Consideration Of Adverse Effects Research Articles

Escitalopram population pharmacokinetics and remedial strategies based on CYP2C19 phenotype

Background and purposeCYP2C19 is a key factor influencing escitalopram (SCIT) exposure. However, different studies reported various results. This study aims to develop a population pharmacokinetic (popPK) model characterizes the disposition of SCIT in the Chinese population. Based on the popPK model, the study simulates non-adherence scenarios and proposes remedial strategies to facilitate SCIT personalized therapy. MethodsNonlinear mixed-effects modeling using data from two Chinese bioequivalence studies was employed. Monte-Carlo simulation was used to explore non-adherence scenarios and propose remedial strategies based on the proportion of time within the therapeutic window. ResultsResults showed that a one-compartment model with transit absorption and linear elimination described the data well, CYP2C19 phenotypes and weight were identified as significant covariates impacting SCIT exposure. Patients were recommended to take the entire delayed dose immediately if the delay time was no >12 h, followed by the regular regimen at the next scheduled time. When there is one or two doses missed, taking a double dose immediately was recommended to the CYP2C19 intermediate and extensive population, and a 1.5-fold dose was recommended to the CYP2C19 poor metabolizers with the consideration of adverse effects. LimitationAll samples were derived from the homogenized Chinese healthy population for model building, which may pose certain constraints on the ability to identify significant covariates, such as age. ConclusionThe study highlights the importance of considering patient characteristics for personalized medication and offers a unique perspective on utilizing the popPK repository in precision dosing.

75-Year-Old Woman With Chest Pain and Shortness of Breath

75-Year-Old Woman With Chest Pain and Shortness of Breath

Review of Cyclin-Dependent Kinase 4/6 Inhibitors for the Treatment of Hormone Receptor-Positive Advanced Breast Cancer.

To evaluate the existing literature regarding the use of cyclin-dependent kinase (CDK) 4/6 inhibitors in the treatment of hormone receptor-positive advanced breast cancer (ABC). A search of the medical literature was performed using PubMed (2014 to June 2018). Search terms included cyclin-dependent kinase, CDK, breast cancer, palbociclib, ribociclib, abemaciclib, PD0332991, LEE011, and LY2835219. Clinicaltrials.gov was also searched. Trials with clinical efficacy outcomes evaluating CDK 4/6 inhibitors in the treatment of advanced hormone-positive breast cancer were considered. Palbociclib, abemaciclib, and ribociclib each demonstrated significant benefit when combined with an aromatase inhibitor, the benefit to patients was similar for each, with an improvement of 42% to 51% in median progression-free survival (PFS). In combination with fulvestrant, CDK 4/6 inhibitors used for the treatment of hormone receptor-positive ABC resulted in a 43% to 58% improvement in median PFS versus fulvestrant alone. CDK inhibitors are relatively well tolerated; however, discontinuation as a result of adverse effects was highest with abemaciclib. Relevance to Patient Care and Clinical Practice: This review considers the use of the 3 commercially available CDK 4/6 inhibitors for treatment of hormone receptor-positive breast cancer, including data on each of the 3 agents in newly advanced and treatment refractory disease. The CDK inhibitors should be used in combination with endocrine therapies for the treatment of ABC. Efficacy of the 3 agents is similar. Selection within the class should include consideration of adverse effects and drug interactions.

Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta-analysis

IntroductionGabapentin has been extensively prescribed off-label for psychiatric indications, with little established evidence of efficacy. Gabapentin and pregabalin, a very similar drug with the same mechanism of action, bind to...

Payer Perspective of the American Academy of Sleep Medicine Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia

Payer Perspective of the American Academy of Sleep Medicine Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia

Year in review 2011: Asthma, chronic obstructive pulmonary disease and airway biology

1UBC James Hogg Research Centre, Institute for Heart + Lung Health, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada, 2The Prince Charles Hospital and The University of Queensland, Brisbane, Queensland, Australia, 3Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, and 4Department of Medicine, National University Hospital, Singapore, Singapore

Interferon therapy following treatment of recurrent hepatocellular carcinoma in an 83-year-old man with hepatitis C virus-related liver cirrhosis.

A sustained virological response and improvement of liver function were achieved by low-dose interferon (IFN) therapy following curative treatment of initial and recurrent hepatocellular carcinoma (HCC) in an 83-year-old man with hepatitis C virus (HCV)-related liver cirrhosis (CLC). Although a fourth HCC episode recurred 16months after IFN therapy, it was successfully treated. The patient is still alive 6years and 7months after diagnosis of the initial HCC and has been in a tumor-free state for 19months following treatment of the last HCC. The results of this case suggest that, given sufficient consideration of adverse effects, IFN therapy for HCV and repeated local treatment for HCC contribute to improving the prognosis even in the case of a CLC patient over 80years of age whose condition is complicated by recurrent HCC.

Are adverse effects incorporated in economic models? A survey of current practice

Clearly the benefits of a treatment must not be outweighed by the adverse effects. If researchers fail to incorporate adverse effects adequately in models, this could limit the validity of the results obtained. In the worst case, interventions that are cost-effective may be shown not to be. The aim of this research was to review current practice when incorporating adverse effects in economic models. A survey of HTA reports commissioned by the National Institute for Health Research (NIHR) Health Technology Assessment programme, published between 2004 and 2007 was conducted. All reports which investigated the clinical and cost-effectiveness of a health technology using a systematic review and an economic model framework were included. A total of eighty reports met the inclusion criteria. Of the models including adverse effects (43/80), 67 percent used a clinical adverse effects parameter, 79 percent a cost of adverse effects parameter, 86 percent used one of these, and 60 percent used both. Of the thirty-seven models that did not include adverse effects, eighteen justified this omission, most commonly lack of data; nineteen appeared to make no explicit consideration of adverse effects in the model. In many cases, poor reporting made it difficult to ascertain if there had been any consideration of adverse effects. We suggest that the findings of this survey support a call for much clearer and explicit reporting of adverse effects, or their exclusion, in decision models and for explicit recognition in future guidelines that "all relevant outcomes" should include some consideration of adverse events.

Are adverse effects incorporated in economic models? An initial review of current practice

To identify methodological research on the incorporation of adverse effects in economic models and to review current practice. Major electronic databases (Cochrane Methodology Register, Health Economic Evaluations Database, NHS Economic Evaluation Database, EconLit, EMBASE, Health Management Information Consortium, IDEAS, MEDLINE and Science Citation Index) were searched from inception to September 2007. Health technology assessment (HTA) reports commissioned by the National Institute for Health Research (NIHR) HTA programme and published between 2004 and 2007 were also reviewed. The reviews of methodological research on the inclusion of adverse effects in decision models and of current practice were carried out according to standard methods. Data were summarised in a narrative synthesis. Of the 719 potentially relevant references in the methodological research review, five met the inclusion criteria; however, they contained little information of direct relevance to the incorporation of adverse effects in models. Of the 194 HTA monographs published from 2004 to 2007, 80 were reviewed, covering a range of research and therapeutic areas. In total, 85% of the reports included adverse effects in the clinical effectiveness review and 54% of the decision models included adverse effects in the model; 49% included adverse effects in the clinical review and model. The link between adverse effects in the clinical review and model was generally weak; only 3/80 (< 4%) used the results of a meta-analysis from the systematic review of clinical effectiveness and none used only data from the review without further manipulation. Of the models including adverse effects, 67% used a clinical adverse effects parameter, 79% used a cost of adverse effects parameter, 86% used one of these and 60% used both. Most models (83%) used utilities, but only two (2.5%) used solely utilities to incorporate adverse effects and were explicit that the utility captured relevant adverse effects; 53% of those models that included utilities derived them from patients on treatment and could therefore be interpreted as capturing adverse effects. In total, 30% of the models that included adverse effects used withdrawals related to drug toxicity and therefore might be interpreted as using withdrawals to capture adverse effects, but this was explicitly stated in only three reports. Of the 37 models that did not include adverse effects, 18 provided justification for this omission, most commonly lack of data; 19 appeared to make no explicit consideration of adverse effects in the model. There is an implicit assumption within modelling guidance that adverse effects are very important but there is a lack of clarity regarding how they should be dealt with and considered in modelling. In many cases a lack of clear reporting in the HTAs made it extremely difficult to ascertain what had actually been carried out in consideration of adverse effects. The main recommendation is for much clearer and explicit reporting of adverse effects, or their exclusion, in decision models and for explicit recognition in future guidelines that 'all relevant outcomes' should include some consideration of adverse events.

Advances in Diabetes Therapy in the Elderly

Diabetes is increasing in prevalence and the choice of medication is expanding with the recent introduction of a new class of oral hypoglycaemics. Emerging data on the older oral hypoglycaemics is adding to the complexity of diabetes management, particularly in the elderly for whom special consideration of adverse effects and dosing are required. As diabetes progresses the inevitable decline in pancreatic β‐cell function diminishes the efficacy of the oral hypoglycaemics and insulin is required. The new synthetic long‐acting insulin analogues are useful in the elderly both for ease of administration and to minimise hypoglycaemia. Exogenous insulin often does not provide optimal control of diabetes and it is envisioned that in the future, therapy may target preservation of pancreatic β‐cell function to produce long‐term glycaemic control with endogenous insulin.

Consensus Guidelines: Treatment Planning and Options

Despite the number of patients affected by diabetic peripheral neuropathic pain (DPNP), little consensus exists about the pathophysiology, best diagnostic tools, and primary treatment choices. Theories about the causes of DPNP are inextricably linked with the causes of diabetic neuropathles, yet most patients with such neuropathies do not experience pain. The factors that differentiate patients with pain from those without remain unknown and are the subject of much research. When choosing treatment for patients with DPNP, physicians are confronted with a myriad of choices, none of which has been shown to be effective for all patients. This article reviews the evidence for these treatments and attempts to guide physicians in choosing those treatments based on evidence from well-designed clinical trials to support their use. Two agents, duloxetine and pregabalin, are formally approved by the Food and Drug Administration for the treatment of DPNP. In addition, several other agents, including the tricyclic class of antidepressants, have been effective in clinical trials. Ultimately, treatment choice must also Include consideration of adverse effects, individual patient factors such as comorbidities, and often cost.

U.S. Food and Drug Administration perspective of the inclusion of effects of low-level exposures in safety and risk assessment.

A brief overview is provided of some of the general safety and risk assessment procedures used by the different centers of the U.S. Food and Drug Administration (U.S. FDA) to evaluate low-level exposures. The U.S. FDA protects public health by regulating a wide variety of consumer products including foods, human and animal drugs, biologics, and medical devices under the federal Food, Drug, and Cosmetic Act. The diverse legal and regulatory standards in the act allow for the consideration of benefits for some products (e.g., drugs) but preclude them from others (e.g., food additives). When not precluded by statutory mandates (e.g., Delaney prohibition), the U.S. FDA considers both physiologic adaptive responses and beneficial effects. For the basic safety assessment paradigm as presently used, for example in the premarket approval of food additives, the emphasis is on the identification of adverse effects and no observed adverse effect level(s) (NOAEL). Generally, the NOAEL is divided by safety factors to establish an acceptable exposure level. This safety assessment paradigm does not preclude the consideration of effects whether they are biologically adaptive or beneficial at lower dose levels. The flexibility to consider issues such as mechanisms of action and adaptive and beneficial responses depends on the product under consideration. For carcinogenic contaminants and radiation from medical devices, the U.S. FDA considers the potential cancer risk at low exposure levels. This generally involves downward extrapolation from the observed dose-response range. The consideration of adverse effects of other toxicologic end points (e.g., reproductive, immunologic, neurologic, developmental) associated with low exposure levels is also becoming more of a reality (e.g., endocrine disrupters). The evaluation of the biologic effects of low-level exposures to toxic substances must include whether the effect is adverse or a normal physiologic adaptive response and also determine the resiliency of a physiologic system. The public health mandate of the U.S. FDA includes an active research program at the National Center for Toxicological Research and the other U.S. FDA centers to support the regulatory mission of the U.S. FDA. This includes the development of knowledge bases, predictive strategies, and toxicologic studies to investigate effects at the lower end of the dose-response range. Because of the wide diversity of legal and regulatory standards for various products regulated by the U.S. FDA agency-wide safety and risk assessment procedures and policies generally do not exist.

Epidemiology, etiology, diagnosis, and treatment of schizophrenia

The epidemiology, etiology, diagnosis, and treatment of schizophrenia are reviewed. In the United States, at least 1 in every 100 persons is afflicted with schizophrenia. The theory that schizophrenia is a biochemical disorder has gained wide acceptance, although none of the etiological theories are conclusive. Criteria contained in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, are most commonly used to diagnose schizophrenia. Accuracy in diagnosing schizophrenia is critical because the treatments and prognoses for different types of psychoses can vary considerably. Treatment primarily involves the use of antipsychotic drugs, which are thought to act by blocking central dopamine receptors. The classical antipsychotics are the phenothiazines; of these, the prototype is chlorpromazine. Other classes of antipsychotics are the thioxanthenes, butyrophenones, dihydroindolones, dibenzoxazepines, diphenylbutylpiperidines, and dibenzodiazepines. Selecting an appropriate agent involves consideration of adverse effects, dosage forms, and the agent's ability to relieve target symptoms. Adverse effects of these agents include sedation, extrapyramidal effects, and anticholinergic effects. Tardive dyskinesia is a serious, irreversible condition associated with long-term antipsychotic therapy. Clozapine, a newer atypical antipsychotic, has been shown to be more effective than chlorpromazine and haloperidol and seems to cause few neurological adverse effects. Treatment of schizophrenia has not changed much since the advent of antipsychotic drug use nearly 30 years ago. Newer atypical antipsychotics show promise in improving target symptoms while causing fewer adverse effects.