Multiple Drug Therapy Research Articles

Vitamin E and Omega-3: What to believe: Observational studies or randomized controlled trials?

The practice of conventional medicine has markedly changed since the introduction of the concept of the evidence-based medicine. Randomized controlled study design and large sample size were the only justifications for level A or B evidence at the summit of what is called the evidence pyramid. A lot of medical interventions that were based on a plethora of basic researches and multiple large real world or observational studies in humans became questioned now by the results of even a single large sized randomized controlled trial (RCT). The conflicting evidences for the value of vitamin E and Omega-3 fatty acids in cardiovascular diseases are famous examples for such perplexity. This article discusses this problem on the basis of scientific, ethical, and statistical critical appraisal. To conclude, in this era of overwhelming flow of data, it should be emphasized in short, fast-to-read articles that it is important to consider not only the level of evidence “as dictated by the study design and sample size” but also the relevance of evidence. Studies tell us about populations but we treat individuals. The type of the studied individuals, the enrollment criteria, the methodology, the dose of the studied drug and all the combined medications in the study should be clearly considered whenever the reported results are to be generalized beyond the specific situation studied. Comparing the effect of an active drug against placebo by giving either one of them to a group already treated with other multiple drugs (optimum medical therapy) could be a misleading indicator for the pure efficacy of the active drug. Many confounding variables such as known “or unknown” drug-drug interactions, sharing mechanisms of action or unexpected adverse drug reactions can afflict only the group randomized to take the active drug. These variables will not affect the control group simply because they add to their optimized multiple drug therapy an inert placebo.

Cutaneous adverse drug reaction profile in a tertiary care out patient setting in Eastern India

Background:Cutaneous adverse drug reactions (CADR) are the most frequent of all manifestations of drug sensitivity and manifest with varied and diverse morphology.Aims:To study the prevalence and clinical spectrum of CADR among patients attending outpatient department (OPD) in a tertiary care hospital.Materials and Methods:An observational study was undertaken over a 1-year period in dermatology OPD of a tertiary care teaching hospital in Eastern India. Patients presenting with suspected drug-related cutaneous lesions were included if drug identity could be ascertained. Clinical profiling was done. Drug history was recorded in a format specified in Indian National Pharmacovigilance Programme and causality assessment carried out as per World Health Organization-Uppsala Monitoring Centre (WHO-UMC) criteria.Results:Commonest CADR in our study was morbilliform eruption (30.18%), followed by fixed drug eruption (24.52%), Stevens–Johnson syndrome (SJS)-Toxic epidermal necrolysis (TEN) and overlap of two (24.50%), exfoliative dermatitis (7.54%), urticaria (5.6%), phototoxic drug reaction (3.8%), pityriasis rosea-like eruptions (1.89%), and severe mucositis (1.80%). Drugs implicated were sulfonamides (17%), fixed-dose combinations of fluoroquinolones with nitroimidazoles (11.30%), analgesics (11.30%), antiepileptics (11.30%), beta-lactam antibiotics (9.40%), fluoroquinolones alone (7.50%), allopurinol (7.50%), and azithromycin (5.70%). Reaction latency varied from 1 to 43 days. Causality assessment was certain and probable for 18.9% and 41.5% of the reactions, respectively, and reactions were serious in 33.96% (95% confidence interval 21.21-46.71%).Conclusions:Cutaneous adverse drug reaction profile in this study is similar in many ways to studies conducted earlier in India. Incidence of life-threatening reactions like SJS-TEN was higher compared with studies conducted abroad. Reaction time and lesion patterns are helpful in identifying an offending drug in the setting of multiple drug therapy.

Drug-drug interactions of beta-adrenoceptor blockers.

Patients with cardiovascular diseases are often treated by concurrent multiple drug therapy. It is therefore plausible that with an increasing number of drugs the risk of drug interactions increases. Such interactions can be either pharmacodynamic (and are due to the mechanism of the administered drugs) or they can be pharmacokinetic (resulting in a reduction or enhancement of drug elimination). Pharmacokinetic interactions can be either due to interactions at the level of drug metabolizing enzymes (most important cytochrome P450 (CYP) enzymes) or interactions at the level of drug transporter proteins (for example P-glycoprotein (MDR1)). It is important to distinguish between both mechanisms because interactions at transporter proteins can be attributed to those drugs that are not enzymatically metabolized. The scope of this article is to give an overview on clinically relevant interactions of the four beta-blockers widely used in the therapy of cardiovascular diseases namely atenolol (CAS 29122-68-7), bisoprolol (CAS 66722-44-9), metoprolol (CAS 37350-58-6) (each beta-1 selective), and carvedilol (CAS 72956-09-3) (beta-1 and beta-2 nonselective). Among these beta-blockers atenolol is mainly eliminated by renal excretion, bisoprolol is in part excreted as parent compound via the renal route (50%), the other 50% are hepatically metabolised, whereas metoprolol and carvedilol are metabolised by CYP2D6. In addition, evidence is accumulating that carvedilol is a substrate for P-glycoprotein. For these four beta-blockers various pharmacodynamic and pharmacokinetic interactions have been demonstrated. Such interactions that result in an altered pharmacokinetics are mainly observed with those beta-blockers that are excreted via metabolism (metoprolol and carvedilol). Accordingly these drugs have a higher potential for drug interactions. However, it should be emphasized that, in general, beta-blockers are well tolerated safe drugs with a large therapeutic index.

S5-3: Basement Membrane Localized Tumor Cells Are Protected from HER2−Targeted Therapy In Vivo.

Abstract Drug resistance compromises the efficacy of HER2−targeted therapy. Results from our laboratory, and previous reports from others, indicate that tumor cell attachment to basement membrane (BM) and other extracellular matrix (ECM) proteins may confer drug resistance. We have discovered a differential drug response between the outer, matrix-attached cells and inner matrix-deprived cells comprising 3-dimensional (3D) tumor spheroids grown in reconstituted basement membrane (T. Muranen and J. Brugge, unpublished data). The outer matrix-attached cells are resistant to multiple drug therapies. To address whether these observations are relevant in vivo, we utilized a previously described model of human-in-mouse HER2−positive ductal carcinoma in situ (DCIS), which involves the intraductal transplantation of human HER2−positive SUM225 tumor cells directly into the ductal network of the mouse mammary gland. The intraductal tumors generated are histologically indistinguishable from human DCIS lesions and recapitulate the architecture of the 3D tumor spheroids. The tumors are characterized by organized nests of noninvasive cells confined within a BM surrounded by ECM. These features permit a direct assessment of differential drug response within the tumor. We focused on the tumor cell response to short-term lapatinib monotherapy in vivo. A close examination of the tumor architecture revealed that cells closest to the basement membrane, and nearest to the vasculature, display a striking insensitivity to lapatinib whereas the remainder of the tumor undergoes extensive cell death in response to treatment. Further characterization also revealed that cells closest to the basement membrane largely maintain proliferative capacity despite an overall significant reduction in the total Ki67-positive cell population. These results provide in vivo evidence that basement membrane-attached tumor cells are protected from lapatinib. We confirmed that these cells maintain HER2 status and also observed an overall reduction in pHER2, pAKT and pERK throughout the tumor suggestive of adaptive response mechanisms, which support the proliferation and survival of these cell populations despite inhibition of the HER2 pathway. To further explore potential mechanisms of the adaptive response, we performed reverse phase protein array (RPPA) analysis on protein lysates prepared from tumor biopsy fragments following lapatinib monotherapy. RPPA profile analysis revealed an adaptive response composed of upregulation of multiple RTKs (HER2, IGFI-R) and altered apoptotic protein levels (Bcl-2, Bim, Bcl-xL) in addition to activation of AKT/S6K and ERK/p38 pathway components. These observations suggest that basement membrane-attached tumor cells may escape from lapatinib response via compensatory activation of these survival mechanisms. Each of these components will serve as targets for designing combined therapeutic approaches capable of targeting the protected basement membrane-attached tumor cells. Our results suggest that resistant populations may be a source of residual disease post-therapy, therefore identifying and characterizing these cells will be crucial to the prevention of disease recurrence in the clinic. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-3.

Defining the Role of Lipoprotein Apheresis in the Management of Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal co-dominant disorder characterized by a marked elevation of serum low-density lipoprotein (LDL) cholesterol (LDL-C) concentration, which in turn is associated with a greatly increased risk of premature cardiovascular disease. International consensus recommends the use of statins as the first line of treatment for patients with this condition. However, homozygote FH patients with persistently elevated LDL-C levels are usually resistant to multiple-drug therapy. Fortunately, LDL apheresis (or simply 'lipoprotein apheresis') provides a treatment option for patients who are refractory or intolerant to lipid-lowering medications, or if there is progressive cardiovascular disease despite maximal drug therapy. Lipoprotein apheresis is an extracorporeal LDL-C-lowering treatment similar in concept to renal dialysis. There are now five main methods for extracorporeal lipoprotein apheresis in use, namely dextran sulfate adsorption (DSA), heparin extracorporeal LDL precipitation (HELP), polyacrylate full blood adsorption (PFBA or DALI® system) using hemoperfusion, immunoadsorption, and filtration plasmapheresis. Lipoprotein apheresis has been shown to be successful in reducing LDL-C levels, as well as levels of lipoprotein(a) [Lp(a)], a prothrombotic proatherogenic lipoprotein. In contrast, however, lipoprotein apheresis seems to have a smaller effect in preventing atherosclerosis progression, thus suggesting that a major component of the reduction in cardiovascular events may be mediated by mitigating Lp(a) levels. Side effects are infrequent and mild, and have mainly consisted of lightheadedness, nausea, vomiting, and hypotension. As these are often bradykinin-mediated and associated with concomitant ACE inhibitor use, angiotensin type 2 receptor antagonists should be used instead of ACE inhibitors with DALI and PFBA. Nevertheless, there is scope for wider application of lipoprotein apheresis. The high cost and invasive nature of lipoprotein apheresis limits uptake; however, it is an important treatment modality that should be considered in carefully selected patients. National and international registries compiling outcome data for lipoprotein apheresis need to be established to help expand the evidence base regarding its effectiveness.

La dénervation rénale un traitement pour l’hypertension artérielle résistante

Arterial hypertension is a major healthcare issue affecting between 30 and 40% of the adult population in industrialized countries. Despite the availability of numerous pharmaceutical treatments, arterial hypertension often remains uncontrolled. A non-negligible percentage of patients are refractory to multiple-drug therapy, which exposes them to an increased risk of cardiovascular events. Percutaneous, renal denervation using a catheter connected to a low energy radiofrequency generator has proven effective in decreasing arterial pressure in patients resistant to medical therapy, by reducing afferent nerve activity. In order to be eligible for this therapeutic approach, patients must have uncontrolled essential hypertension despite treatment with a combination of three anti-hypertensive drugs including a diuretic agent, and ≥ 45 mL/min glomerular filtration rate. The initial registry study demonstrated that catheter-based sympathetic renal denervation was a simple and safe procedure resulting in a significant and durable reduction in arterial pressure. Subsequently, a randomized controlled trial (the Symplicity HTN-2 trial) showed a mean 32/12 mmHg decrease in blood pressure measurements in the group of patients who underwent renal denervation whereas no difference was observed in the control group. The reduction in blood pressure was still present at 24-month follow-up. No procedure-related complications were reported and no instances of renal artery stenosis or aneurysmal dilatation were evidenced during the follow-up period. No cases of renal function impairment or deterioration were recorded. This technique seems to be a promising strategy in patients suffering from this serious condition. In order to demonstrate the actual benefit of this technique, we report the case of two patients who underwent renal denervation in our institution.

Programmatic change: lung disease research in the era of induced pluripotency

Human lung research has made remarkable progress over the last century largely through the use of animal models of disease. The challenge for the future is to translate these findings into human disease and bring about meaningful disease modification or even cure. The ability to generate transformative therapies in the future will require human tissue, currently scarce under the best of circumstances. Unfortunately, patient-derived somatic cells are often poorly characterized and have a limited life span in culture. Moreover, these cells are frequently obtained from patients with end-stage disease exposed to multiple drug therapies, leaving researchers with questions about whether their findings recapitulate disease-initiating processes or are simply the result of pharmacological intervention or subsequent host responses. The goal of studying early disease in multiple cell and tissue types has driven interest in the use of induced pluripotent stem cells (iPSCs) to model lung disease. These cells provide an alternative model for relevant lung research and hold promise in particular for studying the initiation of disease processes in genetic conditions such as heritable pulmonary arterial hypertension as well as other lung diseases. In this Perspective, we focus on potential iPSC use in pulmonary vascular disease research as a model for iPSC use in many types of advanced lung disease.

Editorial

We frequently provide services for patients who present with medical histories that include multiple drug therapies. For example, patients with autoimmune diseases that include lupus erythematosus, psoriasis, progressive inflammatory neuropathy, Sjögren's syndrome, temporal arteritis, ulcerative colitis, and rheumatoid arthritis, which commonly involve long-term glucocorticosteroid (prednisone) therapy. A common side effect of steroid use is glucocorticoid-induced osteoporosis (GIOP) which leads to an increased risk of bone fractures, resorption, and subsequent reduced formation.1–3The American College of Rheumatology (ACR) recently updated guidelines regarding GIOP that include the addition of bisphosphonate drug therapies. Clinicians are aware of the controversy surrounding oral bisphosphonates. Mavrokokki et al found the incidence of bisphosphonate related osteonecrosis of the jaw (BRONJ) in osteoporotic Australian patients, primarily on weekly oral alendronate therapy, is 1 in 2260 to 8470 (0.01% to 0.04%).4 However, if extractions were performed, the incidence was 1 in 296 to 1130 cases (0.09%to 0.34%).Chiu et al noted that when patients have parallel oral bisphosphonate and steroid therapies, osteonecrosis becomes more problematic.5 It was also concluded that: (1) the combination of steroid and bisphosphonate therapy may induce osteonecrosis earlier, (2) osteonecrosis may be more severe, (3) it may respond more slowly to the drug discontinuation, and (4) recovery is less predictable. Glucocorticosteroids promote bone-resorbing osteoclasts and inhibition of bone-modeling osteoblasts.6 Nitrogen containing bisphosphonates (alendronate, risedronate, zoledronate) inhibit osteoclast activity, rendering the osteoclasts unable to release cathepsin-K, which is responsible for bone breakdown and eventual remodeling.7Clinicians must be mindful of the ACR updates. The incidence of BRONJ from oral bisphosphonate therapy appears to be low, but combined with a history of chronic steroid therapy the morbidity becomes BSRONJ, which presents with potentially greater consequences.

A case of a 6-year-old girl with anti-neutrophil cytoplasmic autoantibody-negative pauci-immune crescentic glomerulonephritis

A 6-year-old girl was admitted to our hospital with proteinuria, hematuria, skin rash and joint pain of the lower limbs. Due to rapid progression of renal insufficiency, hemodialysis and peritoneal dialysis were performed. She was diagnosed with rapidly progressive glomerulonephritis. Kidney biopsy showed severe crescent formation (50% of glomeruli) and no deposition of any immunoglobulins or complements. Serologically, anti-neutrophil cytoplasmic autoantibody (ANCA) was negative not only by ELISA against proteinase-3 and myeloperoxidase-ANCA but also by indirect immunofluorescent assay against cytoplasmic and perinuclear ANCA. Anti-glomerular basement membrane antibody was also negative. In the acute phase, proinflammatory cytokines such as soluble tumor necrosis factor receptor 1 (sTNFR1), soluble interleukin (IL)-2 receptor (sIL2R), IL-6 and chemokine IL-8 were elevated. The patient was diagnosed with ANCA-negative pauci-immune crescentic glomerulonephritis (CrGN). Intensive treatment with methylprednisolone pulse therapy, plasma exchange, and multiple drug therapy including prednisolone and cyclophosphamide resulted in histopathological improvement and complete remission of proteinuria. There was a possibility that sTNFR1, sIL2R, IL-6 and IL-8 might be involved in the initiation and progression of ANCA-negative pauci-immune CrGN, and to remove and suppress these cytokines might be an effective way to treat ANCA-negative pauci-immune CrGN.

Aborto diferido como origen de una enfermedad trofoblástica persistente

Persistent trophoblastic disease can be diagnosed after any type of pregnancy, but the frequency of this entity increases after molar pregnancies and consequently early diagnosis and follow-up is vital for prompt and effective treatment. We present a case of missed abortion, with diagnosis of a complete hydatiform mole. Persistent trophoblastic disease was subsequently diagnosed, requiring treatment with multiple drug therapy to achieve complete resolution.

Response to Is It Ethical to Perform Irreversible Renal Denervation Before a Trial of Low Sodium Intake for Treatment-Resistant Hypertension?

We thank the authors of the letter1 for their timely reminder of the importance of maximizing nonpharmacological strategies in addition to use of multiple antihypertensive drug therapy in the treatment of patients with resistant hypertension. In the specific case of our proof-of-concept trial …

Future of Clinical Trials for Pulmonary Hypertension

> “It is better to lose the battle and win the war.” > > —Sun Tzu (circa 6th century BCE Chinese General and military strategist) In 1995, the first successful randomized controlled trial (RCT) for pulmonary arterial hypertension (PAH) led to the approval of the pulmonary vasodilator epoprostenol.1 Under the assumption that PAH was a disease of inappropriate pulmonary vasoconstriction, testing a drug that had vasodilator properties seemed reasonable. The 6-minute walk test was the primary end point in the trial because it was in keeping with the Food and Drug Administration precedent that an outcome assessment in a patient with cardiopulmonary disease needs to reflect how the patient feels, functions, or survives. Article see p 2985 There are now 7 vasodilator therapies for PAH, all approved because they improved exercise capacity for 3 to 4 months.2 Whether they affect long-term survival remains a valid question.3 Recently, a sobering report from a highly respected referral center in France noted that the current 3-year survival for patients with pulmonary hypertension managed with state-of-the-art multiple drug therapy was only 58%, marginally better than in 1980s when there were no treatments at all.4 In addition, it appears that these drugs do not protect patients from developing severe pulmonary vascular disease.5,6 Our knowledge of the pathobiology of PAH today is quite different from what it was 20 years ago. Scientific studies have demonstrated that cellular proliferation, inflammation, and thrombosis are the dominant underlying pathobiological processes and that chronic pulmonary vasoconstriction appears to play a relatively minor role.7 It is therefore understandable why the RCT by Kawut et al8 in this issue of Circulation chose to study the safety and efficacy of simvastatin and/or aspirin, therapies directed at normalizing endothelial cell function and platelet activation, as a treatment for …

Comparative Efficacy and Safety of Combination Aliskiren/Amlodipine and Amlodipine Monotherapy in African Americans With Stage 2 Hypertension

Initial multiple drug therapy for hypertension achieves greater and quicker reductions and higher blood pressure (BP) control rates than monotherapy. This 8-week, prospective, multicenter, randomized, double-blind study compared the efficacy and safety of the initial combination of aliskiren/amlodipine with amlodipine monotherapy in African Americans with stage 2 hypertension. After a 1- to 4-week washout, patients received aliskiren/amlodipine 150/5 mg or amlodipine 5 mg for 1 week and then were force-titrated to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for 7 weeks. At week 8, greater reductions in mean sitting systolic BP were obtained with aliskiren/amlodipine (n = 220) than with amlodipine (n = 223) (least squares mean change [standard error of the mean], -34.1 [1.14] mm Hg vs -28.9 [1.12] mm Hg; P<.001). Ambulatory and central BP measures were consistent with clinic BP findings, although these were conducted in a small subset of patients (n = 94 in ambulatory BP monitoring substudy and n = 136 for central BP). More patients achieved goal BP (<140/90 mm Hg) with aliskiren/amlodipine than with amlodipine at week 8 (57.3% vs 48.0%; P = .051). Both treatment groups had similar adverse event rates (35.0% and 32.7%, respectively). The most common adverse events were peripheral edema (7.7% with aliskiren/amlodipine and 9.0% with amlodipine), headache, fatigue, and nausea. The combination of aliskiren/amlodipine reduced peripheral, ambulatory, and central BP more than amlodipine alone with similar tolerability in African Americans with stage 2 hypertension.

Tapentadol in Pain Management

Several mechanisms can be proposed to explain an apparent synergistic analgesic action between μ-opioid and α(2)-adrenergic receptor agonists. Combining both effects in a single molecule eliminates the potential for drug-drug interactions inherent in multiple drug therapy. Tapentadol is the first US FDA-approved centrally acting analgesic having both μ-opioid receptor agonist and noradrenaline (norepinephrine) reuptake inhibition activity with minimal serotonin reuptake inhibition. This dual mode of action may make tapentadol particularly useful in the treatment of neuropathic pain. Having limited protein binding, no active metabolites and no significant microsomal enzyme induction or inhibition, tapentadol has a limited potential for drug-drug interactions. Clinical trial evidence in acute and chronic non-cancer pain and neuropathic pain supports an opioid-sparing effect that reduces some of the typical opioid-related adverse effects. Specifically, the reduction in treatment-emergent gastrointestinal adverse effects for tapentadol compared with equianalgesic pure μ-opioid receptor agonists results in improved tolerability and adherence to therapy for both the immediate- and extended-release formulations of tapentadol.

Polypharmacy in heart failure: A growing challenge

Current guidelines in heart failure recommend ‘add-on’ prescribing of evidence-based medicines aimed at improving symptoms and prognosis. Heart failure patients therefore commonly receive multiple drug therapies and this ‘polypharmacy’ is set to increase with the recognition of new potential drug targets. Drug regimes in heart failure are further complicated by increasing age and high levels of comorbidity inherent in this patient group. Nurses are central to the patient's care pathway and the commencement and titration of medicines are key component sof the patient's management plan. The development of nursing specialism in heart failure alongside independent prescribing have further extended nurse's responsibilities. Polypharmacy is an important consideration for nursing and this article provides an overview of the development of drug therapies in heart failure as well as the scope of polypharmacy for this group. The key implications of polypharmacy in heart failure will be explored, including side effects, drug interactions, prescription errors, optimal clinical prescribing and patient adherence.

Clinical utility of fixed-combination telmisartan&amp;ndash;amlodipine in the treatment of hypertension

The majority of hypertensive patients, especially those with target organ damage, are likely to require multiple-drug therapy in order to reach blood pressure (BP) targets and reduce their risk of adverse vascular outcomes. The rationale for combination therapy with agents that block the renin–angiotensin system (RAS) and a calcium channel blocker (CCB) or diuretic is well founded in growing evidence. Recent published trials have shown that the combination of an RAS suppressor and a dihydropiridinic CCB would offer additional benefits independently of BP reduction. A telmisartan–amlodipine combination has demonstrated significantly greater BP reductions compared with each monotherapy component in the overall population, and in particular in patients with moderate to severe hypertension and high-risk patients. This combination is well tolerated with a safety profile similar to placebo and is consistent with the known safety profile of its monotherapy components.

Abstract 4838: Longitudinal assessment of high risk t(4;14) multiple myeloma using next generation whole genome sequencing

Abstract Background: In order to understand the genetic events associated with disease progression and the development of drug resistance in multiple myeloma, we studied four longitudinally collected samples from a single, high risk, t(4;14) multiple myeloma patient. Samples over a four-year period were available from diagnosis, at time of first progression on lenalidomide, second progression while on bortezomib, at time of relapsed refractory disease and with end stage plasma cell leukemia. To better understand these genetic events, we utilized DNA extracted from germline tissue and CD138 purified bone marrow tumor cells to conduct whole genome sequencing (WGS) utilizing the Life Technologies SOLiD™ platform. Results: We have sequenced over 100 billion bases per sample with whole genome fragment library sequencing providing an average of 30X aligned coverage at all four time points studied. Each sample was aligned to the reference genome (NCBI36/hg18) with BFAST and post-alignment removal of duplicates and recalibration performed with Picard and Genome Analysis Toolkit (GATK) respectively. We then called point mutations with SolSNP and compared the germline sample to each tumor sample utilizing the Paired Mutation Walker. To date, we have identified 224 nonsynonymous point mutations within 217 genes. We then utilized the Sorting Intolerant from Tolerant (SIFT) algorithm and identified 109 potentially damaging point mutations which include 108 novel mutations in coding exons. Of the 224 somatic mutations observed, only 20 of these mutations are common to all tumor time points. Interestingly, the diagnostic and bortezomib refractory (second progression) samples had 11 mutations in common while the lenalidomide refractory (first progression) sample shared only 4 mutations in common with the bortezomib refractory sample. This suggests the presence of multiple clones at diagnosis that, due to treatment selection pressure, may emerge or regress as the dominant clone. Preliminary pathway analysis reveals the presence of mutations in genes regulating NFKB and Akt, whose pathways are often dysregulated in cancer. Conclusions: Whole genome sequencing has revealed evidence of mutational differences in exons between tumor and germline DNA indicative of the presence of multiple clones at diagnosis and evolution of these clones over time. This data supports the use of multiple drug therapies that target multiple clones and challenges the long held assumption that a patient who becomes refractory to a particular treatment will always be refractory to that treatment. Additional evaluation in a larger population is needed to confirm these findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4838. doi:10.1158/1538-7445.AM2011-4838

To ACCELERATE Hypertension Control

Introduction: According to the latest report from the US Centers for Disease Control and Prevention [1], 31% of adult population of the United States was reported to have hypertension between 2005 and 2008. Of this population, 70% received antihypertensive therapy, and of these, 46% had their condition controlled. Although these results show some improvements compared to previous reports [2], hypertension control is still less than optimal. This public health problem is associated with a major economic burden. Hypertension contributes to increased cardiovascular morbidity and mortality that costs nearly $300 billion a year. Thus, developing strategies to improve hypertension control constitutes a major goal. Most of the major hypertension clinical trials have suggested that a minimum of two antihypertensive drugs are needed to get blood pressure (BP) under control [3–5], but despite the availability of this information, the use of multiple drug therapy in managing hypertension is not widely practiced.

Dravet syndrome and SCN1A gene mutation related‐epilepsies: cognitive impairment and its determinants

Some studies have demonstrated that cognitive decline occurs in Dravet syndrome, starting shortly after the onset of seizures, rapidly progressing and then plateauing within a few years. It is unclear whether children that develop the syndrome had entirely normal cognitive skills before seizure onset, since subtle impairment easily escapes recognition in small infants. It is also difficult to demonstrate whether a recognisable profile of cognitive impairment or a definite behavioural phenotype exists. No clear-cut imaging or neuropathological marker or substrate has been recognised for cognitive impairment in this syndrome. However, there are different potentially causative factors, including the specific effects on the Nav1.1 channels caused by the underlying genic or genomic defect; frequent and prolonged convulsive and non-convulsive seizures or status epilepticus; recurrent subtle ictal phenomena, such as that accompanying pronounced visual sensitivity; the use of antiepileptic drugs with cognitive side effects, especially in heavy multiple-drug therapy; and the restrictions that children with severe epilepsy inevitably undergo.

The neuroprotective effects of NMDAR antagonist, ifenprodil and ASIC1a inhibitor, flurbiprofen on post-ischemic cerebral injury

Owing to the complex and multifactorial pathology of cerebral stroke, multiple drug therapy had long been advocated by STAIR committee for stroke successful treatment. In this context, we analyzed the effect of Ifenprodil, an NR2b selective NMDAR antagonist and its combination at lower doses with flurbiprofen, a selective ASIC1a inhibitor on rat model of focal cerebral ischemia. We found that the combination produced significant neuroprotective effect as produced by ifenprodil at higher doses, which was evidenced by reduction in infarct volume, neurological deficit and MDA levels. Further, histopathological studies revealed that, the combination not only attenuated the cell damage in striatal regions of ischemic brain, but also significantly inhibited apoptotic cell death, which was more pronounced than monotherapy with ifenprodil or flurbiprofen. Thus, it appears that the combination therapy will be more efficacious in offering neuroprotection on one hand and also lower the risks associated by mono-therapy with ifenprodil at higher doses.