Stable Maintenance Dose Research Articles

Personal and Social Functioning and Health-Related Quality of Life in Patients with Schizophrenia Treated with the Long-Acting Injectable Antipsychotic Risperidone ISM.

To analyze the effect of Risperidone ISM on social functioning and health-related quality of life (HR-QoL) in both short- and long-term treatment of patients with schizophrenia. This analysis was based on data from both phases of the PRISMA-3 study, including 433 relapsed patients from the double-blind (DB) phase of the PRISMA-3 trial who were treated for 12-weeks with once-monthly (every 28 days) intramuscular Risperidone ISM 75 mg or 100 mg (n = 288), or placebo (n = 145), as well as 174 patients transitioning from the DB to an open-label 52-week extension (OLE) phase, plus 41 de novo patients treated on a stable maintenance dose of oral risperidone. The clinician-administered Personal and Social Performance (PSP) scale and the patient-reported 20-item Subjective Well-being under Neuroleptics scale (SWN-20) were used to measure social functioning and HR-QoL outcomes, respectively. Risperidone ISM significantly improved PSP total score from baseline to endpoint (Day 85) versus placebo in the DB phase with mean change total score (95% CI) of 10.7 (9; 12) compared to 4.8 (3; 7) for placebo (p < 0.0001). The statistically significant improvement was present from the first measurement time point (Day 29). SWN-20-measured HR-QoL increased on average in patients treated with Risperidone ISM in the DB phase. A significant improvement was also observed for PSP and SWN-20 scores from the OLE baseline to week 52 for patients transitioning from the DB phase. Stable de novo patients maintained similar PSP and SWN-20 scores during the whole OLE phase. Risperidone ISM provided a rapid and sustained improvement in personal and social functioning, and HR-QOL without need of oral risperidone supplementation or loading doses. These findings, along with a fast onset of efficacy, could contribute to reinforcing the therapeutic alliance and possibly an earlier discharge. Moreover, patient functioning continued improving or was maintained with long-term treatment.

Safety, satisfaction and cost savings of accelerated infusions of standard and intensified-dose infliximab for inflammatory bowel disease.

Infliximab remains a mainstay for the treatment of inflammatory bowel disease (IBD), but a long infusion duration and subsequent monitoring can be burdensome to patients and healthcare providers. To assess the safety of accelerated infusions for standard and dose-intensified infliximab regimens, and the effect on patient satisfaction and potential cost savings. Patients with IBD on a stable maintenance dose of infliximab and in clinical remission received one or more accelerated infusions: over 30 min if receiving a standard dose (5 mg/kg), or over 60 min if receiving dose-intensified infliximab (up to 10 mg/kg). Outcomes included incidence of reactions (acute or delayed), patient satisfaction and potential cost savings. We also explored infliximab trough levels after one and three accelerated infusions. Fifty-two patients who received 150 infusions were studied. Incidence of reactions to accelerated infusions was 3.3% (3 out of 89) with a standard dose and 0% (out of 61) with dose-intensified infliximab. Reactions were delayed, mild and self-limiting. None required drug cessation. Patient satisfaction was improved with shortened infusion time as compared with the patients' previous experiences (P = 0.00002). Mean plasma trough level of infliximab reduced from 9.3 mg/L (±4.9) to 7.9 mg/L (±4.1) (P = 0.02) with accelerated infusions, but none developed anti-infliximab antibodies. Nursing cost savings were estimated as $123.52 and $247.04 per patient per year for standard and dose-intensified infliximab respectively. Accelerated infliximab infusions for standard and dose-intensified regimens seem to be safe and improved patient satisfaction. Potential impact on drug trough levels requires further investigations.

The use of transient elastography in identifying sub-clinical chronic ductopenic rejection in adult liver transplant recipients: A case series

BackgroundTransient elastography has become a standard tool for the accurate non-invasive assessment of liver stiffness and fat content. Liver transplant recipients can develop allograft fibrosis during long-term follow-up despite normal or mildly abnormal liver chemistries. Tapering of immunosuppression in long-term liver transplant survivors is performed relying solely on liver chemistries. It is important to know if underlying liver histology would be abnormal or if rejection was present as this would alter the desire to decrease stable maintenance doses of immunosuppression. MethodsWe present our experience of five liver transplant recipients who had transient elastography performed prior to consideration of weaning of their immunosuppression. ResultsAll five patients showed signs of elevated liver stiffness on transient elastography in the setting of normal to slightly abnormal liver tests with very stable immunosuppressant doses. This prompted the performance of liver biopsies which demonstrated immune-mediated liver injury and thus negated the immunosuppression withdrawal. ConclusionTransient elastography has utility as a non-invasive method to evaluate allograft health in long-term liver transplant survivors and can be useful in the decision-making process for immunosuppression weaning.

Aeromedical Decision Making for Military Aircrew with Graves' Disease.

BACKGROUND: Graves' Disease (GD) is a common cause of hyperthyroidism. Although definitive treatment with radioactive iodine (RAI) is preferred for military aircrew, there are cultural and individual differences in receptivity toward RAI, and clinical guidelines that recommend antithyroid drugs (ATD) as the first line therapy. We examined a case series of Republic of Singapore Air Force (RSAF) aviators with GD treated with ATD and the impact of their condition on aeromedical disposition.CASE SERIES: All RSAF aircrew diagnosed with GD and treated with ATD over a 15-yr period were retrospectively identified and analyzed to determine the impact on their fitness for flying duties. The mean age of the 13 aircrew was 33 ± 7.1 yr (range, 25-47 yr), with 11 (84.6%) being males. There were 10 (76.9%) who had ATD as the only treatment while 3 (23.1%) were initially treated with ATD but subsequently underwent RAI or surgery. Of the 10 treated with only ATD, 3 (30.0%) were returned to restricted flying, 6 (60.0%) were returned to unrestricted flying, and 1 (10.0%) is still undergoing ATD titration. There were 10 (76.9%) aircrew who were returned to some form of flying duties while on low doses of ATD.DISCUSSION: This case series suggests that ATD is a viable treatment modality in the aeromedical management of military aviators with GD and it is possible to return military aircrew on a stable maintenance dose of ATD to flying duties. A framework is proposed to support the aeromedical decision-making process for military aircrew in the treatment of GD.Loh EH-T, Soh FW, See B, Tan BBC. Aeromedical decision making for military aircrew with Graves' disease. Aerosp Med Hum Perform. 2021; 92(12):980-986.

Investigating the Potential Impact of Dosing Tolerance to Facilitate Use of Nplate Self-Administration in Adult Patients with ITP

Background and Objective: Romiplostim, is a TPO agonist approved for the treatment for adult ITP. It follows a weight-based and platelet response-guided dose titration algorithm to maintain patients' platelet counts (PC) between 50 and 200x10 9/L, after which a maintenance dose is administered once weekly to keep platelet counts within the target range. While self-administration of romiplostim maintenance dose has been approved in EU for adult patients, in the US romiplostim is only approved for weekly administration by a healthcare provider (HCP) using an 0.01 mL graduation syringe to ensure dosing accuracy; a dose tolerance margin of romiplostim has never been investigated before. The following work explores the impact of dosing tolerance on PC to assess the feasibility of romiplostim self-administration in adult ITP patients.Methods: The analysis was based on a previously developed pharmacodynamic model of romiplostim in ITP patients (Perez-Ruixo et al, 2012, Gibiansky et al, 2021). Previous romiplostim clinical studies in patients with ITP were leveraged to develop an updated model of 475 ITP patients (>50 kg, weekly romiplostim total dose > 100 µg and between 1 and 10 µg/kg stable maintenance dose for at least 1 month, self-administration) and assess potential differences in PC between ITP patients who qualify for self-administration and the general adult ITP population. Comparison of observed and model predicted PC and romiplostim dose over time confirmed the adequacy of the model to assess the impact of varying dose tolerances on PC that may occur with self-administration.Under the proposed guidelines for romiplostim self-administration eligibility, an adult patient would self-administer up to 4 weekly stable maintenance doses of romiplostim between two platelet measurements 1 month apart. To evaluate the impact on PC over 1 month when patients self-administered all four weekly doses versus patients receiving the same prescribed dose by a healthcare provider, three dosing scenarios were considered: (1) exact titrated dose (no dose deviation), (2) titrated dose plus 0.03 mL or 15 µg of romiplostim, and (3) titrated dose minus 0.03 mL or 15 µg of romiplostim. To further characterize the number of ITP patients with clinically meaningful platelet deviations, the predicted number of virtual patients with a PC below 30 x10 9/L or above 400 x10 9/L were also summarized for each simulated scenario.Lastly, the simulated population was divided into four groups based on the magnitude of their prescribed dose and used to evaluate whether the prescribed romiplostim dose influences platelet excursion rates following the investigated dose scenarios.Results: Simulations suggest that 4 successive weekly doses of ± 0.03 mL (or ± 15 µg) the prescribed romiplostim dose is unlikely to cause a significant change in platelet excursion rates relative to continuous administration of the exact prescribed dose. No meaningful increase (0.1 - 0.4%) was observed in the predicted excursion rates across these thresholds for either the under- or overdosing scenarios (Figure 1).This results also show that while there is a slight trend between the magnitude of the prescribed dose and the fraction of subjects that experience a platelet excursion, it does not result in a meaningful increase (<4%) in platelet excursions in any of the evaluated subgroups. Specifically, we observed minimal changes in the fraction of patients with a platelet excursion outside the potentially clinically meaningful thresholds across all simulated dose groups and dosing scenarios (Table 1).The results from this analysis suggest that possible dosing variance expected from the self-administration of romiplostim by an eligible lay person (± 0.03 mL or 15 μg) with monthly PC evaluation will not lead to a significant increase in the rate of platelet count excursions for patients who achieve a stable romiplostim dose and meet the proposed eligibility criteria. [Display omitted] DisclosuresSerrano Castillo: Amgen: Current Employment, Current equity holder in publicly-traded company. Saad: Amgen: Current Employment, Current equity holder in publicly-traded company. Wang: Amgen Inc: Current Employment, Current equity holder in publicly-traded company. Zhang: Amgen: Current Employment, Current equity holder in publicly-traded company. Chow: Amgen: Current Employment, Current equity holder in publicly-traded company. Doshi: Amgen: Current equity holder in publicly-traded company; Amgen: Current Employment.

Vitamin D Level Stability in Dystrophinopathy Patients on Vitamin D Supplementation

Expert guidelines recommend annual monitoring of 25-hydroxyvitamin D (25-OHD) and maintaining 25-OHD ≥30 ng/ml in patients with dystrophinopathies. We hypothesized that 25-OHD remains stable and requires less frequent monitoring in patients taking stable maintenance doses of vitamin D. We performed a retrospective cohort study, using the electronic health record to identify 26 patients with dystrophinopathies with a baseline 25-OHD ≥30 ng/mL and at least one additional 25-OHD measurement. These patients had received a stable dose of vitamin D for ≥3 months prior to their baseline 25-OHD measurement and throughout follow-up. The main outcome measured was the mean duration time the subjects spent with a 25-OHD ≥30 ng/mL. Only 19% of patients dropped their 25-OHD to < 30 ng/ml, with a mean time to drop of 33 months and a median nadir 25-OHD of 28 ng/mL. These results suggest that measurement of 25-OHD every 2-2.5 years may be sufficient in patients with a baseline 25-OHD ≥30 ng/mL and who are on a stable maintenance dose of vitamin D. Other patients may require more frequent assessments.

Chinese Patients With Heart Valve Replacement Do Not Benefit From Warfarin Pharmacogenetic Testing on Anticoagulation Outcomes.

Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry; yet, its utility in Chinese patients with heart valve replacement remains unresolved. A total of 2264 patients who underwent heart valve replacement at Wuhan Asia Heart Hospital were enrolled in this study. Patients were randomly divided into 2 groups, namely, a genotype-guided and a traditional clinically guided warfarin dosing group. In the genotype-guided group (n = 1134), genotyping for CYP2C9 and VKORC1 (-1639 G→A) was performed using TaqMan genotyping assay. Warfarin doses were predicted with the International Warfarin Pharmacogenetics Consortium algorithm. Patients in the control group (n = 1130) were clinically guided. The primary outcome was to compare the incidence of adverse events (major bleeding and thrombotic) during a 90-day follow-up period between 2 groups. Secondary objectives were to describe effects of the pharmacogenetic intervention on the first therapeutic-target-achieving time, the stable maintenance dose, and the hospitalization days. A total of 2245 patients were included in the analysis. Forty-nine events occurred during follow-up. Genotype-guided dosing strategy did not result in a reduction in major bleeding (0.26% versus 0.63%; hazard ratio, 0.44; 95% confidence interval, 0.13-1.53; P = 0.20) and thrombotic events (0.89% versus 1.61%; hazard ratio, 0.56; 95% confidence interval, 0.27-1.17; P = 0.12) compared with clinical dosing group. Compared with traditional dosing, patients in the genotype-guided group reached their therapeutic international normalized ratio in a shorter time (3.8 ± 2.0 versus 4.4 ± 2.0 days, P < 0.001). There was no difference in hospitalization days (P = 0.28). Warfarin pharmacogenetic testing according to the International Warfarin Pharmacogenetics Consortium algorithm cannot improve anticoagulation outcomes in Chinese patients with heart valve replacement.

Post-transplantation diabetes in kidney transplant recipients: an update on management and prevention

Post-transplantation diabetes mellitus (PTDM) may severely impact both short- and long-term outcomes of kidney transplant recipients in terms of graft and patient survival. However, PTDM often goes undiagnosed is underestimated or poorly managed. A diagnosis of PTDM should be delayed until the patient is on stable maintenance doses of immunosuppressive drugs, with stable kidney graft function and in the absence of acute infections. Risk factors for PTDM should be assessed during the pre-transplant evaluation period, in order to reduce the likelihood of developing diabetes. The oral glucose tolerance test is considered as the gold standard for diagnosing PTDM, whereas HbA1c is not reliable during the first months after transplantation. Glycaemic targets should be individualised, and comorbidities such as dyslipidaemia and hypertension should be treated with drugs that have the least possible impact on glucose metabolism, at doses that do not interact with immunosuppressants. While insulin is the preferred agent for treating inpatient hyperglycaemia in the immediate post-transplantation period, little evidence is available to guide therapeutic choices in the management of PTDM. Metformin and incretins may offer some advantage over other glucose-lowering agents, particularly with respect to risk of hypoglycaemia and weight gain. Tailoring immunosuppressive regimens may be of help, although maintenance of good kidney function should be prioritised over prevention/treatment of PTDM. The aim of this narrative review is to provide an overview of the available evidence on management and prevention of PTDM, with a focus on the available therapeutic options.

Safety of Short 30 Minutes Infliximab Infusion: A Pilot Study

BACKGROUND: Infliximab (IFX), a TNF-α inhibitor, plays a major role in the treatment of inflammatory bowel disease (IBD). It's typically infused over 2 hours, progressively increasing the infusion rate to a maximum rate of 160ml/hr. This slow infusion was adopted because of concerns for infusion reactions. However, this strategy increases both direct cost (cost per hour of infusion, facility fee, nurse time) and indirect costs (patient time away from work and family). Our pilot study aimed to assess the safety of a shortened 30 min. infusion protocol of IFX. METHODS: Patients followed at MedStar Georgetown University, who were on a stable maintenance dose of IFX and who had no history of infusion reaction to standard 2hrs IFX infusion were offered to change their infusion time to 30min. We assessed the occurrence of adverse reactions during the infusion and up to 30 days after IFX infusions. Reactions were further classified as drug related or infusion related. We present the data of our 6 months experience with short infusion (i.e. after an average of 3-4 infusions per patient) RESULTS: Of 121 IBD patients receiving IFX at our institution during the last year, 46 (38%) received 30 min. short infusions and 75 (62%) received standard infusions. Maintenance dose of IFX ranged from 5 mg/kg (69% of patients) to 7.5-10mg/kg (31%). Adverse reactions were reported in a total of 10 patients (8.3%), 4 of which in the short infusion group. A total of 5 patients, 3 of which had short infusion, had drug induced paradoxical psoriasis. Five patients had an infusion reactions: 3 had cardiovascular events (high blood pressure, tachycardia) of which 1 had received a short infusion, and 2 had self limited skin rash. None of these infusion reactions were deemed severe and none lead to a change in the subsequent infusion rate. Correlation studies were performed and no correlation was found between the incidence of adverse events and IFX infusion rate, IFX dose, and duration of IFX therapy before the reaction occurred (n=0.893). CONCLUSION(S): Short 30 minute IFX infusions in selected patients who are on a stable dose of IFX and have no history of infusion reaction during standard 2hrs infusions were well tolerated and were not associated with an increased incidence of adverse reactions. Further studies on a larger group of patients and for a longer period are needed to confirm these findings. Reduction of infusion time will decrease direct and indirect cost of therapy and improve patient experience.

A New Approach towards Minimizing the Risk of Misdosing Warfarin Initiation Doses.

It is a challenge to be able to prescribe the optimal initial dose of warfarin. There have been many studies focused on an efficient strategy to determine the optimal initial dose. Numerous clinical, genetic, and environmental factors affect the warfarin dose response. In practice, it is common that the initial warfarin dose is substantially different from the stable maintenance dose, which may increase the risk of bleeding or thrombosis prior to achieving the stable maintenance dose. In order to minimize the risk of misdosing, despite popular warfarin dose prediction models in the literature which create dose predictions solely based on patients' attributes, we have taken physicians' opinions towards the initial dose into consideration. The initial doses selected by clinicians, along with other standard clinical factors, are used to determine an estimate of the difference between the initial dose and estimated maintenance dose using shrinkage methods. The selected shrinkage method was LASSO (Least Absolute Shrinkage and Selection Operator). The estimated maintenance dose was more accurate than the original initial dose, the dose predicted by a linear model without involving the clinicians initial dose, and the values predicted by the most commonly used model in the literature, the Gage clinical model.

Warfarin Dose Model for the Prediction of Stable Maintenance Dose in Indian Patients.

The main aim of this study was to screen various genetic and nongenetic factors that are known to alter warfarin response and to generate a model to predict stable warfarin maintenance dose for Indian patients. The study comprised of 300 warfarin-treated patients. Followed by extensive literature review, 10 single-nucleotide polymorphisms, that is, VKORC1-1639 G>A (rs9923231), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), FVII R353Q (rs6046), GGCX 12970 C>G (rs11676382), CALU c.*4A>G (rs1043550), EPHX1 c.337T>C (rs1051740), GGCX: c.214+597G>A (rs12714145), GGCX: 8016G>A (rs699664), and CYP4F2 V433M (rs2108622), and 5 nongenetic factors, that is, age, gender, smoking, alcoholism, and diet, were selected to find their association with warfarin response. The univariate analysis was carried out for 15 variables (10 genetic and 5 nongenetic). Five variables, that is, VKORC1-1639 G>A, CYP2C9*2, CYP2C9*3, age, and diet, were found to be significantly associated with warfarin response in univariate analysis. These 5 variables were entered in stepwise and multiple regression analysis to generate a prediction model for stable warfarin maintenance dose. The generated model scored R2 of .67, which indicates that this model can explain 67% of warfarin dose variability. The generated model will help in prescribing more accurate warfarin maintenance dosing in Indian patients and will also help in minimizing warfarin-induced adverse drug reactions and a better quality of life in these patients.

Influence of genetic polymorphisms in cytochrome P450 oxidoreductase on the variability in stable warfarin maintenance dose in Han Chinese

The aim of this study was to investigate whether any of the single-nucleotide polymorphisms (SNPs) in the POR gene were significantly associated with CYP activity and expression, and could contribute to the total variability in stable warfarin maintenance doses in Han Chinese. A total of 408 patients treated at the First Affiliated Hospital of Sun Yat-Sen University were eligible for the study and had attained a stable warfarin maintenance dose at the start of the investigation. Demographics, warfarin maintenance doses, and concomitant medications were documented. Genomic DNA was extracted from peripheral blood samples and genotyped for ten SNPs (CYP 2C9*2 and *3, CYP4F2 rs2108622, VKORC1 -1639C>T, and potential POR genes of rs10239977, rs3815455, rs41301394, rs56256515, rs1057868, and rs2286823) using the Sequenom MassARRAY genotyping system. A predictive model of warfarin maintenance dose was established and indicated that age, gender, body surface area, aspirin use, CYP2C9*3, CYP4F2 rs2108622, VKORC1 -1639C>T, and POR*37 831-35C>T accounted for 42.4 % of dose variance in patients undergoing anticoagulant treatment. The contribution of POR*37 831-35C>T to warfarin dose variation was only 3.9 %. For the first time, the SNP POR*37 831-35C>T was confirmed as a minor but statistically significant factor associated with interindividual variation in warfarin maintenance dose in Han Chinese. The POR*37 gene polymorphism should be considered in future algorithms for faster and more reliable achievement of stable warfarin maintenance doses.

Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children.

People with asthma may experience exacerbations or "attacks" during which their symptoms worsen and additional treatment is required. Written action plans may advocate doubling the dose of inhaled steroids in the early stages of an asthma exacerbation to reduce the severity of the attack and to prevent the need for oral steroids or hospital admission. To compare the clinical effectiveness and safety of increased versus stable doses of inhaled corticosteroids (ICS) as part of a patient-initiated action plan for home management of exacerbations in children and adults with persistent asthma. We searched the Cochrane Airways Group Specialised Register, which is derived from searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) to March 2016. We handsearched respiratory journals and meeting abstracts. We included randomised controlled trials (RCTs) that compared increased versus stable doses of ICS for home management of asthma exacerbations. We included studies of children or adults with persistent asthma who were receiving daily maintenance ICS. Two review authors independently selected trials, assessed quality and extracted data. We contacted authors of RCTs for additional information. This review update added three new studies including 419 participants to the review. In total, we identified eight RCTs, most of which were at low risk of bias, involving 1669 participants with mild to moderate asthma. We included three paediatric (n = 422) and five adult (n = 1247) studies; six were parallel-group trials and two had a cross-over design. All but one study followed participants for six months to one year. Allowed maintenance doses of ICS varied in adult and paediatric studies, as did use of concomitant medications and doses of ICS initiated during exacerbations. Investigators gave participants a study inhaler containing additional ICS or placebo to be started as part of an action plan for treatment of exacerbations.The odds of treatment failure, defined as the need for oral corticosteroids, were not significantly reduced among those randomised to increased ICS compared with those taking their usual stable maintenance dose (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.68 to 1.18; participants = 1520; studies = 7). When we analysed only people who actually took their study inhaler for an exacerbation, we found much variation between study results but the evidence did not show a significant benefit of increasing ICS dose (OR 0.84, 95% CI 0.54 to 1.30; participants = 766; studies = 7). The odds of having an unscheduled physician visit (OR 0.96, 95% CI 0.66 to 1.41; participants = 931; studies = 3) or acute visit (Peto OR 0.98, 95% CI 0.24 to 3.98; participants = 450; studies = 3) were not significantly reduced by an increased versus stable dose of ICS, and evidence was insufficient to permit assessment of impact on the duration of exacerbation; our ability to draw conclusions from these outcomes was limited by the number of studies reporting these events and by the number of events included in the analyses. The odds of serious events (OR 1.69, 95% CI 0.77 to 3.71; participants = 394; studies = 2) and non-serious events, such as oral irritation, headaches and changes in appetite (OR 2.15, 95% CI 0.68 to 6.73; participants = 142; studies = 2), were neither increased nor decreased significantly by increased versus stable doses of ICS during an exacerbation. Too few studies are available to allow firm conclusions on the basis of subgroup analyses conducted to investigate the impact of age, time to treatment initiation, doses used, smoking history and the fold increase of ICS on the magnitude of effect; yet, effect size appears similar in children and adults. Current evidence does not support increasing the dose of ICS as part of a self initiated action plan to treat exacerbations in adults and children with mild to moderate asthma. Increased ICS dose is not associated with a statistically significant reduction in the odds of requiring rescue oral corticosteroids for the exacerbation, or of having adverse events, compared with a stable ICS dose. Wide confidence intervals for several outcomes mean we cannot rule out possible benefits of this approach.

Long-term safety and efficacy of armodafinil in bipolar depression: A 6-month open-label extension study

BackgroundSafe/well-tolerated treatments for bipolar I depression remain limited. We assessed safety/tolerability of adjunctive open-label armodafinil, a wakefulness-promoting agent evaluated in 3 acute, controlled efficacy studies with variable efficacy results. MethodsCompleters of three 8-week, double-blind, placebo-controlled adjunctive armodafinil studies (150–200mg/day added to ongoing stable maintenance doses of 1 or 2 protocol-defined mood stabilizers) in bipolar I depression could enter this 6-month, open-label extension study. Objectives included evaluation of safety/tolerability (primary) and efficacy (secondary). Results867 patients enrolled; 863 received ≥1 dose of armodafinil and 506 (58%) completed the 6-month study. Headache, insomnia, and anxiety were the most common adverse events (AEs) reported, whereas akathisia, nausea, sedation/somnolence, and weight increase were uncommon. Mean measures assessing emergence of mania, anxiety, insomnia, or suicidality showed no worsening. Discontinuations due to AEs occurred in 57 (7%) patients. Serious AEs occurred in 27 (3%) patients and were considered treatment-related in 8 (1%) patients. Depressive symptoms improved over the 6 months, as did patient functioning. LimitationsLack of placebo control. ConclusionsAdjunctive armodafinil was generally safe and well tolerated over 6 months of open-label treatment at 150–200mg/day when taken with protocol-defined mood stabilizers for bipolar I depression. This 6-month open-label study suggested that armodafinil augmentation of bipolar maintenance therapies may have a favorable risk profile and may improve depressive symptoms in some patients with bipolar I depression.

Development and Comparison of Warfarin Dosing Algorithms in Stroke Patients.

PurposeThe genes for cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) have been identified as important genetic determinants of warfarin dosing and have been studied. We developed warfarin algorithm for Korean patients with stroke and compared the accuracy of warfarin dose prediction algorithms based on the pharmacogenetics.Materials and MethodsA total of 101 patients on stable maintenance dose of warfarin were enrolled. Warfarin dosing algorithm was developed using multiple linear regression analysis. The performance of all the algorithms was characterized with coefficient of determination, determined by linear regression, and the mean of percent deviation was used to predict doses from the actual dose. In addition, we compared the performance of the algorithms using percentage of predicted dose falling within ±20% of clinically observed doses and dividing the patients into a low-dose group (≤3 mg/day), an intermediate-dose group (3–7 mg/day), and high-dose group (≥7 mg/day).ResultsA new developed algorithms including the variables of age, body weight, and CYP2C9 and VKORC1 genotype. Our algorithm accounted for 51% of variation in the warfarin stable dose, and performed best in predicting dose within 20% of actual dose and intermediate-dose group.ConclusionOur warfarin dosing algorithm may be useful for Korean patients with stroke. Further studies to elucidate clinical utility of genotype-guided dosing and find the additional genetic association are necessary.

VKORC1 gene polymorphisms and adverse events in Croatian patients on warfarin therapy

The objective was to determine the impact of VKORC1 polymorphisms on warfarin anticoagulant therapy (stable warfarin maintenance dose, time required to reach therapeutic dose and time spent in therapeutic range) and its adverse events (overanticoagulation and bleeding events, time to first overanticoagulation or bleeding event, and therapy for bleeding events) in Croatian patients. Blood samples were collected from 186 patients on stable warfarin therapy. VKORC1 1173C>T and VKORC1 –1639G>A gene polymorphisms were analyzed using real-time PCR. Prothrombin time international normalized ratio (INR) values were determined and overanticoagulation as well as bleeding events were recorded. Both tested VKORC1 gene polymorphisms (VKORC1 1173C>T and VKORC1 -1639G>A) were in perfect linkage disequilibrium. Genotype analysis showed that 33.9% of patients were homozygous for wild-type, 46.8% were heterozygous and 19.4% were homozygous for the variant allele. We have found a statistically significant difference between variantallele carriers and wild-type patients in stable warfarin maintenance dose (p<0.001) and incidence of bleeding events (p=0.040). Patients homozygous for variant-allele were more likely to experience an overanticoagulation event in the first 30 days of therapy (p=0.040). Our study showed that VKORC1 1173C>T and VKORC1 -1639G>A gene polymorphisms are associated with stable warfarin maintenance dose and adverse events of warfarin therapy.

Clinical Application of Genotype-guided Dosing of Warfarin in Patients with Acute Stroke

Patients with certain types of stroke need urgent anticoagulation and it is extremely important for them to achieve fast and stable anticoagulant effect and receive individualized treatment during the initiation of warfarin therapy. We conducted a prospective study among 210 acute stroke patients who had an indication for anticoagulation and compared the impact of CYP2C9 and VKORC1 genotype-guided warfarin dosing (PhG) with fixed dosing (NPhG) on anticoagulation control and clinical outcome between groups. PhG achieved target INR values earlier, i.e., on average in 4.2 (4.1-4.7, 95% CI) days compared to NPhG (5.2 days [4.7-6.4, 95% CI]) (p = 0.0009), spent a higher percentage of time in the therapeutic INR range (76.3% [74.7-78.5, 95% CI] vs. 67.1% [64.5-69.6, 95% CI] in NPhG), and spent less time overdosed (INR > 3.1) (PhG 0.4 [0.1-0.7, 95% CI], NPhG 1.7 [1.1-2.3, 95% CI] days; p >0.000). PhG reached stable maintenance dose faster (10 [9.9-10.7, 95% CI] vs. 13.9 [13.3-14.7, 95% CI] days in controls; p = 0.0049) and had a better clinical outcome in relation to neurological deficit on admission as compared to NPhG. We confirmed that warfarin therapy with genotype-guided dosing instead of fixed dosing reduces the time required for stabilization and improves anticoagulant control with better clinical outcome in early stages of warfarin therapy introduction among acute stroke patients, which is essential for clinical practice.

IPF Care: a support program for patients with idiopathic pulmonary fibrosis treated with pirfenidone in Europe.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible fibrotic lung disease that requires long-term treatment. Given the importance of adherence to treatment and management of adverse events (AEs), patients with IPF need long-term, high-quality support in living with their condition, and adhering to therapy so they can derive maximum benefit. The IPF Care Patient Support Program (IPF Care) provides support, education, and empowerment to patients receiving pirfenidone for the treatment of IPF in Europe, through the provision of frequent, patient-managed discussions with specialist IPF nurses. In this review, we describe the structure of IPF Care in the United Kingdom (UK) and Austria, two of the longest-running IPF Care programs to date, and describe the benefits that these programs provide to patients with IPF. Analysis of results demonstrates a low rate of discontinuation from the program, and provides insight into the questions and concerns that patients express, not only with respect to pirfenidone (the only approved treatment for IPF at the time of analysis), but also in relation to other aspects of living with IPF. Pirfenidone dose modifications are common in patients in IPF Care and AEs most commonly occur early in treatment, with the majority of affected patients continuing on a stable maintenance dose. This highlights the value of the advice and support that patients receive in IPF Care regarding management of AEs and staying on treatment. Patient satisfaction was high in a survey of the UK program, with patients reporting high scores regarding ‘feeling in control of their condition’, ‘knowing what to expect from treatment’, and ‘feeling confident about how their disease is managed’. IPF Care in Europe will continue to evolve over time, striving to provide individually tailored support and patient-friendly information to improve treatment outcomes and quality of life for patients living with IPF.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0183-7) contains supplementary material, which is available to authorized users.

Enzyme Polymorphism in Warfarin Dose Management After Pediatric Cardiac Surgery.

Background:Warfarin is an anticoagulant and is widely used for the prevention of thromboembolic events. Genetic variants of the enzymes that metabolize warfarin, i.e. cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1), contribute to differences in patients’ responses to various warfarin doses. There is, however, a dearth of data on the role of these variants during initial anticoagulation in pediatric patients.Objectives:We aimed to evaluate the role of genetic variants of warfarin metabolizing enzymes in anticoagulation in a pediatric population.Patients and Methods:In this prospective cohort study, 200 pediatric patients, who required warfarin therapy after cardiac surgery, were enrolled and divided into two groups. For 50 cases, warfarin was prescribed based on their genotyping (group 1) and for the remaining 150 cases, warfarin was prescribed based on our institute routine warfarin dosing (group 2). The study endpoints were comprised of time to reach the first therapeutic international normalization ratio (INR), time to reach a stable warfarin maintenance dose, time with over-anticoagulation, bleeding episodes, hospital stay days and stable warfarin maintenance dose.Results:There was no significant difference concerning the demographic data between the two groups. The time to stable warfarin maintenance dose and hospital stay days were significantly lower in group 1 (P <0.001). However, there was no statistically significant difference in time to reach the first therapeutic INR, time with over-anticoagulation and bleeding episodes, between the two groups.Conclusions:The determination of warfarin dose, based on genotyping, might reduce the time to achieve stable anticoagulation of warfarin dose and length of hospital stay.

Addition of antileukotriene agents to inhaled corticosteroids in children with persistent asthma.

For the current issue of the Journal, we asked Drs Jimmy Chong and Bhupendrasinh Chauhan to comment on and put into context the Cochrane Review on the efficacy and safety of adding antileukotriene agents (LTRAs) to low-dose inhaled corticosteroids (ICS) in children with persistent asthma (1). In the treatment of children with mild persistent asthma, low-dose ICS are recommended as the preferred monotherapy (referred to as step 2 of therapy). In children with inadequate asthma control on low doses of ICS (step 2), asthma management guidelines recommend adding an LTRA to existing ICS as one of three therapeutic options to intensify therapy (step 3). Trials were identified from the Cochrane Airways Group Specialised Register of Trials, which is derived from systematic searches of bibliographical databases, including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, AMED and CINAHL, and a manual search of respiratory journals and meeting abstracts, as well as the web-site www.clinicaltrials.gov. The search was conducted until January 2013. Randomized controlled trials (RCTs) that involved children and adolescents one to 18 years of age, with asthma, who remained symptomatic despite the use of a stable maintenance dose of ICS, and in whom LTRAs were added to ICS and compared with the same, an increased or a tapering dose of ICS for at least four weeks were considered for inclusion. Sandard methods outlined by The Cochrane Collaboration were used. Five paediatric (parallel group or cross-over) trials met the inclusion criteria. Two (40%) trials were considered to be at a low risk for bias. Four published trials, representing 559 children (≥6 years of age) and adolescents with mild-to-moderate asthma, contributed data to the review. No trial enrolled preschool-age children. All trials used montelukast as the LTRA, administered for between four and 16 weeks. Three trials evaluated the combination of LTRAs and ICS compared with the same dose of ICS alone (step 3 versus step 2). No statistically significant group difference was observed in the only trial reporting participants with exacerbations requiring oral corticosteroids over four weeks (n=268 participants; RR 0.80 [95% CI 0.34 to 1.91]). There was also no statistically significant difference in percent change in forced expiratory volume in 1 s (FEV1) in this trial, with a mean difference (MD) of 1.3 (95% CI -0.09 to 2.69); however, a significant group difference was observed in the morning and evening peak expiratory flow rates: n=218 participants; MD 9.70 L/min (95% CI 1.27 L/min to 18.13 L/min) and MD 10.70 L/min (95% CI 2.41 L/min to 18.99 L/min), respectively. One trial compared the combination of LTRAs and ICS with a higher dose of ICS (step 3 versus step 3). No significant group difference was observed in this trial for participants with exacerbations requiring rescue oral corticosteroids over a 16-week period (n=182 participants; RR 0.82 [95% CI 0.54 to 1.25]), nor was there any significant difference in exacerbations requiring hospitalization. There was no statistically significant group difference in withdrawals overall or because of any cause with either protocol. No trial explored the impact of adding LTRAs as a means to taper the dose of ICS. The addition of LTRAs to ICS is not associated with a statistically significant reduction in the need for rescue oral corticosteroids or hospital admission compared with the same or an increased dose of ICS in children and adolescents with mild to moderate asthma. Although LTRAs have been licensed for use in children for >10 years, the paucity of paediatric trials, the absence of data regarding preschool-age children and the variability in the reporting of relevant clinical outcomes considerably limit firm conclusions. At present, there is no firm evidence to support the efficacy and safety of LTRAs as add-on therapy to ICS as a step 3 option in the therapeutic arsenal for children with uncontrolled asthma symptoms on low-dose ICS. The full text of the Cochrane Review is available in The Cochrane Library (1).