Outpatient Diuretic Protocol Can Keep Some Heart Failure Patients Out of Hospital

MedicalResearch.com Interview with:

Leo F. Buckley, PharmD Virginia Commonwealth University Richmond, Virginia

Dr. Leo Buckley

Leo F. Buckley, PharmD
Virginia Commonwealth University
Richmond, Virginia

MedicalResearch.com: What is the background for this study?

Response: As the prevalence and costs of heart failure are expected to increase through the year 2030, significant efforts have been devoted towards devising alternatives to inpatient hospitalization for the management of heart failure decompensations. Since loop diuretics are the mainstay of treatment during the majority of hospitalizations, administration of high doses of loop diuretics in the outpatient setting has increased in popularity.

We intended to answer two questions with his study: first, can a patient-specific dosing protocol based on a patient’s usual diuretic dose achieve safe decongestion? and second, does this strategy alter the usual course of heart failure decompensation, which oftentimes culminates in inpatient hospitalization?

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Study of Topical Minocycline For Acne Demonstrates No Phototoxicity or Absorption

MedicalResearch.com Interview with:
Kin F. Chan, PhD

Executive Vice President of Research and Technology
BioPharmX Corporation

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There were two studies in this series.  The purpose is to get a better understanding of the blood plasma and skin levels of minocycline in a relevant animal model (minipig) for both the oral form of minocycline (Solodyn) and topical BPX-01, and to elucidate the same for oral minocycline only in a clinical study.

The results provided valuable guidance and assurance to our upcoming Clinical Phase 2b dose-ranging study design.

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Lymphoma Drug Shows Promising Results in Phase 3 Trial

MedicalResearch.com Interview with:

Dirk Huebner, MD Senior Medical Director Oncology Therapeutic Area Unit Takeda Pharmaceutical Company

Dr. Dirk Huebner

Dirk Huebner, MD
Senior Medical Director
Oncology Therapeutic Area Unit
Takeda Pharmaceutical Company

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Cutaneous lymphomas are a category of non-Hodgkin lymphoma that primarily involve the skin. Cutaneous T-cell lymphoma, also known as CTCL, is the most common type of cutaneous lymphoma and typically presents with red, scaly patches or thickened plaques of skin that often mimic eczema or chronic dermatitis.

ADCETRIS® (brentuximab vedotin) is an antibody-drug conjugate directed to CD30, which is expressed on skin lesions in approximately 50 percent of patients with CTCL. The Phase 3 ALCANZA trial compared the use of single-agent ADCETRIS to a control arm of investigator’s choice of standard therapies, methotrexate or bexarotene, in 131 patients with CD30-expressing CTCL who received prior systemic or radiation therapy.

The study met its primary endpoint, demonstrating a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4). The ORR4 was 56.3 percent in the ADCETRIS arm compared to 12.5 percent in the control arm.

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Concomitant Use of Clopidogrel and PPIs Still Prescribed Despite Safety Warnings

MedicalResearch.com Interview with:
Willemien J. Kruik-Kollöffel, PharmD
Medisch Spectrum Twente in Enschede
Netherlands,

MedicalResearch.com: What is the background for this study?

Response: Safety concerns of the concomitant use of clopidogrel and proton pump inhibitors (PPIs) were published in 2009 and 2010 by the medicines regulatory agencies, including a direct healthcare professional communication. Those publications caused a lot of turmoil. We examined the association between various safety statements and prescription behavior for gastroprotective drugs in naïve patients in the Netherlands during the years 2008–2011.

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ACEI and ARBs Had Similar Outcomes in Study of PD Dialysis Patients

MedicalResearch.com Interview with:

Jenny Shen, MD, MS Assistant Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles Biomedical Institute at Harbor-UCLA Medical Center

Dr. Jenny Shen

Jenny Shen, MD, MS
Assistant Professor of Medicine
David Geffen School of Medicine at UCLA
Los Angeles Biomedical Institute at Harbor-UCLA Medical Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: With cardiovascular disease being the No. 1 cause of death in end-stage kidney disease patients on peritoneal dialysis, we examined two classes of medications commonly prescribed to prevent cardiovascular events in these patients and found no significant difference in outcomes.

The two classes of medications, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-II receptor blockers (ARB), have slightly different mechanisms and could theoretically have differing outcomes. Previous studies had suggested that ACEI may lead to a kinin-mediated increase in insulin sensitivity not seen with ARB. This could potentially lower the cardiovascular risk in patients on peritoneal dialysis because they are exposed to high glucose loads in their dialysate that may lead to insulin resistance and its associated cardiovascular risk.

Using a national database, the U.S. Renal Data System, we surveyed records for all patients enrolled in Medicare Part D who initiated maintenance peritoneal dialysis from 2007 to 2011. Of those, we found 1,892 patients using either drug class. Surveying their medical records, we found no difference in cardiovascular events or deaths between the users for each class of medication.

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New Anti-Diabetic Compound May Avoid Bone Loss Seen With Current Medications

MedicalResearch.com Interview with:

Patrick Griffin, PhD Professor Department of Molecular Therapeutics The Scripps Research Institute Florida Campus

Dr. Patrick Griffin

Patrick Griffin, PhD
Professor
Department of Molecular Therapeutics
The Scripps Research Institute Florida Campus

MedicalResearch.com: What is the background for this study?

Response: Over the past decade, our laboratory and that of TSRI Associate Professor Theodore Kamenecka, have focused on molecules that increase sensitivity to insulin. Using newly discovered information, we have made significant advances in developing a family of drug candidates that target a receptor known as peroxisome proliferator-activated receptors gamma (PPARγ), a key regulator of stem cells controlling bone formation and bone resorption and a master regulator of fat.

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What is Risk of Hypoglycemia When Adding Sulphonylurea to Metformin for Diabetes Control?

MedicalResearch.com Interview with:

Stig Ejdrup Andersen MD, PhD Clinical Pharmacology Unit Zealand University Hospital Roskilde Denmark

Dr. Andersen

Stig Ejdrup Andersen MD, PhD
Clinical Pharmacology Unit
Zealand University Hospital
Roskilde Denmark

MedicalResearch.com: What is the background for this study?

Response: For decades, we have used sulphonylurea derivates in the medical treatment of type 2 diabetes. Although several newer drugs have become available, adding an SU is still a recommended and acceptable strategy when metformin monotherapy fails. The SUs are among the cheapest glucose lowering drugs on the marked but the risk of hypoglycaemia make clinicians prefer a newer oral drug such as a DPP-IV inhibitor or a SGLT-2 inhibitor to ansulphonylurea because even mild hypoglycaemia may affect the patients’ quality of life negatively.

Several meta-analyses have examined the effectiveness and safety of noninsulin antidiabetic drug, all of which have considered the SUs a homogenous drug class. Pharmacologically, however, the SU agents are quite different. In 2004, a randomized controlled trial by Shernthaner et al. indicated that in comparison with glimepiride, gliclazide MR is equally effective and is associated with fewer hypoglycaemic episodes. Still, head-to-head comparisons of the SU-agents as add-on to metformin are few. In the absence of robust designed comparative trials, we decided to compare the relative risk of hypoglycaemia among the newer SU-agents in a network meta-analysis.

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Transport System Opens Door To More Drugs Given Orally with Better Brain Penetration

MedicalResearch.com Interview with:

M. N. V. Ravi Kumar PhD Professor of Pharmaceutical Sciences Texas A&M Rangel College of Pharmacy

Dr. M. N. V. Ravi Kumar

M. N. V. Ravi Kumar PhD
Professor of Pharmaceutical Sciences
Texas A&M Rangel College of Pharmacy

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The use of ligands for receptor-mediated drug delivery offers potential for improving both the safety and efficacy of pharmaceuticals. Research to date, however, has yet to overcome some of the significant challenges of targeted drug delivery, one of which is competitive affinity with endogenous ligands. This competition for the receptor binding site can impair both natural cell processes and uptake of the drug complex across the cell wall.

This article presents a unique, non-competitive active transport strategy for crossing the intestinal barrier. Gambogic acid (GA), as a ligand, was coupled with a polymer called poly(lactic-co–glycolic acid) (PLGA) that in turn can encapsulate drugs forming nanosystems to bind to transferrin receptors within the intestinal wall, which facilitated active gut barrier crossing. The study results show peak plasma concentrations of Cyclosporine A (CsA) in orally dosed rodents at 6 hours with the GA-ladened nanosystems vs 24 hours without GA. Additionally, brain concentrations of CsA are twice as high dosing with PLGA-GA NS compared with PLGA-NS (without GA).

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At Lower Dose, Addiction Drug Naltrexone May Have Anti-Cancer Effects

MedicalResearch.com Interview with:

Dr Wai Liu Senior Research Fellow St George's University of London London

Dr. Wai Liu

Dr Wai Liu
Senior Research Fellow
St George’s University of London
London

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Naltrexone is a drug commonly used to wean addicts off alcohol and heroin, but clinical evidence has shown that when the drug is used at lower doses, patients would exhibit alter immunity. The symptoms that patients with a number of autoimmune diseases and those associated with chronic pain would ease significantly. Additionally, a number of reports showed patients with some forms of cancer would experience therapeutic benefit. Interestingly, the doses of the drug was crucial, and the non-conventional effects of naltrexone was only achieved at doses that were lower that what was conventionally used. We set about to understand why a drug could have such different effects when used at differing doses. Our results show that the genetic profile of the drug is subtly different at the two different doses, which helped us identify novel ways in which the drug could be used to induce an anticancer effect.

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Soluble Aspirin May Be Able To Cross Blood-Brain Barrier To Attack Glioblastomas

MedicalResearch.com Interview with:

Dr Kieran Breen PhD Director of Research, Brain Tumour Research University of Portsmouth, UK

Dr. Kieran Breen

Dr Kieran Breen PhD
Director of Research, Brain Tumour Research
University of Portsmouth, UK

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There is evidence that aspirin (acetyl salicylic acid) can be toxic to brain tumour cells. However, its existing preparations cannot readily enter the brain because the drug is a suspension rather than being completely soluble. Furthermore, there can be significant side effects associated with the existing form of the drug including gastric bleeding. The object of this research was to develop a new formulation of aspirin which is truly soluble. When combined with two other compounds, the drug enters the brain and can therefore target the tumour cells. This study also showed that aspirin can kill tumour cells without causing any damage to the normal nerve cells. Continue reading

Biosimilar Insulin Found Equivalent to Brand Lantus

MedicalResearch.com Interview with:

Professor Philip Home D.M., D.Phil Professor of Diabetes Medicine Newcastle University

Prof. Philip Home

Professor Philip Home D.M., D.Phil
Professor of Diabetes Medicine
Newcastle University

MedicalResearch.com: What is the background for this study? What are the main findings?

Prof. Home: MK1293 is a biosimilar insulin designed with the same amino acid sequence, manufacturing process and formulation as originator insulin glargine (Lantus). This is the clinical proving study in type 1 diabetes, being a 24-week randomized study in 508 participants between MK1293 and Lantus. The primary efficacy endpoint of non-inferiority of HbA1c was met, as was a secondary of equivalence (difference in change from baseline 0.04 (95% CI -0.11, 0.19) %-units), with other measures including hypoglycaemia, insulin antibodies and adverse events also consistent with similarity.
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Using Tumor-homing Peptides To Target Drug Delivery to Placenta

MedicalResearch.com Interview with:

Dr-Lynda-Harris

Dr. Lynda Harris

Lynda Harris PhD
Lecturer in Pharmaceutics
University of Manchester
Manchester Pharmacy School
Maternal and Fetal Health Research Centre
Manchester

MedicalResearch.com: What is the background for this study?

Dr. Harris: Pregnancy complications such as pre-eclampsia and fetal growth restriction remain a problem despite advances in antenatal care, and impact heavily on future health: small size at birth is associated with an increased risk of cardiovascular disease and diabetes in later life. Drugs to improve pregnancy outcome are severely lacking, as pregnant women are considered a high risk cohort by drug companies, who fear expensive lawsuits associated with side effects and teratogenicity. The majority of pregnancy complications are caused by a poorly growing or poorly functioning placenta. A number of potential drugs have been identified that enhance placental function in vitro, and improve fetal growth in animal models; however, there is currently no means of restricting their actions to the placenta, and systemic administration of these drugs to pregnant women is not feasible due to the risk of adverse effects in other tissues. To address this issue, we have identified a series of placental “homing peptides” which we have used to create nanocarriers for targeted delivery of drugs to the placenta.

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Informatics and Financial Incentives Can Lead To Safer Drug Prescribing

MedicalResearch.com Interview with:

Prof. Bruce Guthrie Primary Care Medicine and Honorary Consultant NHS Fife University of Dundee Dundee, Scotland

Prof. Bruce Guthrie

Prof. Bruce Guthrie
Primary Care Medicine and Honorary Consultant NHS Fife
University of Dundee
Dundee, Scotland

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Guthrie: Most drug-related harm is caused by commonly prescribed drugs with moderate risk. This prescribing is not always inappropriate, because risk of harm may be outweighed by benefit in an individual, but we have previously shown that high-risk prescribing like this is common and highly variable between primary care practices, consistent with it being improvable. We therefore developed a complex intervention combining education, informatics to make it easy to identify and review patients, and a small financial incentive to review. We evaluated this intervention in a cluster-randomised trial in 33 Scottish primary care practices, targeting nine measures of high-risk non-steroidal anti-inflammatory drug (NSAID) and antiplatelet prescribing (for example, prescription of an NSAID to someone with chronic kidney disease; prescription of an antiplatelet to someone taking an anticoagulant without also prescribing a gastroprotective drug).

The intervention reduced the targeted prescribing by just over one third, and this reduction was sustained in the year after the intervention (including the payment to review) ceased. We also observed reductions in related hospital admissions with gastrointestinal bleeding and heart failure, although not acute kidney injury which was reduced but not statistically significantly.

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Two Generic Lamotrigine Medications Demonstrate Bioequivalence in Epilepsy

MedicalResearch.com Interview with:

Dr. Michael Privitera MD Professor of the Department of Neurology and director of the Epilepsy Center University of Cincinnati Neuroscience Institute

Dr. Michael Privitera

Dr. Michael Privitera MD
Professor of the Department of Neurology and director of the Epilepsy Center
University of Cincinnati Neuroscience Institute 

Medical Research: What is the background for this study? What are the main findings?

Dr. Privitera: Generic substitution of medications has saved the American health care system billions of dollars per year. However, based on a series of uncontrolled studies, patients and clinicians share concerns that generic substitution of antiepileptic drugs may lead to loss of efficacy or emergence of adverse effects. To answer this question we undertook a prospective, randomized study that tested bioequivalence of two generic products of the antiepileptic drug lamotrigine. Lamotrigine was identified in several publications as a possible source of problems after generic switches. FDA studies test a single generic versus the brand name product in a single dose study in normal volunteers. We designed a study that would be most likely to show a difference between generics if one existed. We compared the two generic lamotrigine products showing the most difference in prior testing in patients with epilepsy taking the drug daily using rigorous pharmacokinetic methods. Each patient took each of the two generics for 2 four week periods. Our study showed the two generics were essentially indistinguishable and easily met bioequivalence standards. No patient had loss of seizure control or unexpected adverse effects.

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Incomplete Follow Up Rates Exceed 10% in Oral Antithrombotic Trials

Victor Serebruany, MD, PhD HeartDrug Research, Towson, Maryland Department of Neurology Johns Hopkins University Baltimore, Maryland

Dr. Victor Serebruany

MedicalResearch.com Interview with:
Victor Serebruany, MD, PhD
HeartDrug Research, Towson, Maryland
Department of Neurology Johns Hopkins University Baltimore, Maryland

Medical Research: What is the background for this study? What are the main findings?

Dr. Serebruany: Missing data are common challenges to the validity of trial results, yet it is unclear how to characterize the extent of missing data.  We compared the published lost-to-follow-up rates to incomplete follow-up rates determined from subject records submitted to the FDA for major oral antithrombotic trials.  The 21 trials having both sets of rates included 270,089 patients followed for a median duration of 20 months.  The mean published lost-to-follow-up rates is 0.4% (median 0.3%, range 0.005% to 2%), consistently much lower than the FDA incomplete follow-up rates: mean 12% (median 13%, range 2% to 23%).  There is no correlation between the publication and FDA-calculated  rates (R 0.07, p = 0.76).   The FDA rates exceed greatly the endpoint rate differences: mean 1.3% (median 1,0%, range 0.2% to 3.0%).

Medical Research: What should clinicians and patients take away from your report?

Dr. Serebruany: That the FDA incomplete follow-up rates greatly exceed the endpoint rate differences raises questions of whether the endpoint differences may be due to differential follow-up rather than drug effect.  That they greatly exceed the measures routinely reported for trials, i.e., lost-to-follow-up rates, suggests that current trial reporting is inadequate.  Completeness of follow-up and other indicators of trial data quality should be considered when interpreting trial results.

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Paroxetine – Paxil – Linked To Increase in Cardiac Birth Defects

Anick Bérard PhD FISPE Research chair FRQ-S on Medications and Pregnancy and Director, Réseau Québécois de recherche sur le médicament (RQRM) and Professor, Research Chair on Medications, Pregnancy and Lactation Faculty of Pharmacy University of Montreal and Director, Research Unit on Medications and Pregnancy Research Center CHU Ste-Justine

Dr. Anick Bérard

MedicalResearch.com Interview with:
Anick Bérard PhD FISPE
Research chair FRQ-S on Medications and Pregnancy
and Director, Réseau Québécois de recherche sur le médicament (RQRM)
and Professor, Research Chair on Medications, Pregnancy and Lactation
Faculty of Pharmacy University of Montreal
and Director, Research Unit on Medications and Pregnancy
Research Center
CHU Ste-Justine 

Medical Research: What is the background for this study? What are the main findings?

Dr. Bérard: Paroxetine (one of the most used antidepressant during pregnancy) has been studied extensively over the past 10-12 years. In 2005, a black box warning was put on the Paxil label to caution against use during pregnancy due to the increased risk of cardiac defects. The ACOG 2010 guidelines also suggested switching to other antidepressants during pregnancy. Over the past decade, many studies, including meta-analyses, were performed on on paroxetine use during pregnancy and the risk of cardiac malformations – but results were sometimes statistically significant or not, although a consistent increased risk was observed. It was thought that these variations could be explained by different study designs, patient populations, and because maternal depression was not always taken into account correctly. Hence, we undertook another meta-analysis (the most recent and updated) to quantify the risk of cardiac defects overall as well as specific cardiac defects associated with paoxetine use during pregnancy and to assess the impact of study designs, maternal depression and patient population on the effect of the risk.

We found that women using paroxetine during the first trimester of pregnancy (critical time-window for malformations) were 23% more at risk of having a child with malformations (15 studies combined) – baseline risk of malformation is 3-5% and thus a 23% increased risk is 3.69-6.15% absolute risk; women using paroxetine during the first trimester of pregnancy were 28% more at risk of having a child with cardiac malformations (18 studies combined) – baseline risk of cardiac malformation is 1% and thus a 28% increased risk is 1.28% absolute risk. We found that paroxetine was increasing the risk of many specific cardiac defects as well. Although the estimates varied depending on the comparator group, study design, and malformation detection period, a trend towards increased risk was observed.

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Second Protein Target of Aspirin Metabolite Identified

Prof. Daniel F. Klessig Boyce Thompson Institute for Plant Research, Department of Plant Pathology and Plant-Microbe Biology Cornell University, Ithaca, New York

Dr. Klessig

MedicalResearch.com Interview with:
Prof. Daniel F. Klessig
Boyce Thompson Institute for Plant Research,
Department of Plant Pathology and Plant-Microbe Biology
Cornell University, Ithaca, New York 

MedicalResearch: What is the background for this study?

Prof. Klessig: Acetyl salicylic acid, commonly called aspirin, has been the most widely used drug worldwide for more than a century. Currently, 80 million pounds of aspirin are produced worldwide every year and almost 30 billion tablets are consumed annually in the US alone. Long before German pharmacologist Johann Buchner identified the salicylic acid derivative salicin in 1828 as the ingredient in willow bark that is responsible for its therapeutic effects, different cultures throughout the world were, and many still are, using a variety of plants rich in salicylic acid derivatives, such as willow, wintergreen, and meadowsweet, to treat pain, fever, swelling, and other maladies. Aspirin also is used to reduce the risk of heart attack, stroke, and certain cancers.

One might expect that aspirin’s mechanisms of action would be well understood, given its extraordinarily widespread use and the fact that it was first synthesized by the Bayer chemist Felix Hoffmann over 100 years ago. The prevailing view in the biomedical community has been that aspirin works primarily, if not exclusively, by irreversibly inhibiting the enzymatic activities of cyclooxygenases 1 and 2 (COX1 and COX2), thereby disrupting the synthesis of inflammation-inducing prostaglandins. However, this assumption ignores two important facts.

  • First, aspirin is rapidly converted to salicylic acid (SA) in the body. Indeed, almost all aspirin is metabolized to SA within an hour after ingestion.
  • Second, SA and many of its natural plant derivatives are rather poor inhibitors of COX1 and COX2 as compared to aspirin, yet SA and aspirin have nearly the same beneficial pharmacological effects. Thus, there must be additional targets through which aspirin/SA exerts its many effects. Over the past two decades, a number of proteins whose activities are altered by aspirin/SA have been identified; however, their relevance as aspirin/SA targets has been called into question due to the very high, non-physiological levels of aspirin/SA required to alter their activities.

In light of our unexpected discovery that SA mediates its physiological effects in plants via many targets, and given that SA is a key hormone produced by all plants, we hypothesized that there might be multiple targets through which SA acts in animals, regardless of whether it is obtained in low to moderate levels via the diet or in moderate to high doses through herbal-based medicines or aspirin usage.

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