Venous thromboembolism prophylaxis in medically ill patients: a mixed treatment comparison meta-analysis.

The American College of Chest Physicians guidelines recommend unfractionated heparin (UFH), low molecular weight heparins (LMWHs) or fondaparinux for prevention of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in medically-ill patients. Direct oral anticoagulants (DOACs) have been evaluated relative to enoxaparin for VTE prophylaxis though head-to-head comparisons of these agents are lacking. Therefore, we conducted a mixed treatment comparisons meta-analysis to evaluate the safety and efficacy of established treatments and DOACs for VTE prophylaxis in medically-ill patients. A comprehensive literature search was conducted to identify randomized trials evaluating UFH, LMWHs or DOACS for the prevention of VTE in medically ill patients. Articles were retrieved and cross-referenced for additional trials, evaluated and entered into ADDIS (version 1.16.6) to generate direct and indirect treatment comparisons for VTE, DVT, PE, death from any cause, and bleeding. Ten articles were included and eight anticoagulants were evaluated in a treatment network representing data on 28,382 patients. We found each treatment had similar efficacy in preventing VTE, DVT, PE, death from any cause and each had similar risk of minor and major bleeding. Overall, placebo was associated with more VTE and DVT events compared to LMWHs and DOACs. We found that UFH, LMWHs and DOACs are comparable in preventing VTE, DVT, PE, and death from any cause and in association with minor and major bleeding. Anticoagulant selection for VTE prophylaxis in medically-ill patients should be individualized by patient characteristics, risks and preferences along with specific pharmacokinetic and pharmacodynamic considerations.

Implications of an inpatient warfarin dosing nomogram on safety outcomes post-discharge.

Many hospitals have implemented warfarin dosing nomograms to improve patient safety. To our knowledge, no study has assessed the impact inpatient warfarin initiation has in both medical and surgical patients, on safety outcomes post discharge. To evaluate the impact of a suggested institutional nomogram for the initiation of warfarin, the primary endpoint was the incidence of bleeding throughout follow up. Secondary endpoints included the composite of INR changes ≥0.5/day and INR >4. Patients were followed for a period of 2 weeks post-discharge. The composite endpoint was evaluated for an effect on reaching therapeutic INR, time to reach therapeutic INR, and bleeding events throughout follow up. A single center retrospective study comparing the safety of adherence vs. non-adherence to a warfarin nomogram. A total of 206 patients were included, 73 patients in the nomogram adherence vs. 133 in the nonadherence arm. There was no difference in the proportion of patients who bled throughout the follow up period, adherence 9.6% vs. nonadherence to the nomogram 13.5%, p = 0.407. There was however a statistical difference in the mean total number of bleeding events, 0.096 (7/73) in the adherence vs. 0.158 (21/133) in the non-adherence arm, p = 0.022. There was also no difference in the composite endpoint, 19.2% in the adherence vs. 28.6% in the non-adherence arm p = 0.180. A positive correlation between the inpatient composite and risk of bleeding throughout follow up was noted. The findings of this study support adherence to the nomogram as opposed to non-adherence.

Exploring the effect of complex patients on care delivery tasks.

PURPOSE: The needs of complex patients with chronic conditions can be unpredictable and can strain resources. Exploring how tasks vary for different patients, particularly those with complex needs, can yield insights about designing better processes in healthcare. The purpose of this paper is to explore the tasks required to manage complex patients in an anticoagulation therapy context. DESIGN/METHODOLOGY/APPROACH: The authors analyzed interviews with 55 staff in six anticoagulation clinics using the Systems Engineering Initiative for Patient Safety (SEIPS) work system framework. The authors qualitatively described complex patients and their effects on care delivery. FINDINGS: Data analysis highlighted how identifying complex patients and their effect on tasks and organization, and the interactions between them was important. Managing complex patients required similar tasks as non-complex patients, but with greater frequency or more intensity and several additional tasks. After complex patients and associated patient interaction and care tasks were identified, a work system perspective was applied to explore how such tasks are integrated within clinics and the resulting implications for resource allocation. PRACTICAL IMPLICATIONS: The authors present a complex patient management framework to guide workflow design in specialty clinics, to better support high quality, effective, efficient and safe healthcare. ORIGINALITY/VALUE: The complex patient framework presented here, based on the SEIPS framework, suggests a more formal and integrated analysis be completed to provide better support for appropriate resource allocation and care coordination.

Approaches to Gradual Dose Reduction of Chronic Off-Label Antipsychotics Used for Behavioral and Psychological Symptoms of Dementia.

OBJECTIVE: Little is known about how to best taper antipsychotics used in patients with dementia. To address this gap, we reviewed published antipsychotic discontinuation trials to summarize what is known about tapering strategies for antipsychotics used with older adults with dementia. We further developed pharmacokinetic-based gradual dose reduction (GDR) protocols based on antipsychotic half-lives. DATA SOURCES: MEDLINE, EMBASE, and International Pharmaceutical Abstracts were searched up to October 2014 to identify intervention studies reporting the behavioral and psychological symptoms of dementia outcomes resulting from discontinued off-label use of antipsychotics in nursing facility populations. Recently published pharmacokinetic reviews and standard pharmacology texts were used to determine antipsychotic drug half-lives for the pharmacokinetic-based GDR protocols. STUDY SELECTION: For the review, studies with an intervention resulting in antipsychotic medication discontinuation or tapering were eligible, including randomized controlled trials and pre- and post-intervention studies. DATA EXTRACTION: When available, we extracted the protocols used for antipsychotic GDR from each study included in the review. DATA SYNTHESIS: We found that clinical trials used different approaches to antipsychotic discontinuation, including abrupt discontinuation, slow tapers (more than two weeks), and mixed strategies based on drug dosage. None of the published trials described an approach based on pharmacokinetic principles. We developed a two-stage GDR protocol for tapering antipsychotic medications based on the log dose-response relationship; each stage was designed to result in a 50% dose reduction prior to discontinuation. This pharmacologically based strategy for patients chronically prescribed antipsychotics resulted in recommendations for slow tapers. CONCLUSION: Our theoretically derived GDR recommendations suggest a different approach than previously published in clinical trials. Further study is needed to evaluate the effect of this approach on patients.

2022 ASHP Survey of Health-System Specialty Pharmacy Practice: Clinical Services.

PURPOSE: Results of the first ASHP national survey of clinical services provided by health-system specialty pharmacies (HSSPs) are presented. METHODS: A survey questionnaire was developed by 26 HSSP contacts after reviewing available literature on the role and services of HSSPs. After pilot and cognitive testing resulting in a final questionnaire of 119 questions, a convenience sample of 441 leaders in HSSPs was contacted using email and invited to participate in the survey. RESULTS: The survey response rate was 29%. Almost half of respondents (48%) had offered pharmacy services for 7 years or more, and most (60%) dispensed more than 15,000 prescriptions annually. Respondents most commonly (42%) reported a specialist model wherein staff are dedicated to specific specialty disease states. Over half of respondents reported providing several medication access, pretreatment assessment, and initial counseling services to patients referred to them, regardless of whether the HSSP was used for medication fulfillment. All HSSP activities were noted to be documented in the electronic health record and visible to providers frequently or always. Almost all respondents noted that HSSP pharmacists have a role in specialty medication selection. Disease-specific outcomes were tracked in 95% of responding HSSPs, with 67% reporting that outcomes were used to drive patient monitoring. HSSPs were often involved in continuity of care services such as transitions of care (reported by 89% of respondents), referral to other health-system services (53%), and addressing social determinants of health (60%). Most respondents (80%) reported providing clinical education to specialty clinic staff, including medicine learners (62%). Though only 12% of respondents had dedicated outcomes research staff, many reported annually publishing (47%) or presenting (61%) outcomes research. CONCLUSION: HSSPs are a clinical and educational resource for specialty clinics and have developed robust patient care services that encompass the patient journey from before specialty medication selection through treatment monitoring and optimization.

A polypill for all? Critical review of the polypill literature for primary prevention of cardiovascular disease and stroke.

OBJECTIVE: To evaluate the efficacy and safety of the polypill for prevention of cardiovascular disease (CVD) and stroke and to present literature related to the polypill components (statin, aspirin, antihypertensive) for primary prevention of CVD and stroke. DATA SOURCES: A literature search was conducted in MEDLINE (1948-January 2011) and EMBASE (1974-January 2011) using the terms polypill and Polycap. When limited to clinical trials, systematic reviews, or meta-analyses, 7 studies were identified. Bibliographies of pertinent review articles and studies were scanned for additional references. A similar search was conducted to identify literature related to the use of polypill components for primary prevention of CVD and stroke. STUDY SELECTION AND DATA EXTRACTION: Studies that evaluated the hypothetical benefits of a polypill and controlled trials that assessed a formulation of the polypill related to prevention of CVD and stroke were included. Studies were assessed for efficacy, safety, drug interactions, and clinical pharmacokinetics. DATA SYNTHESIS: An initial study to predict benefit estimated that a hypothetical polypill would reduce diastolic blood pressure by 11 mm Hg and low-density lipoprotein cholesterol (LDL-C) by 70 mg/dL, thus reducing the relative risks of CVD and stroke by 88% and 80%, respectively. One clinical trial in patients at low risk for CVD and stroke found that diastolic blood pressure was reduced by 1.6 mm Hg and LDL-C was reduced by 17.7 mg/dL, correlating with 44% and 21% reduction in the relative risks of CVD and stroke, respectively. Studies in higher risk patients reported reductions in systolic blood pressure of up to 28.8 mm Hg and in LDL-C of up to 54 mg/dL, correlating with 62% and 60% relative reduction in risks of CVD and stroke, respectively. CONCLUSIONS: Polypill study results have been more modest than originally theorized. However, results show promise in patients at higher risk for CVD and stroke.

A case of unsuccessful treatment of heparin-induced thrombocytopenia (HIT) with fondaparinux.

Heparin-induced thrombocytopenia (HIT) is a rare immune-mediated complication associated with unfractionated heparin and to a lesser extent with low-molecular weight heparins. The American College of Chest Physicians recommends treating patients with suspected HIT with a non-heparin product regardless if thrombosis is present. The direct thrombin inhibitors are the preferred agents for the treatment of acute HIT (lepirudin, argatroban [Grade 1C]). Fondaparinux is also suggested as an alternative with a lower level of evidence (Grade 2C). The evidence supporting the use of fondaparinux in the treatment of HIT is limited, but the evidence of fondaparinux causing HIT is even less. We present a case of a patient who developed complications with fondaparinux when used in the acute setting of HIT.

Technological resources and personnel costs required to implement an automated alert system for ambulatory physicians when patients are discharged from hospitals to home.

BACKGROUND: With the adoption of electronic medical records by medical group practices, there are opportunities to improve the quality of care for patients discharged from hospitals. However, there is little guidance for medical groups outside integrated hospital systems to automate the flow of patient information during transitions in care. OBJECTIVE: To describe the technological resources, expertise and time needed to develop an automated system providing information to ambulatory physicians when their patients are discharged from hospitals to home. DEVELOPMENT: Within a medical group practice, we developed an automated alert system that provides notification of discharges, reminders of the need for follow-up visits, drugs added during inpatient stays, and recommendations for laboratory monitoring of high-risk drugs. We tracked components of the information system required and the time spent by team members. We used USA national averages of hourly wages to estimate personnel costs. APPLICATION: Critical components of the information system are notifications of hospital discharges through an admission, discharge and transfer registration (ADT) interface, linkage to the group's scheduling system, access to information on pharmacy dispensing and lab tests, and an interface engine. Total personnel cost was $76,314. Nearly half (47%) was for 614 hours by physicians who developed content, provided overall project management, and reviewed alerts to ensure that only 'actionable' alerts would be sent. CONCLUSION: Implementing a system to provide information about hospital discharges requires strong internal informatics expertise, cooperation between facilities and ambulatory providers, development of electronic linkages, and extensive commitment of physician time.

Health-system specialty pharmacy role and outcomes: A review of current literature.

PURPOSE: Specialty medications can have life-altering outcomes for patients with complex diseases. However, their benefit relies on appropriate treatment selection, patients' ability to afford and initiate treatment, and ongoing treatment optimization based on patient response to therapy. Mounting research demonstrates the benefits of the health-system specialty pharmacies (HSSPs) in improving specialty medication access, affordability, and outcomes. The purpose of this rapid review is to describe the currently reported role and function of HSSP pharmacists and outcomes reported with use of the HSSP model, and to identify gaps in the literature where more information is needed to better understand the HSSP model and outcomes. SUMMARY: Current literature describes the role of HSSP pharmacists in facilitating patient access, affordability, and initiation and maintenance of specialty medications. Though it is clear HSSP pharmacists are involved in treatment monitoring, often through utilizing the electronic health record, more information is needed to elucidate the frequency, method, and extent of monitoring. Despite several valuable continuity of care services reported to be provided by HSSPs, the breadth and degree of standardization of these services remains unclear. There is minimal literature describing HSSP education and research involvement. HSSPs have reported significant benefits of this patient care model, as demonstrated by higher adherence and persistence; better clinical outcomes; financial benefits to patients, payers, and the health system; better quality of care; higher patient and provider satisfaction with services, and highly efficient specialty pharmacy services. More literature comparing clinical and diagnosis-related outcomes in HSSP versus non-HSSP patients is needed. CONCLUSION: HSSPs provide comprehensive, patient-centered specialty medication management that result in improved care across the continuum of the specialty patient journey and act as a valuable resource for specialty clinics and patients beyond medication management. Future research should build on the current description of HSSP services, how services affect patient outcomes, and the impact HSSP network restrictions.

Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis.

The human carboxylesterase 1 (CES1) gene encodes for the enzyme carboxylesterase 1, a serine esterase governing both metabolic deactivation and activation of numerous therapeutic agents. During the course of a study of the pharmacokinetics of the methyl ester racemic psychostimulant methylphenidate, profoundly elevated methylphenidate plasma concentrations, unprecedented distortions in isomer disposition, and increases in hemodynamic measures were observed in a subject of European descent. These observations led to a focused study of the subject's CES1 gene. DNA sequencing detected two coding region single-nucleotide mutations located in exons 4 and 6. The mutation in exon 4 is located in codon 143 and leads to a nonconservative substitution, p.Gly143Glu. A deletion in exon 6 at codon 260 results in a frameshift mutation, p.Asp260fs, altering residues 260-299 before truncating at a premature stop codon. The minor allele frequency of p.Gly143Glu was determined to be 3.7%, 4.3%, 2.0%, and 0% in white, black, Hispanic, and Asian populations, respectively. Of 925 individual DNA samples examined, none carried the p.Asp260fs, indicating it is an extremely rare mutation. In vitro functional studies demonstrated the catalytic functions of both p.Gly143Glu and p.Asp260fs are substantially impaired, resulting in a complete loss of hydrolytic activity toward methylphenidate. When a more sensitive esterase substrate, p-nitrophenyl acetate was utilized, only 21.4% and 0.6% catalytic efficiency (V(max)/K(m)) were determined in p.Gly143Glu and p.Asp260fs, respectively, compared to the wild-type enzyme. These findings indicate that specific CES1 gene variants can lead to clinically significant alterations in pharmacokinetics and drug response of carboxylesterase 1 substrates.

Correlation of inhibition of platelet aggregation after clopidogrel with post discharge bleeding events: assessment by different bleeding classifications.

AIMS: To correlate inhibition of platelet aggregation (IPA) with bleeding events assessed by TIMI, GUSTO, and BleedScore scales in a large cohort of patients with coronary artery disease (CAD) and ischaemic stroke (IS) treated with chronic low-dose aspirin plus clopidogrel. Data from recent trials and registries suggest a link between increased risk of bleeding and cardiovascular mortality. However, the potential association of bleeding risk and IPA is not established. It may play a critical role for the safety of more aggressive platelet inhibition or/and individual tailoring of antiplatelet strategies. METHODS AND RESULTS: Secondary post hoc analyses of 5 microM ADP-induced IPA and bleeding complications assessed by TIMI, GUSTO, and BleedScore scales in a combined data set consisting of patients with documented CAD (n = 246) and previous IS (n = 117). Demographic characteristics differ substantially depending on the underlying vascular disease; however, IPA and bleeding risks were similar between CAD and IS. All three bleeding scales adequately captured serious haemorrhagic events, where the TIMI scale was the most exclusive, whereas BleedScore was the most inclusive. Over half of all patients experienced superficial event(s), most commonly occurring during two to three distinct bleeding episodes. There was no correlation between IPA and duration of antiplatelet therapy. Inhibition of platelet aggregation >50% strongly correlates with minor (r(2) = 0.58, P < 0.001; c-statistic = 0.92), but not severe (r(2) = 0.11, P = 0.038; c-statistic = 0.57), bleeding events. CONCLUSION: Chronic oral combination antiplatelet regimens are associated with a very high (56.5-60.7%) prevalence of superficial bleeding episodes, which are grossly underestimated in trials and registries. The role of such frequent mild complications for the overall benefit of antiplatelet therapy is entirely unknown, as is their effect on compliance. Although IPA is well suited for defining the risk of minor complications, prediction of more severe bleeding events may be challenging.

Effect of a Multifaceted Clinical Pharmacist Intervention on Medication Safety After Hospitalization in Persons Prescribed High-risk Medications: A Randomized Clinical Trial.

Importance: The National Action Plan for Adverse Drug Event (ADE) Prevention identified 3 high-priority, high-risk drug classes as targets for reducing the risk of drug-related injuries: anticoagulants, diabetes agents, and opioids. Objective: To determine whether a multifaceted clinical pharmacist intervention improves medication safety for patients who are discharged from the hospital and prescribed medications within 1 or more of these high-risk drug classes. Design, Setting, and Participants: This randomized clinical trial was conducted at a large multidisciplinary group practice in Massachusetts and included patients 50 years or older who were discharged from the hospital and prescribed at least 1 high-risk medication. Participants were enrolled into the trial from June 2016 through September 2018. Interventions: The pharmacist-directed intervention included an in-home assessment by a clinical pharmacist, evidence-based educational resources, communication with the primary care team, and telephone follow-up. Participants in the control group were provided educational materials via mail. Main Outcomes and Measures: The study assessed 2 outcomes over a 45-day posthospital discharge period: (1) adverse drug-related incidents and (2) a subset defined as clinically important medication errors, which included preventable or ameliorable ADEs and potential ADEs (ie, medication-related errors that may not yet have caused injury to a patient, but have the potential to cause future harm if not addressed). Clinically important medication errors were the primary study outcome. Results: There were 361 participants (mean [SD] age, 68.7 [9.3] years; 177 women [49.0%]; 319 White [88.4%] and 8 Black individuals [2.2%]). Of these, 180 (49.9%) were randomly assigned to the intervention group and 181 (50.1%) to the control group. Among all participants, 100 (27.7%) experienced 1 or more adverse drug-related incidents, and 65 (18%) experienced 1 or more clinically important medication errors. There were 81 adverse drug-related incidents identified in the intervention group and 72 in the control group. There were 44 clinically important medication errors in the intervention group and 45 in the control group. The intervention did not significantly alter the per-patient rate of adverse drug-related incidents (unadjusted incidence rate ratio, 1.13; 95% CI, 0.83-1.56) or clinically important medication errors (unadjusted incidence rate ratio, 0.99; 95% CI, 0.65-1.49). Conclusions and Relevance: In this randomized clinical trial, there was not an observed lower rate of adverse drug-related incidents or clinically important medication errors during the posthospitalization period that was associated with a clinical pharmacist intervention. However, there were study recruitment challenges and lower than expected numbers of events among the study population. Trial Registration: ClinicalTrials.gov Identifier: NCT02781662.

P-glycoprotein inhibition potentiates the behavioural and neurochemical actions of risperidone in rats.

Antipsychotic drugs are the mainstay pharmacotherapy for schizophrenia and related psychiatric disorders. While the metabolic pathways of antipsychotic drugs have been well defined, the role of drug transporters in the disposition and effects of antipsychotic drugs has not been systematically explored. P-glycoprotein has ubiquitous expression in brain endothelial cells and plays a protective role by effluxing substrates for elimination and by limiting their accumulation in the central nervous system. Risperidone and several other antipsychotic drugs are substrates of P-glycoprotein. Increased antipsychotic drug entry into the brain via blockade of the P-glycoprotein transporter may facilitate the amount of available drug to its targets, particularly dopamine receptors. By increasing available antipsychotic drug concentrations, P-glycoprotein inhibition offers a novel means of enhanced drug delivery. This study evaluated whether selective P-glycoprotein transporter inhibition would increase the effects of risperidone on relevant indices of behaviour (catalepsy and locomotion) and neurochemistry (dopamine release and metabolism as measured by in-vivo microdialysis). We administered the P-glycoprotein inhibitor, PSC 833 (100 mg/kg p.o.), to rats prior to administration of risperidone at varying doses (0.01-4.0 mg/kg s.c.). P-glycoprotein inhibition significantly increased risperidone-induced cataleptic effects, blockade of amphetamine-induced locomotion, and effects on dopamine turnover as seen by increased striatal dopamine metabolite levels. These results provide functional evidence concordant with prior data for increased brain levels of risperidone following PSC 833 treatment.

Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic.

The objectives of this retrospective cohort study are to evaluate the accuracy of pharmacogenetic warfarin dosing algorithms in predicting therapeutic dose and to determine if this degree of accuracy warrants the routine use of genotyping to prospectively dose patients newly started on warfarin. Seventy-one patients of an outpatient anticoagulation clinic at an academic medical center who were age 18 years or older on a stable, therapeutic warfarin dose with international normalized ratio (INR) goal between 2.0 and 3.0, and cytochrome P450 isoenzyme 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes available between January 1, 2007 and September 30, 2008 were included. Six pharmacogenetic warfarin dosing algorithms were identified from the medical literature. Additionally, a 5 mg fixed dose approach was evaluated. Three algorithms, Zhu et al. (Clin Chem 53:1199-1205, 2007), Gage et al. (J Clin Ther 84:326-331, 2008), and International Warfarin Pharmacogenetic Consortium (IWPC) (N Engl J Med 360:753-764, 2009) were similar in the primary accuracy endpoints with mean absolute error (MAE) ranging from 1.7 to 1.8 mg/day and coefficient of determination R (2) from 0.61 to 0.66. However, the Zhu et al. algorithm severely over-predicted dose (defined as >or=2x or >or=2 mg/day more than actual dose) in twice as many (14 vs. 7%) patients as Gage et al. 2008 and IWPC 2009. In conclusion, the algorithms published by Gage et al. 2008 and the IWPC 2009 were the two most accurate pharmacogenetically based equations available in the medical literature in predicting therapeutic warfarin dose in our study population. However, the degree of accuracy demonstrated does not support the routine use of genotyping to prospectively dose all patients newly started on warfarin.

Aripiprazole brain concentration is altered in P-glycoprotein deficient mice.

P-glycoprotein (P-gp) is a transporter that mediates the tissue disposition of numerous drugs. To evaluate the role of P-glycoprotein (P-gp) in aripiprazole tissue distribution and penetration across the blood-brain barrier, mice deficient in the P-gp gene (Abcb1a/b-/-) were dosed intraperitoneally with 2 microg/g mouse of the antipsychotic drug aripiprazole. Wildtype FVB mice were administered the same dose as transgenic animals. At one, two, and three hours after dosing, blood and tissue samples were collected and assayed for aripiprazole concentration by HPLC. Deficiency of P-gp did not result in significantly altered plasma drug concentrations but had dramatic effects on drug concentrations in brain tissue. At 1, 2, and 3 h after dosing, aripiprazole brain concentrations in the Abcb1a/b-/- mice were 4.6-, 4.1- and 3.0-fold higher, respectively (P<0.01), compared with the wildtype mice. Increases in drug concentration were also observed in testes and muscle in Abcb1a/b -/- mice. All other tissues including gut, lung, heart, kidney, liver, and spleen did not show significant differences between the two groups. These data provide evidence that aripiprazole is a transportable substrate of P-gp. Thus, factors influencing P-gp activity within the blood brain barrier in humans may have implications for the therapeutic effects and tolerability of aripiprazole.

Pharmacotherapy of Autism Spectrum Disorder: Results from the Randomized BAART Clinical Trial.

The objective of this trial, Biomarkers in Autism of Aripiprazole and Risperidone Treatment (BAART), was to provide support and guidance for an evidence-based approach for the selection and monitoring of initial pharmacotherapy in patients with autism by assessing predictors of efficacy, tolerability, and safety. This randomized double-blind parallel-group study was conducted in three academic medical centers and a single private pediatric practice. Eighty children or adolescents (aged 6-17 yrs) with autistic disorder were enrolled, and 61 patients were randomized to the study drug. Of those patients, 51 completed the 10-week trial, and 31 completed an optional 12-week blinded extension phase. All patients were treated with 2 weeks of placebo before random assignment to receive aripiprazole (31 patients) or risperidone (30 patients) for 10 weeks. Sixteen placebo responders (20%) were excluded from further analysis. Drug dosing followed U.S. Food and Drug Administration (FDA) labeling, and weekly dosage adjustments were allowed until week 4; patients were then maintained on a fixed dose for 6 additional weeks. Safety, physical, and psychological assessments were recorded weekly or every 2 weeks. No significant differences in severity of illness between the aripiprazole and risperidone groups were noted at baseline. All patients significantly improved on the Aberrant Behavior Checklist-Irritability subscale after 1 week and continued for the remaining 9 weeks and the extension phase. Improvement was greatest in the risperidone group at every assessment period and was statistically significantly better than that in the aripiprazole group at weeks 3 and 6 (p<0.05). No dose-limiting adverse events occurred during the dose-titration period. Mean weight gain in the aripiprazole group was significantly less than that in the risperidone group at week 4 (0.62 vs 1.38 kg, p=0.033) and week 10 (1.61 vs 3.31 kg, p<0.001), but the difference became nonsignificant for the 31 patients completing the 3-month extension phase (4.36 vs 5.55 kg, p=0.26). Pharmacotherapy of patients with autism spectrum disorder resulted in behavioral improvement within 1 week and lasted at least 22 weeks. Weight gain occurred to a greater degree with risperidone than aripiprazole initially, but the differences became nonsignificant by the end of the trial. Our trial supports previous results of drug efficacy and safety in patients with autism spectrum disorder from other trials and extends the evidence-based support for choosing an FDA-approved drug for initial pharmacotherapy for autism spectrum disorder.

Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein.

The objective of this study was to assess the potential interactions of the drug transporter P-glycoprotein with attention-deficit/hyperactivity disorder (ADHD) therapeutic agents atomoxetine--and the individual isomers of methylphenidate, amphetamine, and modafinil utilizing established in vitro assay. An initial ATPase assay indicated that both d- and l-methylphenidate have weak affinity for P-glycoprotein. The intracellular accumulation of P-glycoprotein substrates doxorubicin and rhodamine123 in the P-glycoprotein overexpressing cell line LLC-PK1/MDR1 was determined to evaluate potential inhibitory effects on P-glycoprotein. The results demonstrated that all compounds, except both modafinil isomers, significantly increased doxorubicin and rhodamine123 accumulation in LLC-PK1/MDR1 cells at higher concentrations. To investigate the P-glycoprotein substrate properties, the intracellular concentrations of the tested compounds in LLC-PK1/MDR1 and P-glycoprotein negative LLC-PK1 cells were measured in the presence and absence of the P-glycoprotein inhibitor PSC833. The results indicate that the accumulation of d-methylphenidate in LLC-PK1 cells was 32.0% higher than in LLC-PK1/MDR1 cells. Additionally, coadministration of PSC833 leads to 52.9% and 45.6% increases in d-modafinil and l-modafinil accumulation, respectively, in LLC-PK1/MDR1 cells. Further studies demonstrated that l-modafinil transport across LLC-PK1/MDR1 cell monolayers in the basolateral-to-apical (B-A) direction was significantly higher than in the apical-to-basolateral (A-B) direction. PSC833 treatment significantly decreased the transport of l-modafinil in B-A direction. In conclusion, our results suggest that all tested agents with the exception of modafinil isomers are relatively weak P-glycoprotein inhibitors. Furthermore, P-glycoprotein may play a minor role in the transport of d-methylphenidate, d-modafinil, and l-modafinil.

Risperidone and paliperidone inhibit p-glycoprotein activity in vitro.

Risperidone (RSP) and its major active metabolite, 9-hydroxy-risperidone (paliperidone, PALI), are substrates of the drug transporter P-glycoprotein (P-gp). The goal of this study was to examine the in vitro effects of RSP and PALI on P-gp-mediated transport. The intracellular accumulation of rhodamine123 (Rh123) and doxorubicin (DOX) were examined in LLC-PK1/MDR1 cells to evaluate P-gp inhibition by RSP and PALI. Both compounds significantly increased the intracellular accumulation of Rh123 and DOX in a concentration-dependent manner. The IC(50) values of RSP for inhibiting P-gp-mediated transport of Rh123 and DOX were 63.26 and 15.78 microM, respectively, whereas the IC(50) values of PALI were >100 microM, indicating that PALI is a less potent P-gp inhibitor. Caco-2 and primary cultured rat brain microvessel endothelial cells (RBMECs) were utilized to investigate the possible influence of RSP on intestinal absorption and blood-brain barrier (BBB) transport of coadministered drugs that are P-gp substrates. RSP, 1-50 microM, significantly enhanced the intracellular accumulation of Rh123 in Caco-2 cells by inhibiting P-gp activity with an IC(50) value of 5.87 microM. Following exposure to 10 microM RSP, the apparent permeability coefficient of Rh123 across Caco-2 and RBMECs monolayers was increased to 2.02 and 2.63-fold in the apical to basolateral direction, but decreased to 0.37 and 0.21-fold in the basolateral to apical direction, respectively. These data suggest that RSP and PALI, to a lesser extent, have a potential to influence the pharmacokinetics and hence the pharmacodynamics of coadministered drugs via inhibition of P-gp-mediated transport. However, no human data exist that address this issue. In particular, RSP may interact with its own active metabolite PALI by promoting its brain concentration through inhibiting P-gp-mediated efflux of PALI across endothelial cells of the BBB.

Meta-analysis of venous thromboembolism prophylaxis in medically Ill patients.

BACKGROUND: Venous thromboembolism (VTE) prophylaxis in medically ill patients has received a level 1A recommendation in previously published clinical guidelines. Pharmacologic prophylaxis for VTE includes unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux. Few direct comparisons between anticoagulants exist in medically ill patients. OBJECTIVE: This meta-analysis was conducted to assess UFH and LMWH (including the selective factor Xa inhibitor fondaparinux) in the reduction of in-hospital VTE in unselected medically ill patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Registry databases from January 1981 through September 2007 (English language) for randomized controlled trials using the following terms: dalteparin, enoxaparin, fondaparinux, nadroparin, and heparin. References of included articles and key review papers for additional studies were also searched. Data from studies were included in the analysis if the studies included medically ill patients with risk factors for VTE who had been followed up for 7 to 21 days. RESULTS: A total of 12,391 patients (of whom 8357 were in placebo-controlled trials) from 9 studies were included. Mean age for the entire cohort was 72.8 years; mean (SD) body mass index, 25.6 kg/m2; and mean (SD) actual body weight, 68.2 kg. Deep vein thrombosis (DVT) was significantly reduced with the addition of an LMWH compared with placebo (odds ratio [OR], 0.60; 95% CI, 0.47-0.75; P < or = 0.001), but rates of DVT were similar when comparing LMWH with UFH (OR, 0.92; 95% CI, 0.56-1.52). No significant differences in pulmonary embolism (PE) or death were found among the UFH, LMWH, and placebo groups. LMWH was associated with a significant increased risk for minor bleeding compared with placebo (OR, 1.64; 95% CI, 1.18-2.29; P = 0.003). However, no significant difference was found between LMWH and UFH (OR, 0.68; 95% CI, 0.27-1.70). Major bleeding events were similar among all groups: LMWH/fondaparinux versus placebo, OR, 1.65 (95% CI, 0.8-3.4); LMWH/fondaparinux versus UFH, OR, 0.69 (95% CI, 0.29-1.68); LMWH/fondaparinux versus UFH or placebo, OR, 1.16 (95% CI, 0.66-2.04). CONCLUSIONS: This analysis suggests that VTE prophylaxis with an LMWH (including fondaparinux) or UFH is effective in reducing the rate of DVT, but this benefit did not extend to enhanced protection against PE. Additionally, LMWH and UFH had similar bleeding outcomes.

Sensitive quantification of atomoxetine in human plasma by HPLC with fluorescence detection using 4-(4,5-diphenyl-1H-imidazole-2-yl) benzoyl chloride derivatization.

The first HPLC-fluorescence method for the determination of atomoxetine in human plasma was developed and validated. Atomoxetine was derivatized with 4-(4,5-diphenyl-1H-imidazol-2-yl) benzoyl chloride (DIB-Cl) under mild conditions, and separated isocratically on a C18 column using a HPLC system with fluorescence detection (lambdaex: 318 nm, lambdaem: 448 nm). A linear calibration curve was obtained over the concentration range 1-1000 ng/mL (r=0.999). The limit of detection (S/N=3) was 0.3 ng/mL. The relative standard deviations of intra-day and inter-day variations were < or =8.30% and 7.47%, respectively. This method is rapid, sensitive, and suitable for both basic and clinical studies of atomoxetine.