United States Federal Drug Administration Research Articles

Biophysical Insights into the Inhibitory Mechanism of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors.

HIV-1 reverse transcriptase (RT) plays a central role in HIV infection. Current United States Federal Drug Administration (USFDA)-approved antiretroviral therapies can include one of five approved non-nucleoside RT inhibitors (NNRTIs), which are potent inhibitors of RT activity. Despite their crucial clinical role in treating and preventing HIV-1 infection, their mechanism of action remains elusive. In this review, we introduce RT and highlight major advances from experimental and computational biophysical experiments toward an understanding of RT function and the inhibitory mechanism(s) of NNRTIs.

An Overview of PET Neuroimaging

Over the past 35 years or so, PET brain imaging has allowed powerful and unique insights into brain function under normal conditions and in disease states. Initially, as PET instrumentation continued to develop, studies were focused on brain perfusion and glucose metabolism. This permitted refinement of brain imaging for important, non-oncologic clinical indications. The ability of PET to not only provide spatial localization of metabolic changes but also to accurately and consistently quantify their distribution proved valuable for applications in the clinical setting. Specifically, glucose metabolism brain imaging using (F-18) fluorodeoxyglucose continues to be invaluable for evaluating patients with intractable seizures for identifying seizure foci and operative planning. Cerebral glucose metabolism also contributes to diagnosis of neurodegenerative diseases that cause dementia. Alzheimer disease, dementia with Lewy bodies, and the several variants of frontotemporal lobar degeneration have differing typical patterns of hypometabolism. In Alzheimer disease, hypometabolism has furthermore been associated with poorer cognitive performance and ensuing cognitive and functional decline. As the field of radiochemistry evolved, novel radioligands including radiolabeled flumazenil, dopamine transporter ligands, nicotine receptor ligands, and others have allowed for further understanding of molecular changes in the brain associated with various diseases. Recently, PET brain imaging reached another milestone with the approval of (F-18) florbetapir imaging by the United States Federal Drug Administration for detection of amyloid plaque accumulation in brain, the major histopathologic hallmark of Alzheimer disease, and efforts have been made to define the clinical role of this imaging agent in the setting of the currently limited treatment options. Hopefully, this represents the first of many new radiopharmaceuticals that would allow improved diagnostic and prognostic information in these and other clinical applications, including Parkinson disease and traumatic brain injury.

Clinical Trial Registration

As editor of Operative Dentistry, one of my driving motivators is a desire to maintain the journal's stature as an upper echelon dental journal. In an ever-changing publishing world, required decisions go far beyond whether or not a given manuscript should be accepted for publication. For instance, our editorial staff considers recommendations made by the International Committee of Medical Journal Editors (ICMJE), an organization that outlines ethical principles and other publication guidelines for authors and editors in the health sciences.In recent years, the ICMJE has advocated for the registration of all randomized clinical trials in searchable electronic databases available to the public at no cost.1 Because there is no peer review mechanism associated with the registry, these databases hold information concerning the protocols but exclude the results of the trials. One reason for this suggested policy is the belief that a greater level of transparency will enhance the likelihood that a trial will be completed as planned and therefore increases the reliability of the evidence that the trial provides. A description of the required information for the database is included in the United States Federal Drug Administration Amendments Act of 2007.2As with many such initiatives that touch multiple complex issues, this registry has proven to be controversial largely because it makes public, on a broad scale, the path of investigation that a particular research team is taking. In dentistry, many of these trials involve products that do not have patent protection because of their similarity to other existing products. Utilizing a public registry prospectively, before recruiting subjects, could arguably hinder a potential market advantage for dental manufacturers. Of note, the registry guidelines specifically state that feasibility or pilot studies are not intended to be covered. Rather, only larger efficacy studies that carry more clinical relevance for the public are targeted. On the positive side, registering randomized clinical trials provides an additional level of oversight to the appropriate conduct and reporting of the work. These clinical trials are designed to answer specific questions. Registered trials could assist editors and reviewers in discerning whether the aims of a trial were met or whether, retrospectively, data was manipulated or omitted in order to provide a positive result.3At a recent Chicago meeting of journal editors and other interested parties, several journals (including the Journal of Dental Research, the Journal of the American Dental Association and the Journal of Periodontology) made it known that they have instituted a registration requirement. At least one journal is requiring registration, but not prospectively. But, it was clear that not all journals were excited about moving in this direction.One hundred seventy-four dental publications are included in the PubMed/Medline's National Library of Medicine Catalog4 and the American Dental Association holds over 600 journal titles in its library.5 Each of these publications must make a decision about whether it is important for them to require this registration and I fully expect that there will be some who will opt out. Thus, clinical trial registration will become another factor that differentiates our dental publications. I believe that Operative Dentistry must continue to be a reliable source of the best available evidence for decisions regarding oral health. It seems to me that focusing on a high level of credibility in today's world of multiple information sources would uphold the reputation of this journal for the members of its supporting academies.Moving forward, authors submitting to Operative Dentistry will be asked to provide registration information that our editors, reviewers, and staff can validate. (This registration will be in addition to the requirement of providing appropriate approval from a human subjects oversight committee given prospectively for any study using human subjects or tissues.) Completion of the registration process is a fairly innocuous task and can happen on any publically accessible database such as NIHClinicalTrials.gov. More specific instructions will be included in the journal's instructions to authors.It is my hope that clinical trial registration will help keep this journal, and thus our sponsoring Academies, recognized as desiring to provide optimal care for the people we serve. I am grateful for the many researchers around the world who contribute to our quest for knowledge, no matter whether they work in the private or public sector. I look forward to continuing to publish the best of that work.

Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness.

Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug’s efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically-oriented drug information sources (ClinicalTrials.gov, the National Drug File – Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug-drug interaction claims linked to the Drug Interactions section for a drug were potentially novel. The baseline performance characteristics of the proof-of-concept will enable further technical and user-centered research on robust methods for scaling the approach to the many thousands of product labels currently on the market.

Primary and Comprehensive Stroke Centers: History, Value and Certification Criteria

In the United States (US) stroke care has undergone a remarkable transformation in the past decades at several levels. At the clinical level, randomized trials have paved the way for many new stroke preventives, and recently, several new mechanical clot retrieval devices for acute stroke treatment have been cleared for use in practice by the US Federal Drug Administration. Furthermore, in the mid 1990s we witnessed regulatory approval of intravenous recombinant tissue plasminogen activator for administration in acute ischemic stroke. In the domain of organization of medical care and delivery of health services, stroke has transitioned from a disease dominated by neurologic consultation services only to one managed by vascular neurologists in geographical stroke units, stroke teams and care pathways, primary stroke center certification according to The Joint Commission, and most recently comprehensive stroke center designation under the aegis of The Joint Commission. Many organizations in the US have been involved to enhance stroke care. To name a few, the American Heart Association/American Stroke Association, Brain Attack Coalition, and National Stroke Association have been on the forefront of this movement. Additionally, governmental initiatives by the US Centers for Disease Control and Prevention and legislative initiatives such as the Paul Coverdell National Acute Stroke Registry program have paved the way to focus on stroke prevention, acute treatment and quality improvement. In this invited review, we discuss a brief history of organized stroke care in the United States, evidence to support the value of primary and comprehensive stroke centers, and the certification criteria and process to become a primary or comprehensive stroke center.

Clopidogrel, Warfarin, and Statins: Pharmacogenetics versus Laboratory Monitoring - What You Need to Know

This article discusses the use of routine genetic and platelet function testing in the setting of clopidogrel treatment, the use of pharmacogenetics to determine warfarin dosing, predictive genetic testing for statin efficacy and toxicity, cost-effectiveness, and the United States Federal Drug Administration's role in pharmacogenetic data.

Abiomed Impella ® 2.5 patient transport: lessons learned

The Abiomed Impella(®) 2.5 is a micro-axial flow, catheter-based left ventricular assist system (LVAS). Designed for percutaneous insertion into the femoral artery and positioned across the aortic valve, the Impella(®) is capable of pumping 2.5 liters of blood per minute from the patient's left ventricle into the ascending aorta. Since United States Federal Food and Drug Administration clearance in June of 2008, use of the Impella(®) 2.5 has grown rapidly. We operate at the center of a "hub-and-spoke" regional referral network that facilitates the transfer of patients in cardiogenic shock to our facility for definitive care. Based on our recent experience of transporting patients supported on the Impella(®) 2.5 system, we review system operation, pump position, monitoring, and recommendations for providing safe and efficient transport.

Doripenem Use in Pediatrics a€“ Learning from Pharmacokinetic Data of Other Carbapenems

In 2005, doripenem, the newest carbapenem on the market, was developed by a pharmaceutical company in Japan, and it was recently approved by the United States (US) Federal Drug Administration (FDA) to be used in the adult population. Doripenem is a broad spectrum antimicrobial agent that can be used in many different infections ranging from pneumonia to abdominal infections. Even though doripenem has shown to be safe and efficacious in adults, it lacks pharmacokinetic and safety information in the pediatric population. However, by looking at the pediatric pharmacokinetic data of other carbapenems and a recent multicenter study of doripenem in patients between the age of 3 months and 18 years of age, clinicians can gain a better understanding of how to dose this antimicrobial agent in infants, children, and adolescents.

Iron Labeling and Pre-Clinical MRI Visualization of Therapeutic Human Neural Stem Cells in a Murine Glioma Model

BackgroundTreatment strategies for the highly invasive brain tumor, glioblastoma multiforme, require that cells which have invaded into the surrounding brain be specifically targeted. The inherent tumor-tropism of neural stem cells (NSCs) to primary and invasive tumor foci can be exploited to deliver therapeutics to invasive brain tumor cells in humans. Use of the strategy of converting prodrug to drug via therapeutic transgenes delivered by immortalized therapeutic NSC lines have shown efficacy in animal models. Thus therapeutic NSCs are being proposed for use in human brain tumor clinical trials. In the context of NSC-based therapies, MRI can be used both to non-invasively follow dynamic spatio-temporal patterns of the NSC tumor targeting allowing for the optimization of treatment strategies and to assess efficacy of the therapy. Iron-labeling of cells allows their presence to be visualized and tracked by MRI. Thus we aimed to iron-label therapeutic NSCs without affecting their cellular physiology using a method likely to gain United States Federal Drug Administration (FDA) approval.MethodologyFor human use, the characteristics of therapeutic Neural Stem Cells must be clearly defined with any pertubation to the cell including iron labeling requiring reanalysis of cellular physiology. Here, we studied the effect of iron-loading of the therapeutic NSCs, with ferumoxide-protamine sulfate complex (FE-Pro) on viability, proliferation, migratory properties and transgene expression, when compared to non-labeled cells. FE-Pro labeled NSCs were imaged by MRI at tumor sites, after intracranial administration into the hemisphere contralateral to the tumor, in an orthotopic human glioma xenograft mouse model.ConclusionFE-Pro labeled NSCs retain their proliferative status, tumor tropism, and maintain stem cell character, while allowing in vivo cellular MRI tracking at 7 Tesla, to monitor their real-time migration and distribution at brain tumor sites. Of significance, this work directly supports the use of FE-Pro-labeled NSCs for real-time tracking in the clinical trial under development: “A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically modified Neural Stem Cells Expressing Escherichia coli Cytosine Deaminase for Treatment of Recurrent High-Grade Gliomas”.

Isotretinoin and intestinal inflammation: what gastroenterologists need to know

A possible aetiological role in the development or exacerbation of inflammatory bowel disease (IBD) has been suggested for a small number of drugs, including antibiotics,1 non-steroidal anti-inflammatory drugs (NSAIDs)2 and,...

Cervical Disc Replacement in Patients With and Without Previous Adjacent Level Fusion Surgery

Prospective 6-center study. OBJECTIVE.: To evaluate outcomes of cervical disc replacement performed adjacent to a prior cervical fusion. The use of disc replacement adjacent to a prior anterior cervical decompression and fusion (ACDF) is an attractive reconstructive option, obviating the need for a multilevel fusion. This study reports outcomes from patients with and without previous ACDF receiving the porous coated motion (PCM) artificial cervical disc in a United States Federal Drug Administration Investigational Device Exemption trials. Patients between ages of 18 and 65 with single-level cervical radiculopathy and/or myelopathy, unresponsive to at least 6 weeks of nonsurgical therapy, or experiencing progressive neurologic symptoms were enrolled. Clinical outcomes are compared for patients receiving a PCM disc at a level adjacent to a prior ACDF ("adjacent") and those without having previously had fusion ("primary"). 126 PCM patients were primary (mean age: 44.4 years.) and 26 patients had previous "adjacent level" fusion surgery (mean age: 46.4 years). Surgery time was similar in both groups (96 minutes and 98 minutes, respectively; P = 0.761), and mean blood loss was 76 mL and 66 mL in the 2 groups, respectively (P = 0.491). Clinical outcomes using Neck Disability Index and Visual Analog Scores neck and arm scores showed significant improvement after surgery and were similar between groups at all time points. Revision surgery occurred in 2 of 126 primary patients, and in 2 of 26 patients in the adjacent-to-fusion group. Although the level adjacent to a prior cervical fusion is subject to increased biomechanical forces, potentially leading to a higher risk of failure, the PCM disc was well tolerated in the short term. The early clinical results of disc replacement adjacent to a prior fusion are good and comparable to the outcomes after primary disc replacement surgery. However, in view of the small study population and short-term follow-up, continued study is mandatory.

Seprafilm Review and Meta‐analysis

As a surgeon with a long-time interest in the clinical and research aspects of adhesions, I looked forward to reading the review and meta-analysis by Drs. Zeng, Yu, You, and Zhang [1]. Unfortunately, the factual and methodologic errors contained in the article diminished my experience and inadequately supported the author’s conclusions. For a meta-analysis to be valid the analyzed studies need to have similar populations and endpoints. The authors admit this limitation in their discussion but fail to discuss its significance. Of the seven trials included, one used only cancer patients [2], three excluded cancer patients [3–5], one used only pediatric patients [6], and the other six used adults. The type of surgery performed has been shown to affect adhesions. The operations performed in the studies were different: Restorative proctocolectomy in some [3–5], sigmoid colectomy and Hartman’s in others [7], and mostly small-bowel procedures in another [6]. The method of application and number of sheets of Seprafilm used also varied significantly from just under the wound in some studies to application to adhesiogenic areas and wraping the ileostomies [8] or wrapping the anastomosis. Finally, one of the studies [5] did not even use Seprafilm but a different product (glycerol/sodium hyaluronate/carboxymethylcellulose-based bioresorbable membrane) which is chemically different and has different clinical properties. This product is different enough that the United States Federal Drug Administration required separate studies to test its effectiveness and safety. The glycerol component appears to support bacterial growth and after this finding the product was voluntarily removed from the market. In doing data abstraction, the authors failed to include the lack of abscesses in the treatment and control groups in the Inoue article [6]. Removing abscess data from the Cohen study [5] and adding the data from the Inoue article, the new analysis (according to my statistician) confirms that there is insufficient support for a statistical difference in abscess formation when Seprafilm is used. A similar result occurs when the Cohen study is removed from the analysis. Another of my concerns is the evaluation of secondary endpoints or findings that were not prospectively identified in the original study. Events such as bowel obstructions and abscesses have a number of clinical (nausea, vomiting, abdominal distension, lack of flatus), radiologic (distended loops of bowel, air-fluid levels, luminal transition on CT scans), and operative findings as well as different etiologies (technical, luminal, adhesive). In the absence of prospectively defined criteria, interand intraobserver biases are rampant. In addition, most of the studies were not powered adequately to determine secondary endpoints. A minor point, and most likely an editing error, is that Gore-Tex surgical membrane is manufactured by Gore not Genzyme. While I agree with the authors that the data support Seprafilm reducing adhesions, evaluation of appropriate studies fails to provide convincing evidence of an increase in abscesses or fistulas. I was disappointed that this article did not clarify any issues and added little novel information to the literature. Dr. Beck was an investigator in several of the studies reviewed and has been a consultant to Genzyme Corporation.

Molekular zielgerichtete Therapie

Until recently, cancer therapy was based on three modalities: surgery, radiotherapy, and cytostatic chemotherapy. In most instances treatment of solid tumors was a surgical domain. For patients with incomplete resection or relapse after surgery, radiotherapy and chemotherapy usually offered only partial response and mostly of limited duration. By the mid-1990s visions of antibody-based therapies, vaccination strategies, and even gene-specific therapies existed but seemed far from clinical practice. United States Federal Drug Administration approval of the humanized antibody rituximab (1997) and the tyrosine kinase inhibitor imatinib (2001) has changed perceptions of oncologic treatment. These drugs turned visions into reality and led the pharmaceutical industry, clinicians, and patients to new perspectives. This article gives an overview of the development of this fourth modality in cancer therapy, so-called targeted therapy.

Serum creatinine changes in HIV-seropositive patients receiving tenofovir

Serum creatinine changes in HIV-seropositive patients receiving tenofovir

The 41st annual ASCO meeting: targeted therapies, Orlando, Florida

The area of biological and targeted therapies exploded in the late 1990s. After obtaining good results in hematological malignancies, cancer treatment is now being based on monoclonal antibodies. ASCO has integrated various areas of biological therapy into its scope of clinical activity. Trastuzumab (Heceptin) and bevacizumab (Avastin), antibodies targeting HER-2 and vascular endothelial growth factor, respectively, were approved by the United States Federal Drug Administration for first-line treatment of metastatic breast and colorectal cancer in combination with chemotherapy. Bevacizumab is the first approved agent to target tumor angiogenesis. This drug is now combined with chemotherapy to treat breast, lung, and colorectal cancer. In the past several years, significant advances in the underlying biological mechanisms of renal cell carcinoma, particularly the role of tumor angiogenesis, have made it possible to design molecularly targeted therapeutics. This meeting review is organized by tumor type and biotherapy modality.

Use of sodium fluorescein solution for detection of cerebrospinal fluid fistulas: an analysis of 420 administrations and reported complications in Europe and the United States.

Localization of dural fistulas in the region of the anterior or lateral skull base may be difficult. For many years, a sodium fluorescein solution of 0.5 to 5% (2.5-50 mg) has been administered intrathecally by way of the lumbar space. However, fluorescein is not commercially available for this stated purpose in either Germany or the United States. Retrospectively, 420 fluorescein applications by the authors were retrospectively analyzed. Under the Freedom of Information Act, the United States Federal Drug Administration and the manufactures of fluorescein were queried for adverse reaction reports. Four hundred twenty fluorescein applications in 305 patients could be evaluated. Mean age of recipients was 46.9 years, ranging from 1 to 82 years. At a concentration of 5% fluorescein, 26 patients on the day of surgery and 69, 37, 34, and 14 patients on days 2 through 4 suffered from minor side effects that may or may not have been related to this drug. Two of these patients had grand mal seizures, which were attributable to simultaneous intrathecal application of contrast medium. All other side effects were thought to be the result of a postspinal headache and related lumbar puncture. At a concentration of 0.5%, the intraoperative intrathecal administration of 0.5 to 2 mL of fluorescein followed by 4 to 5 days of lumbar drainage resulted in some degree of spinal headache without other complications. In both groups, no patient had sequelae longer than 4 weeks. An additional seven complications were reported to the Federal Drug Administration and the fluorescein manufacturers at doses of 100 to 700 mg. Complications from intrathecal application of fluorescein appears to be dose dependent. At concentrations of 5%, or preferably lower, side effects are transient. A grand mal seizure can be minimized when following the general cautions of lumbar puncture and dose. The patient should be supervised for 24 hours. A written informed consent from patients for use of fluorescein is recommended.

Advances in targeted therapy: safety of biological agents

Tumour necrosis factor (TNF) antagonists have set a new therapeutic standard for rheumatoid arthritis (RA). The agents including infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira) have been shown to substantially...