Months Of Drugs Research Articles

Aging Rate Indicators: Speedometers for Aging Research in Mice.

A "biomarker of aging" is conceptualized as an index of how far an individual has moved along the path from youth to old age. In contrast, an aging rate indicator (ARI) represents a measure of speed, rather than distance, that is, a measure of how rapidly the individual is moving toward the phenotypic changes typical of old age. This essay presents and reviews recent data suggesting common characteristics of slow-aging mice, whether the slowed aging is caused by a mutant allele, the calorie restriction diet, or drugs that slow aging and extend mean and maximal lifespan. Some of the candidate ARIs, shared by nine varieties of slow-aging mice, are physiological changes seen in fat, fat-associated macrophages, muscle, liver, brain, and plasma. Others are molecular measurements, reflecting activity of mTORC1, selective mRNA translation, or each of six MAP kinases in two distinct MAPK cascades in liver, muscle, or kidney. Changes in ARIs are notable in young adult mice after 8 months of drug or diet exposure, are detectable in mutant mice at least as early as 4-6 months of age, and persist until at least 18-22 months. Many of the candidate ARIs are thought to play an influential role in cognition, inflammation, exercise responses, and control of metabolic rate, and are thus plausible as modulators of age-related physiological and neurological illnesses. In principle, screening for drugs that induce alterations in ARIs in normal young adult mice might facilitate the search for preventive medicines that can retard aging and late-life illnesses in mice or in human populations.

When Is Enough, Enough?

When Is Enough, Enough? Megan Homsy This was a case that stuck with many members of our transplant team for a long time. The patient was a 44-year-old Caucasian male evaluated for a liver transplant with a diagnosis of hepatitis C virus (HCV), originally diagnosed 11 years before the transplant evaluation. The patient met the criteria for the following substance use diagnoses: alcohol use disorder moderate in sustained remission, in a controlled environment, opioid use disorder, severe, in sustained remission, on maintenance therapy, in a controlled environment, stimulant use disorder, amphetamine-type, severe, in early remission, in a controlled environment and stimulant use disorder, cocaine-type, severe in early remission, in a controlled environment. The patient had been living in a sober living housing program for approximately ten months prior to his transplant evaluation with me, his social worker. He had also been diagnosed with depression and bipolar disorder. He had been intermittently linked with mental health services and had participated in numerous detox and substance abuse programs over the last ten years, with varying degrees of success. He was in dual diagnosis treatment (i.e., treatment for co-occurring substance use and mental health disorders) through his Suboxone clinic and was completing toxicology screenings on a biweekly basis. After concluding the minimum three months of drug and alcohol treatment set forth by the state's Organ Transplantation Consortium, the patient graduated from his sober living program, moved in with his sister, and was listed for a liver transplant. The patient was transplanted five months after his clinic evaluation. At the time of the surgery, the patient's Suboxone was abruptly discontinued and replaced with IV Dilaudid. Within days of his transplant, the patient frequently expressed concerns about his pain. Several medical services attempted to manage the pain medications, resulting in his pain management plan being changed repeatedly and much confusion over his current medication regimen. During his liver transplant hospitalization, the RN found the patient with a needle in his arm, and after a search of the patient's hospital room, the hospital police found drug paraphernalia and illicit substances. The patient was eventually discharged to an inpatient substance abuse program, which he left before completing the program and against medical advice. During his first year post-transplant, I attempted to arrange other various treatment programs for him (most of which he did not follow through with) and to find housing for him (as he had been forced to leave his sister's home after his relapse). Eventually, the patient was incarcerated on drug-related charges. Numerous times, the patient missed completing his labs and his post-transplant appointments. He did not refill his immunosuppressant medications, and for lengthy periods of time, he was unreachable by the transplant care team, which resulted in my team members and I calling the patient's family, other providers, and the police for safety checks. In the aftermath of these issues, my colleagues and I had to reckon with the realization that we had failed the patient. As a team, our transplant center created a task force to review this case and what to do in the future to prevent such breakdowns in patient care. We created protocols for managing patients who, at the time of their transplant, are on Medication Assisted Treatment (MAT) such as Suboxone and methadone. Staff across the multidisciplinary team attended trainings regarding addiction, pain management, and best practices for MAT services. Additionally, our transplant center collaborated with our hospital's addiction treatment program for a streamlined referral process for transplant patients to addiction services. This patient's case and its sensational nature resulted in many conversations, both professional and unprofessional. Members of the social worker department became aware that personnel within transplant, though not involved in patient care, were inappropriately discussing this patient's case and engaging in unprofessional behavior. Said actions led to the termination of a member of the transplant team. I was placed in the unenviable [End Page E3] position of having to report this behavior to hospital management and legal teams to protect a vulnerable patient. The ethical challenge behind this case really stems from the transplant team attempting to balance two...

Assessment of Use and Safety of Edaravone for Amyotrophic Lateral Sclerosis in the Veterans Affairs Health Care System

Using real-world data, the US Department of Veterans Affairs (VA) initiated a surveillance evaluation of edaravone after its approval for amyotrophic lateral sclerosis (ALS) in 2017. The use and safety of edaravone for patients with ALS in the VA health care system remain to be assessed. To describe a pharmacovigilance surveillance initiative with edaravone to monitor patient characteristics, utilization (edaravone cycles and riluzole use), and safety and to evaluate safety/effectiveness. This propensity score-matched cohort study used data on 369 patients with documented definite or probable ALS in the Veterans Health Administration (VHA) with at least 1 prescription for edaravone between August 1, 2017, and September 30, 2019. The analysis compared edaravone (alone or with riluzole) with riluzole only. For chronic users (≥6 months of drug), a time-to-event model evaluated ALS-related outcomes, with censoring at outcome, death, or end of evaluation. Patients with Parkinson disease, dementia, schizophrenia, or significant respiratory insufficiency per diagnosis codes within 2 years before prescription initiation were excluded. In overall matched cohorts, 223 patients treated with edaravone were 1:3 propensity score matched based on predefined confounders. For the chronic user subgroup analysis, 96 patients receiving edaravone and 424 patients receiving riluzole only were included. Edaravone (alone or with riluzole) vs riluzole only. Patient characteristics, ALS drug use, and mortality. Acute outcomes (within 6 months of index) included proportion and mean time to event for death, discontinuation, or all-cause hospitalization, and outcomes for chronic users (receiving >6 months of treatment) included hazard ratios of outcomes related to disease-state progression. Of 369 patients who received edaravone, most were older (mean [SD] age, 64.6 [11.3] years), male (346 [93.8%]), and White (261 [70.7%]). As of September 2019, 59.9% of edaravone patients had discontinued treatment; of those, 49.5% (108 of 218) received only 1 to 3 treatment cycles. Approximately 30% (110 patients) died. In a matched evaluation, significantly more acute all-cause hospitalization events occurred with edaravone (35.4% vs 22.0% for riluzole only); 72.6% of the edaravone cohort received edaravone with riluzole. Among chronic users, edaravone patients (70.8% edaravone with riluzole) had an increased hazard ratio of ALS-associated hospitalization (2.51; 95% CI, 1.18-8.16). The death rate was lower with edaravone but the difference was not statistically significant. Early edaravone discontinuation was common in the VA. Although outcomes favored use of riluzole only in the matched analysis, results should be interpreted with caution, as unmeasured bias in observational data is likely.

OP0144 EFFECT OF TOCILIZUMAB ON VASCULAR INFLAMMATION BY 18F-FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY: A PROSPECTIVE, LONGITUDINAL STUDY

Background:Two randomized controlled trials have demonstrated clinical efficacy of tocilizumab for the treatment of giant cell arteritis (GCA)(1, 2). In these trials, clinical and laboratory measures were used to define the outcome measures. The direct effect of tocilizumab on vascular inflammation remains poorly characterized.Objectives:To prospectively evaluate vascular inflammation as measured by18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in a longitudinal cohort of patients with GCA treated with tocilizumab over a several year follow-up period.Methods:Patients with GCA were recruited into a prospective, observational cohort. All patients fulfilled modified 1990 American College of Rheumatology (ACR) Classification Criteria for GCA. All patients underwent FDG-PET computed tomography (CT) prior to initiation of tocilizumab. A single reader reviewed all PET scans, blinded to clinical data. Qualitative assessment of FDG uptake relative to liver uptake by visual assessment (scale 0-3) was assessed in 9 arterial territories. A summary score, PET Vascular Activity Score (PETVAS), was calculated (scale 0-27).Patients underwent imaging at 6-12 month intervals per a standardized imaging protocol. In a subset of patients in whom tocilizumab was discontinued due to established remission, a repeat FDG-PET scan was obtained within 6 months of drug discontinuation.Change in PET activity over time was measured by linear regression. PET activity during established remission was compared to PET activity after discontinuation of tocilizumab. For some patients, tocilizumab was added to the existing treatment regimen without a substantive change in concomitant glucocorticoid dose. In a secondary analysis, patients were stratified by prednisone dosing (high dose prednisone >10mg/day prednisone, low dose prednisone ≤10mg/day prednisone during the imaging interval) to determine if tocilizumab had an effect on vascular inflammation independent of glucocorticoids.Results:22 patients were included in the study. All patients had clinically active disease at baseline with median baseline PETVAS 24.5 (23-27). There was a significant reduction in PETVAS over 2 years follow up (p<0.01 for linear trend) (Figure). Of note, there was continued progressive improvement in PETVAS in both year 1 and year 2 of treatment. Eight patients received concomitant high dose glucocorticoids and 14 patients remained on low dose glucocorticoids with the addition of tocilizumab. In patients who only received low dose prednisone, significant reduction in PETVAS was still observed with addition of tocilizumab (PETVAS 25.5 to 19.5, p=0.04). In a subset of 5 patients who discontinued tocilizumab due to established remission [median PETVAS 19 (17.5-22) at time of remission], a repeat FDG-PET scan within 6 months after treatment discontinuation showed worsening PET activity in 4 out of 5 patients [median PETVAS 23 (20-23)]. Two of these patients subsequently experienced a clinical disease relapse.Conclusion:Tocilizumab was associated with improved vascular inflammation as assessed by FDG-PET. There was continued improvement of vascular inflammation at both year 1 and year 2 of treatment, and early evidence suggests a rebound of vascular inflammation when tocilizumab was discontinued. These data provide rationale for long-term tocilizumab therapy in patients with GCA and for consideration of FDG-PET as an outcome measure in future clinical trials.

PO-306 Identification of chromatin modifiers regulating temozolomide resistance in glioblastoma multiforme

IntroductionGlioblastoma multiforme (GBM) is the most common of all malignant brain tumours. Unfortunately, only 5.1% of patients survive five years post diagnosis. Therapy options for GBM patients are very limited, majority of the patients receive radiation therapy and the chemotherapeutic Temozolomide (TMZ). However, most tumours recur making therapy resistance an extremely important issue. Cancers show aberrant global epigenetic alterations, yet, the epigenetic mechanisms that cause therapy resistance are not well-known. In this project, the role of chromatin modifying proteins in TMZ-resistance is studied by a chemical screen.Material and methodsWe established TMZ resistant cell lines by two different methodologies, 1) dose escalation method and 2) high dose TMZ selection. For the dose escalation method, U373 cells were treated TMZ every two days, starting from 25 µM. Every two weeks, dosage was doubled (or when cells become resistant to that dosage) up to 250 µM. For high dose TMZ resistant selection, cells were treated with 250 µM TMZ for 15 days. Both cells lines have been kept under TMZ treatment for 3 months. To identify chemical inhibitors that target resistant cells, the TMZ-resistant cells and their parental controls were treated with a chemical library consisting of 90 epigenetic drugs against chromatin modifiers and cell viability was measured after 72 hours.Results and discussionsWe successfully generated isogenic subpopulations of GBM cell lines that are resistant to TMZ. We observed that the high dosage TMZ treatment regimen caused a more sustainable resistant cell line compared to dose escalation regimen. Both resistant cell line models were stable, as they did not depend on prolonged TMZ treatment and remained resistant to TMZ after 3 months of drug holiday.We then screened for epigenetic compounds that target TMZ-resistant cells. In addition to PARP inhibitors, Olaparib and Rucaparib, we identified Histone Deacetylase (HDAC) inhibitors as TMZ-sensitising agents. We are currently delineating the epigenetic alterations between parental and TMZ-resistant cells and assess the role of HDAC-mediated changes in TMZ-response by RNA-seq.ConclusionHistone acetylation and deacetylation are interesting focus areas in drug resistance because of the central role of these modifications in many aspects of cell physiology and pathology. In our screen, we have shown that various HDAC inhibitors can sensitise GBM cells to TMZ in established cells as well as our newly generated in acquired TMZ resistance models.

P081 The cost of cost-saving HIV drug switches in a small DGH HIV unit

IntroductionIn July 2016 NHSE circulated a letter regarding Commissioning for Value and antiretroviral drug switches. The letter noted that ‘These switches have been identified as not needing to recall patients...

Profiles of miRNAs in serum in severe acute drug induced liver injury and their prognostic significance.

Drug induced liver injury (DILI) is challenging because of the lack of biomarkers to predict mortality. Our aim was to describe miRNA changes in sera of subjects with acute idiosyncratic DILI and determine if levels of miRNAs were associated with 6month mortality. Clinical data and sera were collected from subjects enrolled in the Drug Induced Liver Injury Network prospective study. miRNAs were isolated from serum obtained from 78 subjects within 2weeks of acute DILI and followed up for 6months or longer. miRNAs were compared to 40 normal controls and 6month survivors vs non-survivors. The mean age of the DILI cohort was 48years, and 55% were female. Eleven (14.1%) subjects died, 10 within 6months of DILI onset, 5 (45%) liver related. Lower levels of miRNAs-122, -4463 and -4270 were associated with death within 6months (P<.05). None of the subjects with miRNA-122 greater than the median value died within 6months for a sensitivity of 100% and specificity of 57%. In subjects with a serum albumin <2.8g/dL and miR-122<7.89 RFU the sensitivity, specificity, positive and negative predictive values for death within 6months were 100%, 57%, 38% and 100% respectively. Serum miRNA-122 combined with albumin accurately identified subjects who died within 6months of drug induced liver injury. If confirmed prospectively, miRNA-122 and albumin may be useful in identifying patients at high risk for mortality or liver transplantation.

Real-Life Data and a Single Center Experience on Dasatinib-Induced Pulmonary Arterial Hypertension in Patients with Philadelphia Chromosome-Positive Leukemias

▪Background: Drug-induced pulmonary arterial hypertension (PAH) can be observed as an adverse event (AE) during the administration of dasatinib (DAS), which is a second generation tyrosine kinase inhibitor (TKI), used in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The occurence of DAS-induced PAH at a late onset in most of the cases suggests a chronic pathological mechanism rather than an acute inflammatory or cardiac etiology. The treatment strategies of DAS-induced PAH include the cessation of the drug and PAH-specific therapies.Aim: The aim of the study was to evaluate the frequency, clinical features, management strategies and outcomes of patients with DAS-induced PAH among a cohort consisted of CML and Ph+ ALL patients who had received DAS as a salvage treatment after imatinib (IM) failure or intolerance.Patients and Methods: Forty patients with Ph+ leukemias who received second-line DAS were enrolled. Patients' demographics, Sokal risk scores, molecular and cytogenetic responses, comorbidities [including preexisting cardiac disease, renal insufficiency, hypertension and chronic obstructive pulmonary disease (COPD)], DAS dose, dosing intervals and treatment durations, durations of IM therapy prior to DAS, and if any, treatments prior to IM (interferon (IFN), cytarabine (Ara-C), and hydroxyurea (HU)) and follow-up periods were noted retrospectively. TKI response criteria were based on the recommendations of European LeukemiaNet, and the definitions of the CML phases and responses were as described elsewhere.Results: Twenty-four patients were male, and the median age was 45 years (range, 18-81 years). There were 39 patients with CML and one with Ph+ ALL. Among the thirty-nine CML patients, 3 were in accelerated phase (CML-AP), two with blast crisis (CML-BC), and the rest were in chronic phase (CML-CP). The percentanges of low, intermediate, and high Sokal risk scores were 46%, 33%, and 21%, respectively. Thirteen patients received only IM prior to DAS, whereas the others had used HU, IFN and Ara-C prior to IM. After a median duration of 41.5 months (range, 1-93 months) of IM, the reason for switching to DAS were IM failure and intolerance in 37 and 3 patients, respectively. DAS was administered with a median of 50 months (range, 2-78 months). During DAS treatment hematological AEs were observed in 6 patients, whereas in twenty-one pulmonary complications including exacerbation of COPD and pneumonia (n=1), pleuro/pericaridal effusions (n=19), PAH (n=5) and gastrointestinal bleeding (n=1) were detected. DAS therapy was ceased in 13 patients, of which ten were switched to nilotinib (NIL) due to AEs (n=7) and failure (n=3). Also, two patients received cytotoxic treatment due to BC and one had allogeneic hematopoietic stem cell transplantation (allo-HSCT).Five patients (12.5%) had DAS-induced PAH (Table 1). Four of them were in CML-CP at diagnosis, and one was in CML-AP. All cases received DAS due to IM failure. At the time of DAS initiation, 4 cases were in CML-CP and one in CML-BC. PAH was diagnosed by transthoracic echocardiography (TTE) in 3 patients, and by right heart catheterization (RHC) in 2, and it was observed after a median of 8 months (range, 2-25 months) of DAS. Three patients had accompanying pleuro/pericardial effusions. All patients with DAS-induced PAH were alive at the time of the analysis, and the management of PAH included dose reduction in two, and DAS was switched to NIL in 2 cases and allo-HSCT was performed in one.Conclusion: DAS-induced PAH seems to be reversible with the cessation and/or modification of DAS ± PAH-specific treatments. As pulmonary vascular toxicity related to DAS is thought to be molecule-related rather than class-related, it seems reasonable to switch to another TKI. The patients in our cohort had good responses to dose modification and drug cessation and none received PAH-specific therapy. Although DAS-induced PAH is mainly defined as a late complication, we detected that PAH can be observed even after 2 months of drug exposure.PAH can be observed during DAS treatment and physicians should be aware of this AE. Routine cardiopulmonary evaluation prior to and/or during DAS may be beneficial. Mechanisms under this pathological condition, preceding and prognostic factors, and treatment strategies are needed to be evaluated with prospective trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Trends in clinical development timeframes for antiviral drugs launched in the UK, 1981–2014: a retrospective observational study

ObjectivesRecent decades have witnessed the development of highly innovative new antiviral drug therapies. However, there are concerns that rising costs and lengthening development times could have implications for future patient...

Relative exposure to controller therapy and asthma exacerbations: a validation study in community pharmacies.

"Controllers-to-total asthma drug" ratios computed from claims data identify asthmatics at risk of exacerbations. Direct link of ratios to data obtained from patients, such as control and recent outcomes, would facilitate their interpretation. We studied the relationship between R1 ratio (inhaled corticosteroids (ICS)/total anti-asthma drug ratio) and the Asthma Control Test. Comparisons were also conducted for secondary outcomes (asthma-related hospital contacts, monthly medical contacts, use of oral corticosteroids, and perception of disease burden). Results with R1 ratio were compared with those obtained with a second ratio, "ICS-plus-leukotriene receptor antagonist/total asthma drug" (R2 = ICS + leukotriene receptor antagonist/total anti-asthma drugs). A survey was conducted in community pharmacies. Patients visiting with a prescription of anti-asthma drug and ≥12 months of drug dispensing recorded in the pharmacy were consecutively recruited. Dispensing data were linked to patient-reported outcomes. Asthma control and secondary outcomes were compared for both ratios between low-controller-ratio (R < 50%) and high-controller-ratio groups (R ≥ 50%), after excluding null values. Of the 919 eligible patients (mean age 37 years, 55% women), 90.2% and 92.4% had non-null values for R1 and R2, respectively. Compared with the low-controller-ratio groups, adjusted risks of being uncontrolled were significantly lower in the high-controller-ratio groups (RR = 0.64, 95%CI [0.54, 0.77] and RR = 0.57, 95%CI [0.47, 0.70], for R1 and R2 ratios, respectively). Likewise, fewer patients with secondary outcomes were observed in the high-controller-ratio groups, for both ratios. Asthma was better controlled among patients with high controller ratios, along with fewer asthma-related outcomes, for both R1 and R2 ratios. This confirms the utility of asthma/drug ratios in identifying patients at risk of exacerbations, notably in claims data.

Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014.

The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or 'mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.

Less Education Predicts Anticholinesterase Discontinuation in Dementia Patients

We investigated patient socio-demographic, clinical and functional factors predicting cholinesterase inhibitor discontinuation by patients presenting to a memory clinic in Saskatoon, Saskatchewan. Data collection began in March 2004 at the Rural and Remote Memory Clinic where family physicians referred their non-institutionalized patients. Neurological and neuropsychological assessment, patient and caregiver questionnaires provided the socio-demographic, clinical and functional variables. Univariate logistic regression analysis was used to examine possible associations between each independent variable and the binary outcome variable of treatment discontinuation. Multivariate logistic regression was used to determine predictors of cholinesterase inhibitor discontinuation within six months of drug initiation. Our sample consisted of the first 63 patients (60.3% female) for whom we prescribed a cholinesterase inhibitor. The mean age at clinic day was 74.56 years (SD=7.78). We found that years of formal education was the only variable significantly associated with cholinesterase inhibitor discontinuation by six months. The more years of formal education, the lower the rate of drug discontinuation by six months. Likelihood of cholinesterase inhibitor discontinuation by six months was predicted by fewer years of formal education.

Maternal Antiretroviral Therapy for the Prevention of Mother-To-Child Transmission of HIV in Malawi: Maternal and Infant Outcomes Two Years after Delivery

BackgroundOptimized preventive strategies are needed to reach the objective of eliminating pediatric AIDS. This study aimed to define the determinants of residual HIV transmission in the context of maternal antiretroviral therapy (ART) administration to pregnant women, to assess infant safety of this strategy, and to evaluate its impact on maternal disease.Methodology/Principal FindingsA total of 311 HIV-infected pregnant women were enrolled in Malawi in an observational study and received a nevirapine-based regimen from week 25 of gestation until 6 months after delivery (end of breastfeeding period) if their CD4+ count was > 350/mm3 at baseline (n = 147), or indefinitely if they met the criteria for treatment (n. 164). Mother/child pairs were followed until 2 years after delivery. The Kaplan-Meier method was used to estimate HIV transmission, maternal disease progression, and survival at 24 months. The rate of HIV infant infection was 3.2% [95% confidence intervals (CI) 1.0-5.4]. Six of the 8 transmissions occurred among mothers with baseline CD4+ count > 350/mm3. HIV-free survival of children was 85.8% (95% CI 81.4-90.1). Children born to mothers with baseline CD4+ count < 350/mm3 were at increased risk of death (hazard ratio 2.6, 95% CI 1.1-6.1). Among women who had stopped treatment the risk of progression to CD4+ count < 350/mm3 was 20.6% (95% CI 9.2-31.9) by 18 months of drug discontinuation.ConclusionsHIV transmission in this cohort was rare however, it occurred in a significative proportion among women with high CD4+ counts. Strategies to improve treatment adherence should be implemented to further reduce HIV transmission. Mortality in the uninfected exposed children was the major determinant of HIV-free survival and was associated to maternal disease stage. Given the considerable proportion of women reaching the criteria for treatment within 18 months of drug discontinuation, life-long ART administration to HIV-infected women should be considered.

PTH-079 Thiopurine Withdrawal for Sustained Remission in IBD: A UK Multicentre Study

IntroductionThiopurine therapy is effective in maintaining clinical remission in IBD. However, long-term therapy is associated with an increased risk of lymphoma; therefore in clinical practise it may be appropriate to...

Relative importance of attributes of drug benefit plans: Thai civil servants' perspective

The drug benefit plan of Thailand's Civil Servant Medical Benefit Scheme (CSMBS) must be amended to control increasing costs; to that end, it is important to gather the views of beneficiaries before making changes to the benefit plan. To examine the relative importance of attributes of drug benefit plans from the perspective of CSMBS beneficiaries. Attributes and levels adopted from focus group discussions and a preliminary survey were used to develop a questionnaire concerning hypothetical drug benefit plans. A convenience sample of 650 CSMBS beneficiaries in Songkhla province was asked to rate the drug benefit plans. To determine the beneficiaries' decision models, judgment analysis was used. Policy-capturing analysis was used to examine the beneficiaries' preferences, and cluster analysis was conducted to explore the variability among judgment plans. Judgment policy insight was also examined. The results of the study showed that the beneficiaries weighed on cost-sharing as their most important attribute. The results remained unchanged, although only data from the beneficiaries who used the compensatory model were analyzed. The results of the cluster analysis showed that the largest cluster of beneficiaries weighed mostly on the cost-sharing attribute. The judgment policy insight results not only supported the finding that most beneficiaries focused on the cost-sharing attribute but also revealed that they might have the least understanding of how the formulary attribute affected beneficiaries' decision making. Cost-sharing was the most important attribute for the CSMBS beneficiaries. This study indicated that a possible preferred drug benefit plan should have no cost-sharing, permit access only to drugs listed in a closed formulary, allow beneficiaries to obtain 3 months of drugs, and allow them to obtain drugs from either a community pharmacy or a government hospital.

Liraglutide withdrawal rates: ‘real world’ practice

AbstractImportant side effects and potential clinical hazards have emerged from long‐term follow up in some drug classes used in type 2 diabetes treatment. Systematic phase 4 post‐marketing data in early use of newer diabetes drugs may have a role in informing drug choice in practice and assist in pharmacoeconomic assessments of these drug choices.We carried out a comparison of the prevalence of drug withdrawals derived from both liraglutide registration trial data, and a systematic, prospective case‐note review of all new liraglutide prescriptions (n=176) from a specialist diabetes clinic over the first 12 months of drug introduction.Trial data used for the marketing authorisation application for liraglutide reported 7.0% withdrawal due to adverse events. Equal numbers of patients experienced mild, moderate and severe side effects. By contrast, data derived from a ‘real world’ clinical group describe 14.8% withdrawal due to adverse events, with withdrawal typically occurring early, by three months. Adverse events were more frequently responsible for treatment withdrawal at lower, compared to higher, doses of liraglutide therapy.Systematic observations of withdrawals in early use of new drugs in current clinical practice are higher than reported in registration trial data. These data highlight that post‐marketing surveillance should inform guideline recommendations and pharmacoeconomic evaluations. Copyright © 2012 John Wiley &amp; Sons.

Cardiac, Neuroadrenergic, and Portal Hemodynamic Effects of Prolonged Aldosterone Blockade in Postviral Child A Cirrhosis

The present study was designed to determine the effects of long-term antialdosterone treatment on cardiac structural and functional alterations, portal and systemic hemodynamic as well as adrenergic dysfunction characterizing Child A cirrhotic patients with F1 esophageal varices. Twenty-two Child A postviral preascitic cirrhotic patients were randomly allocated to 200 mg/day K-Canrenoate (13 patients, age 59.6 +/- 2.2 yr, mean + SEM) or no-drug treatment (9 patients, age 61.8 +/- 2.3) for a 6-month-period. Measurements, which included hepatic venous pressure gradient (HVPG), left ventricular wall thickness, left ventricular end-diastolic volume and diastolic function (LVWT, LVEDV, and E/A ratio, echocardiography), and muscle sympathetic nerve activity (MSNA, microneurography, peroneal nerve), were obtained at baseline and following 6 months of drug or no-drug treatment. Ten healthy age-matched subjects served as controls. Cirrhotic patients were characterized by increased HVPG, LVWT, and MSNA values and by a depressed E/A ratio. K-Canrenoate treatment significantly reduced HVPG (from 15.3 +/- 1.0 to 13.8 +/- 0.8 mmHg, p < 0.05), LVWT (from 21.8 +/- 0.5 to 20.7 +/- 0.6 mm, p < 0.02), and LVEDV (from 99.2 +/- 7 to 86.4 +/- 6 ml, p < 0.01), leaving E/A ratio and MSNA almost unaltered. No significant change was observed in the untreated group of cirrhotic patients followed for 6 months without intervention. These data provide evidence that aldosterone blockade by long-term K-Canrenoate administration improves hepatic hemodynamics by lowering HVPG and ameliorates cardiac structure and function by favoring a reduction in LVWT and LVEDV as well. They also show, however, that this therapeutic intervention neither improves left ventricular diastolic dysfunction nor exerts sympathoinhibitory effects.

The efficacy of Liv-52 on liver cirrhotic patients: A randomized, double-blind, placebo-controlled first approach

Cirrhosis is the irreversible sequel of various disorders that damage liver cells permanently over time. Presently, the use of herbal medicines for prevention and control of chronic liver diseases is in the focus of attention for both the physicians and the patients; the reasons for such shift toward the use of herbals include the expensive cost of conventional drugs, adverse drug reactions, and their inefficacy. In the present study, the efficacy of herbal medicine Liv-52 (consisting of Mandur basma, Tamarix gallica and herbal extracts of Capparis spinosa, Cichorium intybus, Solanum nigrum, Terminalia arjuna and Achillea millefolium) on liver cirrhosis outcomes was compared with the placebo for 6 months in 36 cirrhotic patients referred to Tehran Hepatic Center. The outcome measures included child-pugh score, ascites, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total billirubin, albumin, prothrombin time, platelet and white blood cells counts. The indices were recorded in all patients before and after 6 months of drug or placebo treatment. The results demonstrated that the patients treated with Liv-52 for 6 months had significantly better child-pugh score, decreased ascites, decreased serum ALT and AST. In placebo administered patients all the clinical parameters recorded at beginning of the study were not significantly different than after 6 months. We conclude that Liv-52 possess hepatoprotective effect in cirrhotic patients. This protective effect of Liv-52 can be attributed to the diuretic, anti-inflammatory, anti-oxidative, and immunomodulating properties of the component herbs.

Implantable technology for long-term delivery of nalmefene for treatment of alcoholism

Pharmacotherapy treatment for alcoholism is limited by poor compliance, adverse effects, and fluctuating drug levels after bolus administration. A long-term delivery system would improve upon these limitations. The current study describes the characterization of a sustained release implant containing nalmefene, an opioid antagonist, for treatment of alcoholism. Nalmefene was blended with ethylene vinyl acetate (EVA), extruded into 2.8 mm × 27 mm rods, and coated with EVA to optimize release. In vitro release was determined by HPLC, and in vivo release characteristics after subcutaneous implantation into rats were determined by LC–MS/MS analyses. Extrusion produced rods containing 80.09 ± 6.0 mg nalmefene. In vitro release was high from the uncoated rods, and they were depleted of drug fairly quickly; however EVA coatings maintained release over longer periods. The 25 wt.% coated rods provided in vitro release of 0.36 mg/day/rod, and in vivo release of 0.29 mg/day/rod over 6 months, and showed dose-dependent nalmefene plasma concentrations (one rod: 3.33 ± 0.56 ng/ml, three rods: 10.19 ± 2.31 ng/ml). After explantation, nalmefene plasma concentrations were undetectable by 6 h. A sustained release nalmefene rod provides 6 months of drug with no adverse effects.

Striatal Volume Changes in the Rat Following Long-term Administration of Typical and Atypical Antipsychotic Drugs

Striatal enlargement has been consistently reported in schizophrenics receiving chronic neuroleptic treatment although the results following atypical antipsychotic treatment have been equivocal. In order to disentangle patient illness from a possible drug effect on brain structure, young adult rats were administered either haloperidol, risperidone, clozapine, olanzapine, or vehicle daily for four or eight months via drinking water. Significant increases in caudate-putamen volumes were seen in animals receiving either haloperidol or clozapine when compared with control animals following eight months of drug administration. Conversely, olanzapine-treated animals showed significant decreases in caudate-putamen volumes when compared with control animals after eight months of drug. Thus, converging evidence indicates that the neuroplastic response of the striatum following neuroleptic exposure causes volumetric increases, whereas atypical antipsychotics affect the basal ganglia differentially. The current data suggests that such differential responses may be due to both the pharmacological properties and the relative doses of the atypical agents.