Tablet Scorings
Selected summaries of published journal articles
Rete Com Reaches Publication Milestone
With the posting of a review article on the American Journal of Cardiology website in August, 20 papers have now been published in top-tier peer-reviewed journals with assistance from Rete Biomedical Communications Corp. in 2008. Three manuscripts have recently been accepted, including one each by the Archives of Ophthalmology and the Journal of Sexual Medicine. One of these reports resulted from pooled analyses of clinical trials, and the company is also involved in other, related “data-mining” projects. A total of 24 papers are projected to have been accepted and/or published by the end of 2008―an average of two each month. Rete Com was also recently awarded a contract to provide editorial support in 2008-2009 to Eli Lilly Canada (Ontario; www.lilly.ca) as scientists with the company prepare to submit study reports on two CNS medications to peer-reviewed journals.
Supplement on Aortic Stenosis Published
Hot topics in aortic stenosis. Eur Heart J 2008;10:E4-E40.
Proceedings from a December 6, 2007 satellite symposium to EUROECHO 2007, the 11th Annual Meeting of the Association of Echocardiography, a registered branch of the European Society of Cardiology, have been published as a supplement to the European Heart Journal.
The symposium and supplement were supported by Merck/Schering-Plough, and the supplement is available online at http://eurheartjsupp.oxfordjournals.org/current.dtl
Rete Com collaborated with an internationally renowned faculty, including Nalini M. Rajamannan, MD, Valve Director, Bluhm Cardiovascular Institute, Division of Cardiology and Department of Pathology, Northwestern University, Feinberg School of Medicine (Chicago), on her article entitled “Update on the pathophysiology of aortic stenosis”; Nikolaus Jander, MD, Internist/Kardiologe, Oberarzt und Leiter der Echokardiographie Herz-Zentrum, Bad Krozingen, Germany, on his article entitled “Low-gradient ‘severe’ aortic stenosis with preserved ejection fraction: new entity, or discrepant definitions?”; Kristian Wachtell, MD, PhD, FESC, Department of Medicine B, The Heart Center, Rigshospitalet, Copenhagen, on his article entitled “Left ventricular systolic performance in asymptomatic aortic stenosis”; Eva Gerdts, MD, PhD, Professor of Medicine, Institute of Medicine, University of Bergen, Director, Noninvasive Imaging Unit, Department of Heart Disease, Haukeland University Hospital, Bergen, Norway, on her article entitled “Left ventricular structure in different types of chronic pressure overload”; and Terje R. Pedersen, MD, Centre for Preventive Medicine, Ullevål University Hospital, Oslo, Norway on his article entitled “Overview of clinical trials on calcific aortic stenosis.”
This is the second journal supplement published in 2008 with editorial assistance from Rete Com. The other was published in the journal Diabetes, Obesity and Metabolism and concerned management of type 2 diabetes mellitus with an incretin enhancer (DPP-IV inhibitor). Diabetes, Obesity and Metabolism is published by Blackwell Publishing
(http://www.blackwellpublishing.com/journal.asp?ref=1462-8902&site=1).
The Gila Monster (Heloderma suspectum) Strikes Again:
Review of Incretin Mimetics and Analogues for Type 2 Diabetes Mellitus (DM2)
Van Gaal LF, Gutkin SW, Nauck MA. Exploiting the antidiabetic properties of incretins to treat type 2 diabetes mellitus: glucagon-like peptide 1 receptor agonists or insulin for patients with inadequate glycemic control. Eur J Endocrinol 2008;158(6):773-784.
Peptide hormones secreted into the saliva of the venomous Gila monster, a slow-moving nocturnal predator indigenous to the American Southwest that can survive for months without food, were found by Eng and Raufman to be long-lived agonists of the glucagon-like protein (GLP-1) receptor in mammals. These findings spawned pharmaceutical research to synthesize compounds sharing these properties. One such agent, exenatide (Byetta®; Amylin/Eli Lilly), was initially termed “exendin” because it was secreted by an exocrine gland (in the Gila) but also exerted endocrine effects in mammals. In human beings, GLP-1 is secreted by entero-endocrine cells—hormone-secreting cells within the distal small intestine (ileum)—in response to meal intake.These compounds were the objects of intense scrutiny at the recent 68th Scientific Sessions of the American Diabetes Association, June 6-10, 2008, in San Francisco, CA
(http://professional.diabetes.org/Congress_Display.aspx?TYP=9&CID=58000).
A review of the topic that was researched, drafted, and edited with assistance from
Rete Com was published in the June 2008 issue of European Journal of Endocrinology. Through a uniquely balanced therapeutic attack on both components of Unger’s “bihormonal hypothesis,” which involves the counter-regulatory hormone glucagon secreted by α-cells and insulin secreted by β-cells in the pancreatic Islets of Langerhans, these compounds can delay gastric emptying, promote a sense of satiety, and exert glucose-dependent insulinotropic effects. Consequently, treatment with some of these agents can help to normalize the endocrine and metabolic disturbances of DM2 without inducing weight gain (or even promoting weight loss in overweight or obese patients) or increasing the risk of hypoglycemia when administered as monotherapy.
The review focused on injectable incretin mimetics and analogues. Oral agents that enhance circulating levels of endogenous incretins (GLP-1 and GIP) have also been developed (DPP-IV inhibitors). After discussing the biology of incretins, as well as the efficacy, safety, and tolerability profiles of certain incretin mimetics and analogues, the review considered patient factors consistent with incretin mimetics or insulin.
Stephen W. Gutkin of Rete Com collaborated with Prof. Drs. Luc F. Van Gaal, Department of Diabetology, Metabolism and Clinical Nutrition, Antwerp (Belgium) University Hospital, and Michael A. Nauck, Diabeteszentrum, Bad Lauterberg IM Harz, Germany, on the paper, which was supported by Eli Lilly. The article is available online at www.eje-online.org.
Cholesterol Goal Attainment Rate No Better Than Chance in Largest Pan-Asian Pharmacoepidemiologic Study Published to Date
Kim H-S, Wu Y, Lin S-J, Deerochanawong C, Zambahari R, Zhao L, Zhang Q, Yan P. Current status of cholesterol goal attainment after statin therapy among patients with hypercholesterolemia in Asian countries and region: the Return on Expenditure Achieved for Lipid Therapy in Asia (REALITY-Asia) study. Curr Med Res Opin 2008;24(7):1951-1963.
Less than half (48%) of 2,622 patients with hypercholesterolemia in the People’s Republic of China, Korea, Malaysia, Singapore, Taiwan, and Thailand achieved consensus cholesterol treatment targets, according to this study report from the international Return on Expenditure Achieved for Lipid Therapy (REALITY) program.Approximately 9 of every 10 patients in the study population had coronary heart disease (CHD) or at least two CHD risk factors. Echoing previous findings in other pharmacoepidemiologic studies, including the Lipid Treatment Assessment Program (LTAP), the likelihood of goal achievement in Asian patients varied inversely with their absolute cardiovascular risk: only 38% of those at highest risk, individuals with CHD and/or diabetes mellitus, followed by 62% of those with at least two risk factors but no CHD, and 81% in those with less than two CHD risk factors.
With urbanization and economic development in many regions of Asia over the past
20 years, residents have become more susceptible to “the diseases of affluence,” including CHD. As in other populations, rising mean levels of serum total cholesterol and LDL cholesterol have been associated with increasing incidences of CHD morbidity and mortality in Asia, although there is considerable regional variation, particularly between rural and urban populations. Despite solid evidence from clinical trials showing that therapeutic lifestyle modification and lipid-modifying therapy help to limit atherosclerotic progression and reduce cardiovascular risk in Asian patients, published data on cholesterol goal attainment in Asia had been fairly scant before this study report.
Collaborating with corresponding author Dr. Peter Yan, Gleneagles Medical Centre (Singapore) and other Asian investigators, Rete Com assisted in researching, drafting, editing, and proofreading the manuscript. The findings are also consistent with data from other study reports supported editorially by Rete Com, including the REALITY-Europe program, the FINRISK trial in Finland, the Hong Kong Hospital Audit Study, and the ASACT trial in Singapore. These studies were supported by Merck & Co., the Merck/Schering Plough joint venture, and/or their affiliates.
The REALITY-Asia study report is available online at www.cmrojournal.com.
Effects of modifying triglycerides and triglyceride-rich lipoproteins on cardiovascular outcomes
Abdel Maksoud M, Sazonov V, Gutkin SW, Hokanson JE. J Cardiovasc Pharmacol 2008 Apr;51(4):331-351.
Although treatment with HMG-CoA reductase inhibitors (statins) significantly reduces cardiovascular risk compared with placebo in patients at elevated risk, such treatment alone does not prevent the majority of cardiovascular events in such patients. Other lipid and lipoprotein abnormalities, including elevated serum triglycerides and low HDL-cholesterol (HDL-C; “good” cholesterol), are also rational targets for lifestyle modification and/or pharmacotherapy.
Published as the first paper in the April issue of the Journal of Cardiovascular Risk, this
>8,000-word review focuses on the published literature concerning the effects on cardiovascular events and coronary arterial atherosclerotic progression of treatment with agents having more profound effects on triglycerides (and HDL-C) compared with statins, including fibric-acid derivatives (fibrates) and nicotinic acid (niacin).
In collaboration with senior author Dr. John E. Hokanson (University of Colorado Denver & Health Sciences Center) and Dr. Madiha Abdel-Maksoud (Tanta University, Egypt), whose previous work on the topic has been cited widely, Stephen W. Gutkin of Rete Com assisted in researching the topic and preparing the manuscript, which covers data from nearly 200 published references. Included among the papers reviewed are the Veterans Affairs HDL Intervention Trial (VA-HIT), Helsinki Heart Study (including 18-year mortality data recently published), Bezafibrate Infarction Prevention (BIP) study (clinical trial and registry), and Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), all of which involved fibrates; the Coronary Drug Project involving niacin; as well as consensus guidelines from the National Cholesterol Education Program (NCEP).
The review was supported by Merck & Co., Inc., Whitehouse Station, NJ (www.merck.com), and is available online at http://www.cardiovascularpharm.com.
Comprehensive Review of the Effects of Niacin on Glycemic Regulation Published in April 2008 Issue of Mayo Clinic Proceedings
Goldberg RB, Jacobson TA. Effects of niacin on glucose control in patients with dyslipidemia. Mayo Clin Proc 2008 Apr;83(4):470-8.
Potentially through an effect on peripheral insulin sensitivity secondary to a rebound rise in circulating free fatty acids, nicotinic acid (niacin) treatment of dyslipidemia may result in modest, typically transient and/or reversible increases in indices of glycemic control, including hemoglobin A1c and fasting glucose. Accordingly, consensus treatment guidelines issued by the National Lipid Association, National Cholesterol Education Program, and other health authorities include recommendations for the use of this treatment in patients with and/or at elevated risk of type 2 diabetes mellitus. This review considers such guideline recommendations in the context of a risk:benefit analysis weighing the potential effects of niacin on glucose control against the potential long-term benefits of such treatment, which has been shown in published subgroup analyses of the Coronary Drug Project to confer significant long-term cardioprotective effects (vs placebo) even in patients with insulin-resistance syndromes at baseline.
Collaborating with Drs. Ronald Goldberg of the University of Miami Leonard M. Miller School of Medicine, Miami, FL (www.med.miami.edu), and Terry A. Jacobson of Emory University School of Medicine, Atlanta, GA (www.med.emory.edu), Rete Com assisted in researching the topic and preparing the manuscript. Rete Com has been collaborating with Dr. Jacobson since 1993, including papers previously published in the Journal of the American Medical Association (JAMA), Annals of Internal Medicine, Archives of Internal Medicine, American Journal of Cardiology, Drug Safety, and Expert Opinion in Drug Safety.
The article was supported by Merck & Co., Inc., Whitehouse Station, NJ (www.merck.com), and is available online at www.mayoclinicproceedings.com.
Recent Meta-Analysis Suggests Superiority of Infliximab Over Other Biological Therapies for Induction Treatment of Psoriasis
Reich K, Sinclair R, Roberts G, Griffiths CE, Tabberer M, Barker J. Comparative effects of biological therapies on the severity of skin symptoms and health-related quality of life in patients with plaque-type psoriasis: a meta-analysis. Curr Med Res Opin 2008 Mar 19 [Epub ahead of print]
The pooled relative risk for achieving a 75% reduction of baseline Psoriasis Area Severity Index (PASI 75) scores using biological response modifiers (vs placebo) was 3.37 for alefacept, 7.47 for efalizumab, 11.92 for etanercept, and 25.48 for infliximab. Studies involving all therapies demonstrated more pronounced improvements (vs placebo) in health-related quality of life (HRQOL). Proportions of patients discontinuing treatment were similar in patients randomly assigned to each active treatment compared with placebo. These findings resulted from a systematic review of Medline and other databases evaluating the effects on PASI, HRQOL, and other endpoints of induction therapy with alefacept, efalizumab, etanercept, or infliximab in patients with active but chronic stable plaque psoriasis vulgaris. Data extracted from all randomized clinical trials were pooled by outcome and dose using both fixed- and random-effects statistical models.
Rete Com collaborated with Dr. Kristian Reich of Dermatologikum Hamburg, Hamburg, Germany, and other investigators and scientists across three continents to provide assistance in researching the topic and preparing the manuscript. Supported by Schering-Plough Pharmaceuticals, Kenilworth, NJ (www.schering-plough.com), the study report is available online at www.cmrojournal.com.
Tadalafil Effective, Well Tolerated in Elderly Men: Findings of the
MOMENTUS study
Sharlip ID, Shumaker BP, Hakim LS, Goldfischer E, Natanegara F, Wong DG. Tadalafil is efficacious and well tolerated in the treatment of erectile dysfunction (ED) in men over 65 years of age: results from the Multiple Observations in Men with ED in National Tadalafil Study in the United States [MOMENTUS]. J Sex Med 2008 Mar;5(3):716-725.
Advancing age is arguably the most salient risk factor for the development of erectile dysfunction (ED) in male species, human or rodent. In this multicenter trial,
188 men ages > 65 (mean = 71.6 )years were treated open-label with “on-demand” tadalafil 20 mg (not more than once daily) for up to 12 weeks. Men receiving tadalafil experienced significant improvement in erectile function according to multiple measures of the International Index of Erectile Function and also by their diary entries of sexual encounters for the Sexual Encounter Profile. A total of 40% of patients with ED at baseline experienced normalization of erectile function, and 81% reported improved erections, following tadalafil treatment. More than 50% of sexual-intercourse attempts were completed successfully for up to 36 hours after elderly men took tadalafil. After such treatment, men also rated their sexual self-confidence higher than at baseline (before treatment). Tadalafil was also well tolerated, with proportions of elderly men discontinuing because of adverse events (<5%) being similar to data from more heterogeneous populations.
Rete Com collaborated with Dr. Ira D. Sharlip of the University of California, San Francisco (www.ucsf.edu), and other investigators to research the topic and prepare the manuscript.
The study report was supported by Eli Lilly and Company, Indianapolis, IN (www.lilly.com), and published in the March issue of the Journal of Sexual Medicine, The Official Journal of the International Society for Sexual Medicine and the International Society for the Study of Women's Sexual Health. It is available online at http://www.jsm.issir.org.
The above-referenced study provides context for a prior review of the topic for which Rete Com provided research and editorial assistance:
Seftel AD. From aspiration to achievement: assessment and noninvasive treatment of erectile dysfunction in aging men. J Am Geriatr Soc 2005 Jan;53(1):119-130.
The above-referenced review is also available online, at http://www.blackwell-synergy.com/loi/JGS.
Atomoxetine Effective in Management of ADHD Within Usual-Care
Clinical Settings
Bakken RJ, Paczkowski M, Kramer HP, Axelson AA, Williams DW, Malcolm SK, Sumner CR, Kelsey DK. Effects of atomoxetine on attention-deficit/hyperactivity disorder [ADHD] in clinical pediatric treatment settings: a naturalistic study. Curr Med Res Opin. 2008 Feb;24(2):449-460.
This open-label observational study demonstrated that once-daily atomoxetine treatment for, on average, 21 weeks was effective in reducing ADHD symptom severity among children and adolescents treated in a clinical pediatric treatment setting. Most (59%-69%) youngsters experienced control of their ADHD symptoms throughout the day and into the evening hours while using atomoxetine. Other positive effects included decreases in academic, emotional, behavioral, and relationship problems.
Study participants (N=627) included children and adolescents ranging between 6 and 17 (mean=11) years of age. All patients had a current or prior diagnosis of ADHD and were eligible for atomoxetine treatment. The average duration of treatment was 21.2 (range 0-89) weeks. These results obtained in naturalistic outpatient treatment settings support findings from randomized, controlled trials in children, adolescents, and adults demonstrating that atomoxetine is an effective nonstimulant medication for the management of ADHD.
To research the topic and provide editorial assistance in preparing the manuscript,
Rete Biomedical Communications collaborated with Drs. Hal P. Kramer of the Nemours Children’s Clinic, Wilmington, DE (www.nemours.org), Alan A. Axelson of InterCare Health Systems, Ltd., Pittsburgh, PA, and Calvin R. Sumner, who was with Eli Lilly when the study was conducted and the manuscript prepared but is now chief medical officer with Biobehavioral Diagnostics Company, Cambridge, MA (www.biobdx.com), as well as investigators and other scientists with Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (www.lilly.com). The article is available online at www.cmrojournal.com.
Study on the Effects of Ezetimibe and Statins on Noncholesterol Sterols Confirms Their Complementary Mechanisms of Action
Assmann G, Kannenberg F, Ramey DR, Musliner TA, Gutkin SW, Veltri EP. Effects of ezetimibe, simvastatin, atorvastatin, and ezetimibe-statin therapies on noncholesterol sterols in patients with primary hypercholesterolemia. Curr Med Res Opin 2008 Jan;24(1):249-259.
In this post-hoc analysis, ezetimibe monotherapy significantly reduced plasma levels of phytosterols (sitosterol and campesterol), which are considered markers of cholesterol absorption, whereas statin (atorvastatin and simvastatin) monotherapy significantly reduced plasma levels of the cholesterol precursor sterols (lathosterol and desmosterol), which are regarded as markers of endogenous cholesterol biosynthesis. When ezetimibe was taken in combination with either statin, levels of all of these sterols were significantly decreased. Ezetimibe alone lowered LDL-cholesterol (LDL-C; “bad cholesterol”) by a least-squares (LS) mean value of 18.5% and total cholesterol (TC) by 13.5% from baseline while raising HDL-cholesterol (HDL-C; “good cholesterol”) by 5.5%. Statin monotherapy lowered LDL-C by a LS mean value of 37.1% to 43.6% and TC 26.8% to 33.0%, while raising HDL-C by 5.2% to 7.2%. Co-administration of ezetimibe with a statin resulted in a decrease of 51.4% to 56.4% in LDL-C and 37.8% to 43.9% in TC, as well as an increase of 8.8% to 9.8% in HDL-C. For LDL-C, TC, and HDL-C, the changes from baseline to study end were significantly greater for the combination ezetimibe-statin therapy than either component monotherapy. It is most probable that these favorable effects of ezetimibe-statin combination therapy on surrogate endpoints is due to dual inhibition of both cholesterol absorption and synthesis.
The above findings derived from a pooled analysis of two randomized controlled trials involving 975 patients with primary hypercholesterolemia (LDL-C = 145–250 mg/dL; triglycerides ≤ 350 mg/dL). Patients were treated for 12 weeks with ezetimibe 10 mg in combination with the HMG-CoA reductase inhibitor simvastatin 10-80 mg or atorvastatin 10-80 mg.
Stephen W. Gutkin and Rete Biomedical Communications collaborated with Drs. Gerd Assmann and Frank Kannenberg of the Leibniz-Institute of Arteriosclerosis Research in Münster, Germany; as well as Dena Ramey of Merck Research Laboratories, Rahway, NJ (www.merck.com); and Dr. Enrico Veltri of Schering-Plough Pharmaceuticals, Kenilworth, NJ (www.schering-plough.com) to research, draft, and edit the study report.
The article is available online at www.cmrojournal.com.
Laropiprant (MK-0524): an Investigational Prostaglandin D2 receptor subtype 1 Antagonist for Niacin-Induced Flushing
Lai E, Wenning LA, Crumley TM, De Lepeleire I, Liu F, de Hoon JN, Van Hecken A, Depré M, Hilliard D, Greenberg H, O’Neill G, Metters K, Gottesdiener KG, Wagner JA. Pharmacokinetics, pharmacodynamics, and safety of a prostaglandin D(2) receptor antagonist. Clin Pharmacol Ther. 2007 Sep 19; [Epub ahead of print]
Most individuals who take nicotinic acid (niacin) for dyslipidemia experience cutaneous vasodilation, including the symptom of flushing, which can compromise patient acceptance and treatment adherence. A selective prostaglandin D2 (PGD2) receptor subtype 1 (DP1) antagonist, laropiprant (MK-0524) showed rapid oral absorption (Tmax = 0.8-2.0 h) and a terminal half-life of approximately 12-18 h, neither of which were effected by food. It was also well tolerated in both single (900-mg)- and multiple (450-mg)-dose regimens. Functional DP1 antagonism was seen with single doses of 6 mg or higher via antagonism of PGD2-induced cAMP accumulation in platelets. Although laropiprant is believed to be active at the thromboxane A2 receptor, no clinically significant effect was seen on collagen-induced platelet aggregation or bleeding in doses up to 200mg. These data were obtained from three randomized, double-blind, placebo-controlled studies conducted in healthy non-smoking male subjects ages 18 to 45 years.
In April 2008, an advisory panel of the Food and Drug Administration rejected an application to market a combination of laropiprant with niacin as a treatment for patients with dyslipidemia and also rejected the proposed brand name of Cordaptive™ for this medication. An advisory committee also recommended that European Union countries approve the medication.
Rete Biomedical Communications collaborated with Dr. Eseng Lai and co-workers at Merck Research Laboratories and other investigators to research the topic and provide editorial support in preparing the manuscript. Supported by Merck & Co., Inc., Whitehouse Station, NJ (www.merck.com), the study report is available online at www.nature.com/clpt/index.html.
Tadalafil Effective and Well-Tolerated Treatment for Erectile Dysfunction in Men With Spinal-Cord Injuries
Giuliano F, Sanchez-Ramos A, Löchner-Ernst D, Del Popolo G, Cruz N, Leriche A, Lombardi G, Reichert S, Dahl P, Elion-Mboussa A, Casariego J. Efficacy and safety of Tadalafil in men with erectile dysfunction following spinal cord injury. Arch Neurol 2007 Nov; 64(11):1584-1592.
In part because male erection is a neurovascular phenomenon, many patients experience erectile dysfunction (ED) after suffering spinal-cord injuries. In a European multicenter randomized, double-blind, placebo-controlled, flexible-dose titration study, treatment with tadalafil significantly improved erectile function (vs placebo) across a number of indices, including the International Index of Erectile Function and the Sexual Encounter Profile. After treatment with “on-demand” tadalafil 10-20 mg (not more than once daily) for up to 12 weeks (after a 4-week active-treatment run-in period), men in the tadalafil group were able to complete about 75% of intercourse attempts, as compared with about 40% in those receiving placebo (P<0.001) was significantly greater than the placebo group. Approximately 85% of tadalafil-treated patients reported that their erections had improved as compared with about 20% of men receiving placebo. Tadalafil was also well tolerated, with the most frequently reported treatment-emergent adverse events being headache, which was reported by 8.5% of men in the tadalafil treatment group (vs 4.5% in the placebo group) and urinary tract infection (7.7% vs 6.8%).
Rete Biomedical Communications collaborated with Dr. François Giuliano of the Department of Physical Medicine and Rehabilitation, Raymond Poincare Hospital, Garches, France, and other investigators and scientists in preparing the final manuscript of the study report, which was supported by Eli Lilly and Company, Indianapolis, IN (www.lilly.com).
The article is available online at www.archneur.ama-assn.org.
Azelastine Nasal Spray Has Rapid Onset of Action After Allergen Challenge
Patel P, D’Andrea C, Sacks H. Onset of action of azelastine nasal spray compared with mometasone nasal spray and placebo in subjects with seasonal allergic rhinitis evaluated in an environmental exposure chamber. Am J Rhinol. 2007;21(4):499-503.
With a 15-minute onset of action, azelastine nasal spray showed superior efficacy in an active-comparator placebo-controlled trial of 450 patients with seasonal allergic rhinitis (SAR). Study participants who had a history of SAR were exposed to ragweed pollen in an environmental exposure chamber. Patients enrolled were symptomatic after the allergen challenge and randomized (1:1:1) to Azelastine hydrochloride, the intranasal steroid mometasone furoate, and placebo. Total nasal symptom scores (TNSS; defined as sneezing, nasal pruritus, rhinorrhea, and congestion) were recorded over 8 hours. Azelastine demonstrated statistically significant improvement in TNSS at 15 minutes versus placebo and at each time point during the 8-hour study for both placebo and mometasone.
Rete Com collaborated with Piyush Patel, MD, Allied Research International, Inc., Mississauga, Ontario, Canada, as well as Carrie D’Andrea, MS, and Harry Sacks, MD, MedPointe Pharmaceuticals, Somerset, NJ to research, draft, and edit the study report, which is available online at http://oceansidepubl.com/ajr.
Preference for Effective Regimens (PREFER)-International: Women Surveyed Rank Efficacy as Primary Criterion in Selecting Osteoporosis Medication
Duarte JW, Bolge SC, Sen SS. An evaluation of patients' preferences for osteoporosis medications and their attributes: the PREFER-International study. Clin Ther. 2007;29(3):488-503.
When asked to rank selection criteria for prescription osteoporosis medication in a cross-sectional survey, postmenopausal women in France, Germany, Mexico, Spain, and the United Kingdom cited fracture risk reduction as the primary reason for choosing a medication. The Preference for Effective Regimens (PREFER)-International study evaluated seven medication attributes: side effects, out-of-pocket costs, efficacy in improving bone health and preventing fractures, frequency of dosing, formulation, administration, and time on market. Participants (N=3,000) in the four European countries were recruited by their physicians; in Mexico, trained interviewers went door to door. About half the women were receiving prescription osteoporosis treatment.
Effectiveness in reducing risk of fracture topped the list of attributes designated as the primary reason for choosing a medication, followed by tolerability profile. The remaining five attributes were considered less important by the women in most countries.
Rete Com collaborated with Jesús Walliser Duarte, MD, Clínica de Metabolismo Oseo y Mineral del Hospital Angeles del Pedregal, Mexico City, Mexico; Susan C. Bolge, PhD, Consumer Health Sciences, Princeton, NJ; and Shuvayu S. Sen, PhD, Outcomes Research, Merck & Co., Inc., Whitehouse Station, NJ to research the topic and draft and edit the manuscript.
The article is available online at http://www.clinicaltherapeutics.com.
Meta-analysis Supports Conclusion That Reducing Total and LDL Cholesterol Is Associated with Reduced CHD Risk
Gould AL, Davies GM, Alemao E, Yin DD, Cook JR. Cholesterol reduction yields clinical benefits: meta-analysis including recent trials. Clin Ther. 2007;29(5):778-794.
A meta-analysis of 62 studies (N=216,616) adds further support to the conclusion that total and LDL-cholesterol lowering confers clinical benefit to patients with coronary heart disease (CHD) or elevated CHD risk. The current review included 126,474 patients from 24 randomized controlled trials published since a previous meta-analysis, also reported by Gould and colleagues, in 1998.
The authors used the same analytic approach as in the 1998 review to determine the effects of net absolute reductions (1 mmol/L [38.7 mg/dL]) in total cholesterol (TC) and LDL-C on relative risk (RR) for four outcomes: all-cause mortality, CHD-related mortality, any CHD event (mortality or nonfatal myocardial infarction), and non-CHD–related mortality. They found that, for every 1-mmol/L (39-mg/dL) decrease in TC, there was a reduction in RR of 17.5% for all-cause mortality, 24.5% for CHD-related mortality, and 29.5% for any CHD event. There was no causal relationship found between non-CHD–related mortality and lipid reduction, which supported findings from the previous analysis. For every 1-mmol/L decrease in LDL-C, there were corresponding reductions in RR of 15.6%, 28.0%, and 26.6%, respectively. Results in patients without CHD demonstrated similar findings .
Rete Com collaborated with A. Lawrence Gould, PhD, and coworkers from Merck Research Laboratories, Upper Gwynedd, PA, and Merck & Co., Inc., Whitehouse Station, NJ, to research, draft, and edit the article, which is available online at http://www.clinicaltherapeutics.com.
Database Research Shows Substantial Treatment Gap in Prescribing of Vitamin D to Prevent Osteoporosis
Hanley DA, Zhang Q, Meilleur M-C, Mavros P, Sen SS. Prescriptions for vitamin D among patients taking antiresorptive agents in Canada. Curr Med Res Opin. 2007;23(6):1473-1480.
Most patients taking prescription antiresorptive agents for osteoporosis treatment are not taking vitamin D, indicating a substantive treatment gap. Because of limited data on the rate of vitamin D use with antiresorptive medications, Hanley and colleagues examined prescription vitamin D utilization patterns in a retrospective analysis of patients aged ≥65 years.
Participants (N=46,226) were part of a Canadian pharmacy-insurance organization (RAMQ) and had received at least one prescription for an antiresorptive agent (alendronate, risedronate, raloxifene) from January 1, 1996, through December 31, 2003. Although data on prescription vitamin D, such as alfacalcidol, calcitriol, cholecalciferol, doxercalciferol, ergocalciferol, were captured, corresponding information on generic or over-the-counter vitamin D was not available.
Patients receiving antiresorptive agents were predominately women (>90%); 17,151 (37.1%) had concomitant vitamin D prescriptions. The authors found that possession and overlap ratios were significantly higher in patients on weekly prescription bisphosphonate compared with once-a-day regimens (bisphosphonates or raloxifene); however, only about 63% of patients on prescription antiresorptives were also receiving prescription vitamin D.
Rete Com collaborated with Dr. David Hanley, Departments of Medicine and Community Health Sciences and Oncology, Faculty of Medicine, University of Calgary, Alberta; and Drs. Qiaoyi Zhang, Panagiotis Mavros, and Shuvayu S. Sen, Outcomes Research, Merck & Co., Inc., Whitehouse Station, NJ; and Dr. Marie-Claude Meilleur, Merck Frosst Canada, Quebec, to research, draft, and edit the article, which is available online at http://www.cmrojournal.com.
Hepatotoxicity Less Likely When IV N-acetylcysteine Is Administered Within 8 Hours After Acetaminophen Overdose
Whyte IM, Francis B, Dawson AH. Safety and efficacy of intravenous N-acetylcysteine for acetaminophen overdose: analysis of the Hunter Area Toxicology Service (HATS) database. Curr Med Res Opin. 2007;23(10):2359-2368.
A retrospective analysis of an Australian database showed that hepatotoxicity was significantly less likely when patients received intravenous N-acetylcysteine (IV-NAC) within 8 hours after acetaminophen (APAP) overdose compared with longer intervals. Data were collected from the Hunter Area Toxicology Service database of residents of New South Wales from January 1987 to January 2003.
Of 1,749 patients, 399 (22.8%) were treated with IV-NAC. Five hospitalized patients died (mortality rate = 0.3%), of which two deaths were attributed to APAP overdose. No death was attributed to IV-NAC treatment. A total of 37 (9.3%) of the 399 treated patients reported an adverse drug reaction, of which 7 (1.8%) were classified as anaphylactoid.
Two (3.1%) of 64 patients receiving IV-NAC within 8 hours after APAP overdose developed hepatotoxicity (AST/ALT >1,000 IU/L); in contrast, hepatotoxicity was found in 32 (25%) of 128 patients who received IV-NAC >8 hours after APAP ingestion. Hospital stays were also significantly shorter for patients who received IV-NAC within 8 hours.
To research, draft and edit the manuscript, Rete Com collaborated with Australian investigators Drs. Ian Whyte and Andrew Dawson, Department of Clinical Toxicology and Pharmacology, Newcastle Mater Misericordiae Hospital and the University of Newcastle; and Dr. Barbara Francis, CMAX, Division of the Institute of Drug Technology Australia Limited, Royal Adelaide Hospital.
The article is available online at www.cmrojournal.com
Fewer Than One in Three UK Residents Achieves Joint British Societies’ (JBS 2) Cholesterol Treatment Targets
Rajagopalan S, Alemao E, Finch L, Yin D. Impact of new Joint British Societies’ (JBS 2) guidelines on prevention of cardiovascular disease: evaluation of serum total cholesterol goal achievement in UK clinical practice. Curr Med Res Opinion 2007;23(8):2027-2034.
Like other consensus treatment panels, the JBS has issued increasingly stringent targets for cholesterol management, including TC < 155 mg/dL (< 4.0 mmol/L) in the JBS 2 guidelines. In a cross-sectional study involving 28,874 UK outpatients receiving statin prescriptions in 2005 (before publication of the JBS 2 guidelines), only 7,827 (27.1%) achieved this treatment target. In more than half of patients, TC values were ≥10% above the JBS 2 target, suggesting that these patients would not have achieved their goals even after doubling statin doses. For each twofold increase in the dose of statin monotherapy, there is only a further 5%–7% decrement in cholesterol.
Rete Com collaborated with Srinivasan Rajagopalan, PhD, of Med Data Analytics Inc. (Williamsville, NY) in researching and drafting the report, which was e-published ahead of print by Current Medical Research and Opinion on July 20, 2007, and is available at www.cmrojournal.com.
These findings are consistent with previous published data from retrospective cohort (observational) studies in Western Europe (REALITY), Finland (FINRISK), and Singapore (A-SACT), among others. Since 2005, Rete Com has been collaborating with Merck & Co., Inc., to research, draft, and edit a series of pharmacoepidemiologic studies on cholesterol goal achievement in diverse cultures. In many of these observational studies conducted in naturalistic outpatient settings, approximately two-thirds to three-quarters of patients did not achieve their consensus or national cholesterol treatment targets. Most of these patients received HMG-CoA reductase inhibitors (statins) at medium (maximum daily dose = atorvastatin 20 mg, rosuvastatin 10 mg, simvastatin 40 mg) or lower equipotency doses irrespective of their baseline absolute cardiovascular risk even though the cardioprotective benefits of statins are largely dependent on baseline absolute cardiovascular risk (not baseline cholesterol levels per se). Small minorities of patients received combination lipid-modifying regimens or had their regimens adjusted.
Short Communications: Active Management Strategy Associated With Cholesterol Goal Achievement
Lindgren P, Borgström F, Stålhammar J et al. Determinants of cholesterol goal attainment at 12 months in patients with hypercholesterolaemia not at consensus goal after 3 months of treatment with lipid-lowering drugs. Int J Clin Pract 2007;61:1410-1414. In a logistic regression analysis of Scandinavian patients not initially at consensus cholesterol goals, those whose regimens were altered at 3 months were significantly more likely to achieve these goals at 12 months compared to their counterparts without such changes. These findings extend data from previously published pharmacoepidemiologic study reports (communicated with support from Rete Com) showing that most patients did not achieve their consensus cholesterol goals and never had their regimens altered. In preparing the Swedish study report, which was published in the August 2007 International Journal of Clinical Practice, Rete Com collaborated with Swedish researchers at European Health Economics (Stockholm) and the University of Uppsala, as well as scientists at the Health Outcomes Research division of Merck & Co., Inc. (Whitehouse Station, NJ).
The article is available at www.blackwell-synergy.com.
Prostaglandin D2 Receptor (DP1) Antagonist MK-0524 Is Effective in Limiting Subjective and Objective Manifestations of Niacin-Induced Vasodilation
Lai E, De Lepeleire I, Crumley TM, Liu F, Wenning LA, Michiels N, Vets E, O'Neill G, Wagner JA, Gottesdiener K. Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D(2) receptor subtype 1. Clin Pharmacol Ther 2007;81:849-857.
Niacin (nicotinic acid) is the most effective available drug for raising high-density lipoprotein cholesterol. It reduces the risks of cardiovascular events and all-cause mortality over the long term in patients with dyslipidemia and has been available for decades. However, treatment with this vitamin also results in cutaneous vasodilation with flushing, which has largely limited patient acceptance and overall use.
A proof-of-concept clinical pharmacologic study was undertaken to examine the efficacy and tolerability of MK-0524 (laropiprant), a selective prostaglandin D2 receptor (DP1) antagonist, in reducing niacin-induced vasodilation. When administered in tandem with extended-release niacin, laropiprant lowered subjective flushing scores by ≥50% (vs placebo). No patient receiving this combination regimen experienced severe (patient-rated) flushing. Laropiprant also significantly blunted niacin-induced increases in malar (cheek) blood flow as assessed by laser doppler perfusion imaging. The ongoing HPS2-THRIVE study is evaluating the effects of niacin (coadministered with laropiprant to minimize flushing) on cardiovascular events in approximately 20,000 patients with vascular diseases already receiving statins to lower LDL-C in the United Kingdom, Scandinavia, and China.
Rete Biomedical Communications collaborated with Eseng Lai, PhD and other researchers at Merck Research Laboratories in researching the topic and drafting the manuscript, which was published in the June 2007 Clinical Pharmacology and Therapeutics and is available at www.blackwellpublishing.com/journal.asp?ref=0269-4727&site=1
Ezetimibe Lowers LDL Cholesterol Irrespective of Apolipoprotein E Genotype
Mark L, Dani G, Fazekas O, Kovacs H, Katona A. Effects of ezetimibe on lipids and lipoproteins in patients with hypercholesterolemia and different apolipoprotein E genotypes. Curr Med Res Opin 2007;23(7):1541-1548.
Many patients with the epsilon-4 (ε4) allele of the apolipoprotein E (APOE) gene have high levels of both TC and LDL-C and are at increased risk of CHD. Compounding these problems, these patients may respond less effectively to lipid-modifying pharmacotherapy and/or certain lifestyle changes. This Hungarian study examined the effects of ezetimibe 10 mg in 14 carriers of the ε4 allele compared with 14 age-and gender-matched apoE3 homozygotes. After 6 weeks of treatment, APOE3 homozygotes and individuals with the ε4 genotype showed statistically indistinguishable percent decreases from baseline in TC (12.1% vs. 13.7%, respectively; P=0.139) and LDL-C (22.8% vs 19.6% respectively; P=0.081), as well as similar increases in HDL-C (+8.0% vs +8.9%, respectively; P=0.120). Though preliminary and limited in scope, these findings suggest that ezetimibe improves lipids and lipoproteins in carriers of the ε4 allele with equivalent efficacy as in APOE3 homozygotes.
Stephen W. Gutkin and Johanna B. Grossman, PhD, of Rete Biomedical Communications collaborated with Laszlo Mark, MD, of the Department of Internal Medicine II - Cardiology, Pándy Kálmán Békés County Hospital, Gyula, Hungary in researching the topic and drafting the manuscript, which is available at www.cmrojournal.com.
Further Evidence of Suboptimal Cholesterol Goal Achievement Reported:
Pharmacoepidemiologic Studies in Finland and Singapore
Alemao E, Yin D, Sintonen H, Salomaa V, Jousilahti P. Evaluation of lipid-lowering therapy and cholesterol goal attainment in Finland: the national FINRISK study. Am J Cardiovasc Drugs 2006;6(5):349-355.
Ho K-T, Chin K-W, Ng K-S, Alemao E, Rajagopalan S, Yin D. The A-SACT (Achievement in Singapore of Cholesterol Targets) study in patients with coronary heart disease. Am J Cardiovasc Drugs 2006;6(6):383-391.
As suggested by the Return on Expenditure Achieved for Lipid Therapy (REALITY) study in Europe, the majority of patients with coronary heart disease (CHD) and others with increased cardiovascular risk do not achieve consensus cholesterol goals. Now, two study reports published by the American Journal of Cardiovascular Drugs (Adis/Wolters Kluwer) in November-December 2006 confirm and extend these findings to two diverse societies: Finland and Singapore. The reports can be accessed at http://cardiovascular.adisonline.com.
Lipid-lowering treatment in Finland was evaluated in a subgroup analysis of the FINRISK study, a national evaluation of cardiovascular risk factors. Among 554 Finnish participants receiving lipid-lowering treatment, 92% received monotherapy with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). A total of 210 (38%) had CHD, and 51% had 10-year absolute coronary risk ≥ 20%. Approximately two-thirds of subjects received prescriptions for simvastatin (42%) or atorvastatin (26%), and about half (51%) of all statins were prescribed at low-potency doses. Despite treatment, 54% of patients did not achieve the European consensus treatment goal of total cholesterol < 5.0 mmol/L (<194 mg/dL). Patients receiving medium-to-high-potency statin doses were more likely to achieve cholesterol goals compared with those receiving lower-potency doses (odds ratio [OR]=1.93; 95% CI=1.35-2.76), whereas postmenopausal women were less likely than similarly aged men to achieve these targets (OR=0.61; 95% CI 0.42-0.88).
Rete Com collaborated with Pekka Jousilahti, MD, of the Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, and the School of Public Health, University of Tampere, Finland, to research the topic and draft the study report, which was funded by MSP (Merck/Schering Plough) Singapore Company, LLC.
In Singapore, the majority of patients with CHD also did not achieve consensus treatment targets for low-density lipoprotein cholesterol (LDL-C), according to a historical cohort study using data from the Singapore Cardiac Databank. Among 4,479 survivors of acute myocardial infarction or coronary revascularization with baseline and at least one follow-up LDL-C measurement 14 months after hospital discharge, only 1,372 (30.6%) had LDL-C < 100 mg/dL. As in the FINRISK study, most Singapore residents who received statin prescriptions were treated with low- to medium-potency doses that were never adjusted. Patients receiving higher-potency-dose statin regimens were significantly more likely to achieve LDL-C goals, whereas those with higher baseline LDL-C levels were less likely. Of 3,811 patients at very high risk, approximately 94% did not achieve the updated LDL-C goal of < 70 mg/dL, which was recommended by the National Heart, Lung, and Blood Institute as an optional therapeutic target for such individuals. Enhanced adherence to prescribed medications and therapeutic lifestyle counseling, improved targeting of initial statin doses according to baseline cardiovascular risk and consensus cholesterol targets, and more effective use of well-tolerated therapies including statin combination regimens may be necessary to increase the likelihood of patients’ achieving consensus cholesterol targets.
Rete Com collaborated with Keng-Thye Ho, MD, and his colleagues at the Tan Tock Seng Hospital (Singapore) to research the topic and assist in preparing the draft of the article, which was also funded by MSP (Merck/Schering Plough) Singapore Company, LLC.
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Patients Prefer Tadalafil and Are More Satisfied With Treatment, Canadian Studies Show
Brock G, Chan J, Carrier S, Chan M, Salgado L, Klein AH, Lang C, Horner R, Gutkin S,
Dickson R. The Treatment of Erectile Dysfunction study: focus on treatment satisfaction of patients and partners. Br J Urol Int 2006. e-published November 28, 2006, ahead of print.
As previously observed in the Canadian observational Treatment of Erectile Dysfunction (TED) study, most men with erectile dysfunction (ED) who expressed an interest in changing treatment from the phosphodiesterase type 5 (PDE5) inhibitor tadalafil to sildenafil (or vice versa) preferred tadalafil after receiving treatment with the two agents in succession. Further research from the TED series now demonstrates that most patients and their partners were also more satisfied with tadalafil treatment, according to data from the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire. The study was funded by Lilly ICOS LLC (Bothell, WA, and Indianapolis, IN), and the report was posted by the British Journal of Urology International on November 28, 2006, ahead of its scheduled publication in the February 2007 issue of the journal. The article is available at http://www.blackwell-synergy.com/toc/bju/0/0.
Other Studies on Tadalafil e-Published Ahead of Print in 2006
Pharmacokinetics of Tadalafil Unaffected by Intrinsic Factors
Forgue ST, Phillips DL, Bedding AW, Payne CD, Jewell H, Patterson BE, Wrishko RE, Mitchell MI. Effects of gender, age, diabetes mellitus and renal and hepatic impairment on tadalafil pharmacokinetics. Br J Clin Pharmacol 2007;63(1):24-35.
Age, gender, diabetes mellitus, and other intrinsic factors exert no significant influences on the pharmacokinetics of tadalafil. These conclusions are based on single-dose pharmacokinetic studies conducted in the United Kingdom, Belgium, Poland, and Germany. The report of these studies was published in the British Journal of Clinical Pharmacology (Blackwell).
The systemic exposure (AUC) of tadalafil was modestly increased (by 25%) in elderly subjects compared with their younger counterparts and slightly reduced (by 19%) in patients with diabetes mellitus compared with their healthy counterparts. Neither of these alterations is consistent with any need to adjust tadalafil doses on the basis of age or glycemic regulation alone. Systemic exposure of the parent compound was approximately twice as high in patients with mild-to-moderate renal insufficiency, and systemic exposure of the major metabolite (methylcatechol glucuronide) also increased about threefold in patients with end-stage renal failure. Hepatic impairment had no major effects on systemic exposure. Tadalafil was not associated with serious or clinically significant adverse events or study discontinuations because of adverse events, although the 10-mg dose was not well tolerated in patients with moderate renal dysfunction.
Rete Com provided editorial support to S. Thomas Forgue, PhD, of Lilly Research Laboratories (Indianapolis, IN) in preparing the report, which was funded by Lilly ICOS LLC. The report was published in the January 2007 issue of BJCP and is available at http://www.blackwell-synergy.com/toc/bcp/63/1.