 dosing interval were around 1, with 90% confidence interval ranging from 0.87 to 1.30. Aprocitentan was safe and well tolerated in both groups. As no clinically relevant differences were found between Japanese and Caucasian subjects, it is unlikely that the pharmacokinetics of aprocitentan would differ significantly between Caucasian subjects and other ethnicities. Aprocitentan can therefore be administered at a dose level of up to 25 mg in any ethnicity without dose adjustment.

Aim Quantitative and kinetic insights into the drug exposure-disease response relationship might enhance our knowledge on loss of response and support more effective monitoring of inflammatory activity by biomarkers in patients with inflammatory bowel disease (IBD) treated with infliximab (IFX). This study aimed to derive recommendations for dose adjustment and treatment optimisation based on mechanistic characterisation of the relationship between IFX serum concentration and C-reactive protein (CRP) concentration. Methods Data from an investigator-initiated trial included 121 patients with IBD during IFX maintenance treatment. Serum concentrations of IFX, antidrug antibodies (ADA), CRP, and disease-related covariates were determined at the mid-term and end of a dosing interval. Data were analysed using a pharmacometric nonlinear mixed-effects modelling approach. An IFX exposure-CRP model was generated and applied to evaluate dosing regimens to achieve CRP remission. Results The generated quantitative model showed that IFX has the potential to inhibit up to 72% (9% relative standard error [RSE]) of CRP synthesis in a patient. IFX concentration leading to 90% of the maximum CRP synthesis inhibition was 18.4 mu g/mL (43% RSE). Presence of ADA was the most influential factor on IFX exposure. With standard dosing strategy, >= 55% of ADA+ patients experienced CRP nonremission. Shortening the dosing interval and co-therapy with immunomodulators were found to be the most beneficial strategies to maintain CRP remission. Conclusions With the generated model we could for the first time establish a robust relationship between IFX exposure and CRP synthesis inhibition, which could be utilised for treatment optimisation in IBD patients.

Caro Editor, Esta carta visa complementar os dados publicados por Silva et al., ( ) apresentando os resultados das concentracoes plasmaticas de pacientes que utilizaram piperacilina (PIP) em dose empirica (DE) ou dose ajustada (DA) pelo software Optimum Dosing Strategies (ID-ODS), alem de expor alguns pontos limitadores observados pelos autores durante a utilizacao do software na realidade de um hospital brasileiro. […] Software para ajuste de doses de antimicrobianos. Implicacoes nas concentracoes plasmaticas e limitacoes praticas

Authorities around the world have committed to limiting the use of chemical pesticides by reducing doses, among other strategies. Nevertheless, different dose expression models and decision support systems (DSSs) for dose adjustment coexist for high growing crops (3D crops). Among them, leaf wall area (LWA) and tree row volume (TRV) models have recently been proposed by the European and Mediterranean Plant Protection Organization (EPPO) for pre-registration trials. In this paper, the background and technical bases of six dose adjustment DSSs in fruit crops (PACE, AGMET, DOSA3D, OMAX and PULVARBO) and four in grape orchards (AGMET, OPTIDOSE, DOSAVIÑA and DOSA3D) are described and compared. The discussion leads to the conclusion that LWA and TRV represents a substantial improvement compared to the former crop ground area-based dose expression model. However, total leaf area is the most important parameter for dose adjustment, while sprayer efficiency is also a key factor. Additionally, it is suggested that deposition on leaves (mean values and variability) should be reported in pesticide efficacy evaluations in order to establish the required doses independently from the dose expression mode. The DOSA3D system, based on leaf area index estimation, was found to be the most conservative DSS regarding the spraying volume ratio to TRV because low spraying efficiencies are considered. Instead, AGMET was found to be the most effective for dose adjustment. However, despite the differences between the recommendations, all the analysed DSSs are useful tools for rational decision making about spraying volume rate and pesticide doses at national level. Their use should be promoted by the competent authorities. This study wasfinanced by the EU Horizon 2020 project EUCLID[grant number 633999], the Spanish Ministry of Economy and Compet-itiveness project AgVance [AGL2013-48297-C2-2-R] and the SpanishMinistry of Agriculture, Fisheries and Food project GOPHYTOVID [con-tract 2018002001192]. We are also grateful for funding by theSecretaria d'Universitats i Recerca del Departament d'Empresa iConeixement de la Generalitat de Catalunya under Grant 2017 SGR 646

BackgroundCytomegalovirus (CMV) infection continues to negatively affect outcomes for solid organ transplant recipients, despite the advent of strategies for preemptive surveillance and prophylaxis. The impact is especially great for CMV seronegative recipients of donor seropositive organs, who typically lack the ability to control CMV infection at the time of transplantation.MethodsWe reviewed episodes of CMV DNAemia in a modern cohort of kidney transplant recipients over a 3-year period at a high-volume transplant center to investigate the frequency of DNAemia during antiviral prophylaxis.ResultsDespite receipt of antiviral prophylaxis per current guidelines, 75 cases of CMV DNAemia were observed in the first 100days after transplantation. For high risk patients, median time to DNAemia was 75days after transplantation, and the majority of patients had experienced dose-reduction of valganciclovir due to renal insufficiency. Review of CMV seropositive intermediate risk patients demonstrated DNAemia occurring earlier after transplantation compared with high risk patients with a median time of 64days (P=.029). The impact of valganciclovir dose adjustment was less notable in the intermediate risk group.ConclusionsGuidelines recommend beginning routine surveillance for CMV after the completion of antiviral prophylaxis. Our findings suggest that closer monitoring may be beneficial, especially for high risk patients at risk for DNAemia. Patients requiring dose adjustment of valganciclovir due to renal insufficiency may be at increased risk for CMV DNAemia. Improved methods for CMV prophylaxis and evaluation of immunologic risk for CMV DNAemia and disease are needed to improve patient outcomes after kidney transplantation.

A “one-size-fits-all” approach has been the standard for drug dosing, in particular for agents with a wide therapeutic index. The scientific principles of drug titration, most commonly used for medications with a narrow therapeutic index, are to give the patient adequate and effective treatment, at the lowest dose possible, with the aim of minimizing unnecessary medication use and side effects. The art of drug titration involves the interplay of scientific drug titration principles with the clinical expertise of the healthcare provider, and an individualized, patient-centered partnership between the provider and the patient to review the delicate balance of perceived benefits and risks from both perspectives. Drug titration may occur as up-, down-, or cross-titration depending on whether the goal is to reach or maintain a therapeutic outcome, decrease the risk of adverse effects, or prevent withdrawal/discontinuation syndromes or recurrence of disease. Drug titration introduces additional complexities surrounding the conduct of clinical trials and real-world studies, confounding our understanding of the true effect of medications. In clinical practice, wide variations in titration schedules may exist due to a lack of evidence and consensus on titration approaches that achieve an optimal benefit-harm profile. Further, drug titration may be challenging for patients to follow, resulting in suboptimal adherence and may require increased healthcare-related visits and coordination of care amongst providers. Despite the challenges associated with drug titration, it is a personalized approach to drug dosing that blends science with art, and with supportive real-world outcomes-based evidence, can be effective for optimizing pharmacotherapeutic outcomes and improving drug safety.

Background To our knowledge, there are no preexisting reports concerning rilpivirine (RPV) removal by hemodialysis and peritoneal dialysis. Case presentation This study aimed to evaluate the effect of hemodialysis and peritoneal dialysis on plasma concentrations of RPV in a 45-year-old man infected with HIV and exhibiting end-stage renal disease (ESRD). The extraction ratio of RPV by hemodialysis was 4.5%. Plasma concentrations of RPV remained far above the protein-binding-adjusted inhibitory levels during a combination therapy of hemodialysis and peritoneal dialysis. Our results suggest minimal RPV removal via hemodialysis and peritoneal dialysis with no specific dosage adjustments required in an HIV-infected patient undergoing this combination therapy. Conclusion In conclusion, this study showed that RPV administered without dose adjustment resulted in steady-state plasma drug concentration in an HIV-infected patient treated with a combination therapy of hemodialysis and peritoneal dialysis.

As COVID-19 has been expanding rapidly around the world, the types of patients and their backgrounds vary. The substantially altered GI anatomy/physiology after bariatric surgery presents new challenges to the field of oral drug therapy. In this report we highlight issues for consideration when treating COVID-19 patients who previously underwent bariatric surgery and provide practical tools to allow optimal care of these patients. Post-bariatric absorption/pharmacokinetic changes may warrant dose adjustment, as well as the use of liquid oral dosage forms or parenteral routes of administration, if available. Realizing the potentially altered pharmacokinetics of various drugs after bariatric surgery is essential for providing optimal pharmacological therapy and overall patient care.

Context Somapacitan is a long-acting growth hormone (GH) in development for once-weekly treatment of GH deficiency (GHD). Optimal monitoring of insulin-like growth factor-I (IGF-I) levels must account for weekly IGF-I fluctuations following somapacitan administration. Objective To develop and assess the reliability of linear models for predicting mean and peak IGF-I levels from samples taken on different days after dosing. Design A pharmacokinetic/pharmacodynamic model was used to simulate IGF-I data in adults and children following weekly somapacitan treatment of GHD. Setting and Patients 39 200 IGF-I profiles were simulated with reference to data from 26 adults and 23 children with GHD. Intervention(s) The simulated dose range was 0.02 to 0.12 mg/kg for adults and 0.02 to 0.16 mg/kg for children. Simulated data with >4 average standard deviation score were excluded. Main Outcome Measure(s) Linear models for predicting mean and peak IGF-I levels based on IGF-I samples from different days after somapacitan dose. Results Robust linear relationships were found between IGF-I sampled on any day after somapacitan dose and the weekly mean (R2 > 0.94) and peak (R2 > 0.84). Prediction uncertainties were generally low when predicting mean from samples taken on any day (residual standard deviation [RSD] ≤ 0.36) and peak from samples taken on day 1 to 4 (RSD ≤ 0.34). IGF-I monitoring on day 4 and day 2 after dose provided the most accurate estimate of IGF-I mean (RSD Conclusions Linear models provided a simple and reliable tool to aid optimal monitoring of IGF-I by predicting mean and peak IGF-I levels based on an IGF-I sample following dosing of somapacitan. A short visual summary of our work is available (1).

Direct oral anticoagulants (DOACs) are widely prescribed nowadays. Available DOACs are renally eliminated to some extent and need dose adjustment in patients with kidney dysfunction. Cockcroft-Gault (CG) formula has been used to estimate creatinine clearance in DOACs trials. Nowadays, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) are preferred equations for estimating glomerular filtration rate (GFR). We reviewed studies that simulated DOACs dosing in patients with atrial fibrillation by MDRD, CKD-EPI, and CG.DOACs dose discordance varies from 28.8% underdosing to 59.2% overdosing when MDRD or CKD-EPI equations are substituted for CG. MDRD and CKD-EPI overestimate the GFR in lower thresholds of kidney function especially in elderly and females and result in overestimation of DOACs dosing or misclassifying the patients to be eligible for receiving DOACs when they are contraindicated. Compared with CG, MDRD and CKD-EPI underestimate the level of kidney function in higher GFR extremes and in these patients suggest DOACs when they are not recommended or suggest lower doses.Until running large clinical studies on efficacy/safety of DOACs dosing using MDRD or CKD-EPI equations, use of CG method for DOACs dosing is recommended in real practice.

Background Dose adjustment of non‐vitamin K antagonist oral anticoagulants ( NOAC s) is indicated in some patients with atrial fibrillation ( AF ), based on selected patient factors or concomitant medications. We assessed the frequency of label adherence of NOAC dosing among AF patients and the associations between off‐label NOAC dosing and clinical outcomes. Methods and Results We evaluated 53 649 AF patients treated with an NOAC using Korean National Health Insurance Service database during the period from 2013 to 2016. NOAC doses were classified as either underdosed or overdosed, consistent with Korea Food and Drug Administration labeling. Cox proportional hazards regression was performed to investigate the effectiveness and safety outcomes including stroke or systemic embolism, major bleeding, and all‐cause mortality. Overall, 16 757 NOAC ‐treated patients (31.2%) were underdosed, 4492 were overdosed (8.4%), and 32 400 (60.4%) were dosed appropriately according to drug labeling. Compared with patients with label adherence, those who were underdosed or overdosed were older (aged 71±8 and 75±7 years versus 70±9 years, respectively; P CHA 2 DS 2 ‐ VAS c scores (4.6±1.7 and 5.3±1.7 versus 4.5±1.8, respectively; P NOAC overdosing was associated with increased risk for stroke or systemic embolism (5.76 versus 4.03 events/100 patient‐years, P P P Conclusions In real‐world practice, a significant proportion (almost 2 in 5) of AF patients received NOAC doses inconsistent with drug labeling. NOAC overdosing is associated with worse clinical outcomes in Asian AF patients.

Elderly patients are the main users of drugs and they differ from younger patients. They are a heterogeneous population that cannot be defined only by age but should rather be stratified based on their frailty. The elderly have distinctive pharmacokinetic and pharmacodynamic characteristics, are frequently polymorbid, and are therefore treated with multiple drugs. They may experience adverse reactions that are difficult to recognize, since some of them present non-specific symptoms easily mistaken for geriatric conditions. Paradoxically, the elderly are underrepresented in clinical trials, especially the frail individuals whose pharmacological response and expected treatment outcome can be different from those of non-frail patients. This means that the benefit–risk balance of drugs used in frail elderly patients is frequently unknown. We present some proposals to overcome the barriers preventing the enrollment of frail elderly patients in clinical trials, and strategies for monitoring their therapy to minimize the risk of adverse reactions. Automated alerts for drug and drug–disease interactions could help appropriate prescribing but should flag only clinically relevant interactions. Pharmaceutical forms should be designed to allow easy dose adjustment and, together with packaging and labeling, should account for the physical and cognitive limitations of frail elderly patients. Aggregate pharmacovigilance reports should summarize the safety profile in the elderly, but rather than presenting the results by age they should focus on patients’ frailty, perhaps using the number of comorbidities as a proxy when information on frailty is not available.

Lenalidomide is a backbone agent in the treatment of multiple myeloma, but dose adjustment is required for those with renal impairment (RI). We evaluated the pharmacokinetics (PK) and safety of lenalidomide and dexamethasone as frontline pre-transplant induction, with doses adjusted at start of each cycle based on creatinine clearance, as per the official dosing guidelines. After 4 cycles, PK studies showed that patients with moderate RI (30 ≤ CrCl60 mL/min) receiving 10 mg dosing may be under-dosed and those with severe RI (CrCl30ml/min) appeared appropriately dosed initially, but sustained significant decreases in maximum serum concentration (Cmax) after repeated dosing, due to rapid clinical improvement and enhanced drug clearance. PK drug monitoring during cycle 1 may facilitate appropriate and timely dose adjustments. Adverse events rates did not vary based on severity of RI. No patient discontinued lenalidomide for toxicity. This supports the feasibility and safety of frontline lenalidomide in transplant-eligible patients with RI.

A precise and efficient method for estimating kidney function in cancer patients is important to determine their eligibility for clinical trials and surgery and to allow for appropriate dose adjustment of anti-cancer drugs, especially toxic drugs with a narrow therapeutic index. Since direct measurement of glomerular filtration rate (GFR) is cumbersome, several formulae have been developed to estimate kidney function. Most of these are based on serum creatinine concentration. Though the CKD-EPI formula is recognised as being the most accurate, there is an ongoing debate on which is the optimal formula for cancer patients. In this review, we provide an overview of different GFR estimating equations for kidney function and the advantages and disadvantages of each method and compare their performance in cancer patients. We discuss the importance of body surface area-indexing and propose a framework for evaluating kidney function in cancer patients. ispartof: EUROPEAN JOURNAL OF CANCER vol:132 pages:141-149 ispartof: location:England status: published

Despite advances in diabetes technology and treatment, many youth with type 1 diabetes (T1D) continue to have hemoglobin A1c (HbA1c) above target. Consistent use of continuous glucose monitors (CGM) improves HbA1c and time in range (TIR 70-180 mg/dl) glucose, while minimizing hypoglycemia in youth with T1D. A previous study suggested that long-term HbA1c outcomes may be determined early in the course of T1D. Thus, increased awareness of glucose trends and frequent insulin dose adjustments early in the course of T1D is hypothesized to improve long-term HbA1c and health outcomes. We have initiated CGM in the first month of T1D diagnosis. In March 2019, we added weekly remote review of CGM data by a pediatric endocrinologist or certified diabetes educator to provide dose adjustments. Data sharing is facilitated by using a custom platform including Apple HealthKit to transmit data from the Dexcom G6 mobile app to Epic MyChart. Inclusion criteria were diagnosis of T1D within the past 30 days and intention to follow in our clinic. During the initial 8 months of this study, we enrolled 43 youth (age at diagnosis 9.2±4.2 years, 57% male, 78% on private insurance, 42.5% non-Hispanic White, initial HbA1c 12.0±2.0%). Twenty-eight youth had at least 1 documented data review with an average of 15.8±8.1 reviews/patient and 5.4 dose adjustments/youth (∼1 dose adjustment every 3 weeks) via phone calls or secure MyChart messages. Based on CGM downloads, users had a high percentage of time of CGM wear (88±11% of time over 2-week periods), high percentage of TIR glucose (72.2±18.4%), and low incidence of hypoglycemia (32±54 min/day, 2.2±3.8%). This pilot study demonstrates that implementing routine data review as part of a new onset program increases the frequency of insulin dose adjustments. Tools should be developed to allow for efficient data review for population health management. Further follow up is needed to determine long-term outcomes, scalability, and sustainability of this new onset program. Disclosure M. Lee: None. J. Leverenz: None. B. Leverenz: None. N.M. Pageler: None. D. Scheinker: None. D.M. Maahs: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S. Consultant; Self; Abbott, Sanofi. Research Support; Self; Bigfoot Biomedical, Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care. P. Prahalad: None. Funding Stanford Diabetes Research Center (P30DK116074)

This study aimed to compare the effectiveness and safety of basal insulin (BI) and mid-mixture insulin (MMI) in a real-world setting. Chinese patients with T2DM uncontrolled on oral antihyperglycemic medications (OAMs) were randomized 1:1 to receive add-on BI (QD) or MMI (BID) for 48 weeks (wks). Insulin titration and OAM dose adjustment were based on clinical practice. Compared to BI, MMI led to numerically greater decrease in HbA1c from baseline to wk 24 and statistically greater decrease in HbA1c at wk 48. Fasting blood glucose (FBG) in both groups further decreased from wk 24 to wk 48, and BI caused greater decrease at wk 48 compared to MMI. Both groups had similar decreases in postprandial glucose. Also, significant intergroup difference in OAM use change was detected (p Disclosure L. Chen: Consultant; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. H. Chen: Employee; Self; Eli Lilly and Company. L. Du: Employee; Self; Eli Lilly and Company. Y. Lou: Employee; Self; Eli Lilly and Company. L. Ji: None.

Tablet subdivision by physicians or patients frequently occurs in various clinical settings for multiple reasons, including dose adjustment, alleviation of swallowing difficulties, or cost savings. However, not all tablets are suitable for subdivision, and it might cause side effects. It is informative to know which medicines are regularly subdivided, which healthcare institutions prescribe subdivided medicines, and to whom the medicines are prescribed from the perspectives of quality of care and patient safety. In this study, we aimed to examine recent trends in tablet subdivision and to address factors associated with subdivision of tablets both at the patient and healthcare institution levels. The yearly claims data in 2016 retrieved from the National Patients Sample provided by the Health Insurance Review and Assessment (HIRA-NPS). This study used descriptive statistics to examine characteristics of medicines that were frequently prescribed in subdivided forms, and retrieved information regarding the medicines to assess the appropriateness for tablet splitting. Then, we selected five medicines, and performed a multivariate logistic regression analysis to estimate the effect of the variables of interest on tablet subdivision. We presented the top 25 medicines prescribed in subdivided forms in 2016, and confirmed these medicines could be relevantly halved according to their Summary of Product Characteristics. Of the 25 medicines, 14 (56%), 5 (20%), and 3 (12%) medicines belonged to the respiratory system (R), nervous system (N), and systemic hormonal preparations (H), according to the first category of Anatomical Therapeutic Chemical (ATC) classification system, respectively. Being female at the patient level and tertiary healthcare institutions and private owned institutions at the institution level were positively associated with subdivision of medicines. Subdivision of tablets frequently occurred for vulnerable populations with various reasons. Female and geriatric patients are prescribed split medicines for clinical reasons, while low-income patients are prescribed nonsplit medicines for cost savings. It would be better if medicines were not so small, and if they had dividing lines on their surfaces to enable successful splitting of the tablet and to protect the health of vulnerable patients. Furthermore, avoid splitting those pharmacotherapies with a narrow therapeutic range, and provide a pharmacist assistance and a splitting device for unavoidable splitting.

Unless contraindicated, anticoagulant therapy should be prescribed to elderly patients with atrial fibrillation. Direct-acting oral anticoagulants (DOACs) are superior to vitamin K antagonists for preventing stroke. This, together with their higher net clinical benefit, makes DOACs the treatment of choice in this population. However, due to the concerns about bleeding and the need for dose adjustment based on clinical variables, underdosing of DOACs is common and the risk of stroke high. Drugs with more easily adjusted doses are likely associated with a lower risk of dosing errors and, therefore, a greater protective effect. Correct dosing can ensure a maximal net benefit of DOACs in elderly patients with atrial fibrillation.

Summary Background Hepatotoxicity and visual symptoms are common adverse effects (AEs) of voriconazole therapy. Objective To retrospectively evaluate the effects of treatment modification based on therapeutic drug monitoring on AEs in patients undergoing voriconazole therapy. Methods The target voriconazole trough concentration (C min) was 1‐5 µg/mL. Receiver operating characteristic curves were used to determine C min cut‐offs for AEs. Results A total of 401 patients were included. Among 108 patients with high initial C min, voriconazole was discontinued in 32 and the dose was reduced in 71. Among 44 patients with low initial C min, voriconazole was discontinued in 4 and the dose was increased in 19. Hepatotoxicity occurred in 6.0% of patients, after a median of 10 days. Visual symptoms were evident in 9.5% of patients after a median of 4 days. Initial C min was significantly associated with visual symptoms but not hepatotoxicity, which suggested the effect of treatment modification on hepatotoxicity. However, both hepatotoxicity and visual symptoms were significantly correlated with C min at the onset of AEs, and the C min cut‐offs were 3.5 μg/mL for hepatotoxicity and 4.2 μg/mL for visual symptoms. Voriconazole was discontinued after the occurrence of AEs in 62.5% of patients with hepatotoxicity but only 26.3% of patients with visual symptoms. With dose adjustment, treatment was completed in 8/9 patients with hepatotoxicity and 27/28 patients with visual symptoms. Conclusions A significant preventive effect was demonstrated on hepatotoxicity, but not on visual symptoms because of earlier occurrence. With treatment modification after the occurrence of AEs, most patients completed therapy.

ObjectiveThe American Academy of Ophthalmology recommends a maximum hydroxychloroquine (HCQ) dose of ≤5.0 mg/kg/day to reduce the risk of HCQ-induced retinopathy. To determine if this dose adjustment would have an impact on the clinical course of SLE, we compared outcome measures in a cohort of patients with SLE before and after adjusting HCQ dose.MethodsSixty Puerto Ricans with SLE (per 1997 American College of Rheumatology criteria) treated with HCQ who were changed to HCQ ≤5.0 mg/kg/day were studied. Visits were ascertained every 6 months for 2 years before and 2 years after HCQ dose adjustment (baseline visit). Disease activity (per Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)), SLE exacerbations, emergency room visits, hospitalisations, disease damage (per Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), corticosteroids exposure, prednisone dose and immunosuppressive drugs exposure were determined before and after HCQ dose change.ResultsAt baseline visit, the mean age was 43.8±15.1 years. All patients were women. The mean disease duration was 13.8±9.1 years. After HCQ dose adjustment, patients required a lower prednisone dose when compared with visits before HCQ dose reduction. No significant differences were observed for mean SLEDAI scores, lupus exacerbations, emergency room visits, hospitalisations, disease damage and exposure to immunosuppressive drugs before and after HCQ dose adjustment.ConclusionsThis study suggests that adjustment of daily HCQ dose to ≤5.0 mg/kg/day of actual body weight does not have a significant impact on the short-term and mid-term outcomes in this group of patients with SLE.

The estimated glomerular filtration rate (eGFR) equations based on serum creatinine (SCR) have been used for pediatric dose adjustment in drug labeling. This study evaluated the performance of those equations in estimating individual clearance of drugs that are predominantly eliminated by glomerular filtration, using clinical data from the renally eliminated drugs gadobutrol, gadoterate, amikacin, and vancomycin. The eGFR was compared with the observed drug clearance (CL) in 352 pediatric patients from birth to 12 years of age. Multiple eGFR equations overestimated the drug CL on average, including the original and bedside Schwartz equations, which showed an average eGFR/CL ratio between 1 and 3. Further analysis with bedside Schwartz equation showed a higher eGFR/CL ratio in the subjects with a lower SCR or CL. Supraphysiological eGFR as high as 380 mL/min/1.73 m2 was obtained using the bedside Schwartz equation for some of the subjects, most of whom are children < 2 years of age with SCR < 0.2 mg/dL. Excluding the subjects with supraphysiological eGFR from the analysis did not change the overall trend of overestimation. In conclusion, Schwartz equations led to an overestimation of drug clearance for the drugs evaluated. When greater precision is required in predicting eGFR for pediatric patients, such as in drug dosing, revised k constants for the Schwartz equation or new methods of glomerular filtration rate estimation may be necessary.

Implantable infusion pumps might improve the convenience and safety of intravenous treprostinil for pulmonary arterial hypertension. The LENUS Pro (R) pump (approved in Europe) has a fixed flow rate. Based on 126 pumps and 2853 refills, we retrospectively analyzed the actual flow rate from 09/2010 to 09/2018. A relevant flow rate variance is evident after three years; therefore, flow rate monitoring and dose adjustment are mandatory.

Metformin pharmacokinetics in a liquid extemporaneous formulation from commercial tablets was determined in paediatric patients. A randomized, transversal clinical trial was conducted in 34 children and adolescents between 7 and 17 years of age. 17 children were randomized to take metformin in the liquid formulation and, after a 1-week wash period, a 500 mg metformin tablet was administered to them. Blood samples were obtained in Whatman 903® cards at 0, 1, 2, 4, 8, 12 and 24 hours. Extraction was made by direct precipitation with acetonitrile (ACN) and methanol, detection by UPLC and tandem mass spectrometry. The method was accurate, precise, selective and linear from 50 to 1000 ng/mL (r = .9982). Comparative pharmacokinetics, tablet vs formulation, were as follows: Cmax1503.2 ng/mL vs 1521.4, Tmax1.5 h vs 2.3, and half-life 8.2 vs 7.5 h. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, and the ratios (90% CI) of geometric mean for metformin were 100.63% (89.13–113.6), 98.08% (88.04–109.2), and 97.52% (84.9–112.01), for Cmax, AUC0-t, and AUC 0-∞, respectively. Pharmacokinetics was determined using WinNonlin Pro 3.1 software. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, allowing a more precise dose adjustment and ease of administration.

Narrowband ultraviolet B has been applied to the treatment of vitiligo for more than 10 years in China. Currently, there are no consistent standards for clinical treatment parameters, and patients cannot benefit from non-standard treatment, which is liable to cause erythema, blisters, photoaging and other adverse reactions. Based on the Vitiligo Working Group recommendations for narrowband ultraviolet B phototherapy for vitiligo, relevant literature and clinical experiences, the authors discuss parameters of narrowband ultraviolet B phototherapy for vitiligo from the aspects of treatment frequency, initial dosing, dose adjustment during consecutive treatment or after missed treatment, response plateau, treatment course and maximum acceptable number of phototherapy, so as to improve the efficacy of narrowband ultraviolet B phototherapy for vitiligo. Key words: Vitiligo; Ultraviolet therapy; Narrowband ultraviolet B; Parameters

Highlights Based on nationwide insurance data in Korea, the use of dipeptidyl peptidase IV inhibitors (DPP-IVi) not requiring renal dose adjustment (NRDA DPP-IVi) is widespread in the type 2 diabetes chronic kidney disease (T2D CKD) population. Instead of prescribing NRDA DPP-IVi, the use of DPP-IVi requiring renal dose adjustment with appropriate renal dose adjustments in T2D CKD patients can achieve a considerable annual cost saving of up to 7.8%.主要内容: 二肽基肽酶IV抑制剂(DPP-IVi)可用于2型糖尿病合并慢性肾脏病(T2D CKD)患者的治疗, 可以根据药物药代动力学特性调整或不调整剂量。鉴于DPP-IVi是一大类药物, 在T2D CKD患者中恰当使用需根据肾功能调整用量的DPP-IVi(RDA DPP-IVi), 而不是使用NRDA DPP-IVi, 将可以节约相当大的成本。 虽然一些研究揭示了T2D CKD患者DPP-IVi的处方模式, 但这些研究没有从经济影响的角度进行分析, 也没有使用具有全国代表性的数据。作者利用国家数据进行了一项真实的观察性研究, 以评估T2D CKD患者的DPP-IVi的处方模式, 以分析RDA DPP-IVi代替NRDA DPP-IVi的处方的经济影响。.

Clopidogrel is still widely used in acute coronary syndrome despite the development of more potent P2Y12 inhibitors. Previously, we conducted a trial that evaluated serial clopidogrel dose adjustment based on platelet function testing in acute coronary syndrome patients with initial high on-treatment platelet reactivity (HTPR). In this substudy, we performed post hoc analysis of the effect of ABCB1 genetic variants C3435T and G2677T/A on platelet inhibition and outcomes. There were no differences in the proportion of HTPR patients among C3435T carriers and noncarriers in both interventional and control group. G2677T carriers expressed significantly higher proportion of HTPR pattern throughout 12-month follow-up in the control group with no difference in the interventional group. There was no difference in ischemic outcomes between C3435T and G2677T carriers and noncarriers in both groups of patients. The results indicate that ABCB1 genotyping is not useful to guide clopidogrel therapy tailoring to improve high-risk patient management.

The preferable route for treatment of peritoneal dialysis related peritonitis remains the intraperitoneal administration of antibiotics admixed to peritoneal dialysis fluids. It is important to know whether the administered drug is compatible with the PD fluids and its container. In the present study the compatibility of aztreonam with four commercial PDFs at storing temperatures and duration representative for storing conditions in the clinical settings was investigated. Aztreonam concentrations were determined using high-performance liquid chromatography. The antimicrobial activity of aztreonam was evaluated using an E. coli diffusion disk inhibition assay and P. aeruginosa time-kill curves. In Extraneal evaluated at 6 °C, 25 °C and 37 °C aztreonam was stable over the whole study period of 14 days and 24 hours, respectively. In Physioneal and Nutrineal aztreonam was stable at 6 °C for up to 14 days. Antimicrobial activity was retained in all PD fluids over the whole study period. Aztreonam remained stable and was compatible with the PD fluids, particularly with Extraneal or Nutrineal, and no compensatory dose adjustment is needed when stored for up to 14 days at refrigeration temperature before use.

Background: Using an algorithm by which the effect-site concentration of propofol (esTEC) necessary for BIS level set from information input from BIS monitor and target controlled infusion (TCI) pump is estimated, we evaluated the accuracy of administration of propofol guided esTEC, whether it is equivalent to that guided BIS value. Methodology: The clinical data of 29 adult patients, who received head/neck surgery and 27 adult patients, who received gynecological surgery, in our hospital from February 2016 and December 2017 were analyzed. Patients were divided into 2 groups: BIS group (adjustment the propofol dose using a target BIS index of 35 to 55, head/neck surgery n = 15, gynecological surgery n = 14); and esTEC group (adjustment the propofol based on esTEC45, head/neck surgery n = 14, gynecological surgery n = 13). The relevant data from 2 groups were collected and analyzed. For statistical analysis, the unpaired t-test, chi-squared test and Wilcoxon test were used, and p < 0.05 was considered statistically significant. Results were expressed as means ± standard deviation. Results: For head and neck surgery, the percentage of time with BIS35-55 was significantly greater in the esTEC group than the BIS group (95 ± 5% and 81 ± 18%, respectively, p < 0.01), as was the percentage of time with BIS

What is known and objective Anti-infective therapy is the major daily work for most clinical pharmacists in China, and information technology (IT) support for them is very important. However, the current situation of pharmacists' roles in anti-infective therapy and related IT support are seldom reported. The aim of the study was to investigate the current situation of pharmacists participating in anti-infective therapy and the corresponding hospital IT support, which may help identify and solve related problems and facilitate pharmacists to play better roles. Methods A 15-item questionnaire was distributed online to clinical pharmacists from Chinese hospitals. Pharmacists answered the questions on the WeChat platform. Data were analysed using descriptive statistics. Results and discussion A total of 272 valid questionnaires were returned, and the respondents were from 27 provinces (or autonomous regions or municipalities) of China covering over 15 specialties. Most of the respondents (76.1%) were from tertiary hospitals and 72.4% of all the respondents participated in anti-infective therapy. They mainly performed drug selection (95.4%), dose adjustment (88.8%) and adverse drug reaction monitoring (84.8%) for anti-infective therapy, in ways such as consultation (71.1%), drug consult (86.3%) and prescription evaluation (88.8%). Most pharmacists (93.0%) thought that the modules of anti-infective therapy in hospital IT system needed to be advanced, in the aspects of doctor-pharmacist interaction, convenience for pharmacists to control drug expenses and integration of multi-functions for anti-infective therapy. What is new and conclusion The roles of Chinese clinical pharmacists in anti-infective therapy are becoming increasingly clear, and establishing smart, pharmacist-friendly and highly-integrated electronic interfaces will facilitate the establishment of pharmacist-driven anti-infective therapy team, thus improving work efficiency and user experience.

Glioblastoma (GBM) is one of the most aggressive and vascularized brain tumors in adults, with a median survival of 20.9 months. In newly diagnosed and recurrent GBM, bevacizumab demonstrated an increase in progression-free survival, but not in overall survival. We conducted an in silico analysis of VEGF expression, in a cohort of 1082 glioma patients. Then, to determine whether appropriate bevacizumab dose adjustment could increase the anti-angiogenic response, we used in vitro and in vivo GBM models. Additionally, we analyzed VEGFA expression in tissue, serum, and plasma in a cohort of GBM patients before and during bevacizumab treatment. We identified that 20% of primary GBM did not express VEGFA suggesting that these patients would probably not respond to bevacizumab therapy as we proved in vitro and in vivo. We found that a specific dose of bevacizumab calculated based on VEGFA expression levels increases the response to treatment in cell culture and serum samples from mice bearing GBM tumors. Additionally, in a cohort of GBM patients, we observed a correlation of VEGFA levels in serum, but not in plasma, with bevacizumab treatment performance. Our data suggest that bevacizumab dose adjustment could improve clinical outcomes in Glioblastoma treatment. This work was supported by grants from the “Fondo de Investigaciones Sanitarias” (FIS) (PI17-01489), the Miguel Servet Program (CP11/00147) del Instituto de Salud Carlos III (AAS), and the Ministerio de Economía y Competitividad–FEDERER (RTC-2016-4990-1). IPA was supported by “Ayudas para la contratación de ayudantes de investigación cofinanciadas por el Fondo Social Europeo a través del Programa Operativo de Empleo Juvenil y la Iniciativa de Empleo Juvenil (YEI),” and SER was supported by FPI-CEU predoctoral fellowship. Sí

Contains fulltext : 218240.pdf (Publisher’s version ) (Open Access) Introduction: The global burden of cirrhosis is rising, and clinicians increasingly face the challenge of safely prescribing medicines for complications of hepatic disease and comorbidities. Prescribing in patients with cirrhosis is complicated by alterations that can occur in the pharmacology of medicines.Areas covered: This paper provides an overview of current knowledge on the pharmacokinetics and pharmacodynamics of medicines in patients with cirrhosis. We describe the pathophysiological changes that occur and their consequences on pharmacokinetic parameters. We explain that the influence of cirrhosis on the pharmacokinetics depends on several drug and patient characteristics. Patients with cirrhosis also have an increased susceptibility to some toxicological effects of medicines, such as renal impairment and hematological toxicity, which we describe in detail. In addition, we discuss approaches to apply this knowledge in practice and improve safe medication use in patients with cirrhosis.Expert opinion: Tailored pharmacotherapy is needed to ensure safe and appropriate use of medicines in patients with cirrhosis. Clinicians are supported by freely available recommendations on safe drug use in cirrhosis published on a website. In addition, a regular evaluation of medication use in patients with cirrhosis could resolve and prevent medication-related problems.

Prevention of infection in ICU setting is very difficult and needs multidisciplinary approach to monitor and control it. The major infections of concern are central line associated blood-stream infection, ventilator-associated pneumonia, catheter-associated urinary tract infection, clostridium-difficile induced colitis, surgical site infection or infected decubitus ulcer, etc. increasing resistant micro-organisms due to prolonged unnecessary use of broad-spectrum antibiotics without dose adjustment, lack of following the protocols of isolation and hand hygiene with general preventive measures, failure to maintain surveillance strategies are major factors for failure to control infections in ICU. There is urgent need of teaching and training of health care workers regarding various type of infections, its mode of transmissions and effective way of its prevention in ICU like WHO hand hygine guidelines and other recomended bundle cares.Besides this environmental control including safe designing and manintence of ICU, antibiotics stewardship, effective teamwork and good communication are the key to success of infection prevention in ICU.