Therapeutics and Clinical Risk Management

Intramuscular interferon beta-1a (IFNβ-1a), a multiple sclerosis (MS) therapy that has been commercially available for over a decade, provides a unique opportunity to retrospectively assess postmarketing data for evidence of malignancy risk, compared with relatively limited data available for more recently approved therapies. Postmarketing and claims data were analyzed to determine the risk of malignancy in MS patients treated with intramuscular IFNβ-1a. The cumulative reporting rates of suspected adverse drug reactions coded to malignancy in the intramuscular IFNβ-1a global safety database were compared with malignancy incidence rates in the World Health Organization GLOBOCAN database. In addition, using data from a large US claims database, the cumulative prevalence of malignancy in MS patients treated with intramuscular IFNβ-1a was compared with non-MS population controls, MS patients without intramuscular IFNβ-1a use, and untreated MS patients. Mean follow-up was approximately 3 years for all groups, ie, 3.1 years for the intramuscular IFNβ-1a group (range 0.02-6.0 years), 2.6 years for non-MS population controls (range 0-6.0 years), 2.6 years for the intramuscular IFNβ-1a nonuse group (range 0.01-6.0 years), and 2.4 years for the untreated MS group (range 0.01-6.0 years). An estimated 402,250 patients received intramuscular IFNβ-1a during the postmarketing period. Cumulative reporting rates of malignancy in this population were consistent with GLOBOCAN incidence rates observed within the general population. The claims database included 12,894 MS patients who received intramuscular IFNβ-1a. No significant difference in malignancy prevalence was observed in intramuscular IFNβ-1a users compared with other groups. Results from this evaluation provide no evidence of an increased risk of malignancy with intramuscular IFNβ-1a use.

Abacavir has been at the center of research and clinical interest in the last two years. The frequency of the associated abacavir hypersensitivity syndrome has decreased substantially since the introduction of routine testing for the HLA-B*5701 allele; the activity of the drug in HIV-infected persons with HIV RNA values more than 100,000 copies/mL has been questioned; the possible increased risk of myocardial infarction after recent exposure to abacavir has been debated; and the drug has been moved from the "recommended" category to the "alternative" category in several guidelines. Still, the drug remains a useful agent in combination with other drugs, including lamivudine, for the treatment of HIV infection. This review will focus on the pharmacokinetics, activity, side effects, and resistance profile of both abacavir and lamivudine, including a thorough review of all of the recent studies relevant to both drugs.

Medication errors may occur during prescribing, transcribing, prescription auditing, preparing, dispensing, administration, and monitoring. Medication administration errors (MAEs) are those that actually reach patients and remain a threat to patient safety. The Joint Commission International (JCI) advocates medication error prevention, but experience in reducing MAEs during the period of before and after JCI accreditation has not been reported. An intervention study, aimed at reducing MAEs in hospitalized patients, was performed in the Second Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China, during the journey to JCI accreditation and in the post-JCI accreditation era (first half-year of 2011 to first half-year of 2014). Comprehensive interventions included organizational, information technology, educational, and process optimization-based measures. Data mining was performed on MAEs derived from a compulsory electronic reporting system. The number of MAEs continuously decreased from 143 (first half-year of 2012) to 64 (first half-year of 2014), with a decrease in occurrence rate by 60.9% (0.338% versus 0.132%, P<0.05). The number of MAEs related to high-alert medications decreased from 32 (the second half-year of 2011) to 16 (the first half-year of 2014), with a decrease in occurrence rate by 57.9% (0.0787% versus 0.0331%, P<0.05). Omission was the top type of MAE during the first half-year of 2011 to the first half-year of 2014, with a decrease by 50% (40 cases versus 20 cases). Intravenous administration error was the top type of error regarding administration route, but it continuously decreased from 64 (first half-year of 2012) to 27 (first half-year of 2014). More experienced registered nurses made fewer medication errors. The number of MAEs in surgical wards was twice that in medicinal wards. Compared with non-intensive care units, the intensive care units exhibited higher occurrence rates of MAEs (1.81% versus 0.24%, P<0.001). A 3-and-a-half-year intervention program on MAEs was confirmed to be effective. MAEs made by nursing staff can be reduced, but cannot be eliminated. The depth, breadth, and efficiency of multidiscipline collaboration among physicians, pharmacists, nurses, information engineers, and hospital administrators are pivotal to safety in medication administration. JCI accreditation may help health systems enhance the awareness and ability to prevent MAEs and achieve successful quality improvements.

Language barrier, race, immigration status, mental health illness, substance abuse and socioeconomic status are often not considered when evaluating hepatitis C virus (HCV) sustained virological response (SVR) in human immunodeficiency virus (HIV) infection. The influence of these factors on HCV work-up, treatment initiation and SVR were assessed in an HIV-HCV coinfected population and compared to patients with HCV mono-infection. The setting was a publicly funded, urban-based, multidisciplinary viral hepatitis clinic. A clinical database was utilized to identify HIV and HCV consults between June 2000 and June 2007. Measures of access to HCV care (ie, liver biopsy and HCV antiviral initiation) and SVR as a function of the above variables were evaluated and compared between patients with HIV-HCV and HCV. HIV-HCV co-infected (n = 106) and HCV mono-infected (n = 802) patients were evaluated. HIV-HCV patients were more often white (94% versus 84%) and male (87% versus 69%). Bridging fibrosis or cirrhosis on biopsy was more frequent in HIV-HCV (37% versus 22%; P = 0.03). HIV infection itself did not influence access to biopsy (50% versus 52%) or treatment initiation (39% versus 38%). Race, language barrier, immigration status, injection drug history and socioeconomic status did not influence access to biopsy or treatment. SVR was 54% in HCV and 30% in HIV-HCV (P = 0.003). Genotype and HIV were the only evaluated variables to predict SVR. Within the context of a socialized, multidisciplinary clinic, HIV-HCV co-infected patients received similar access to HCV work-up and care as HCV mono-infected patients. SVR is diminished in HIV-HCV co-infection independent of language barrier, race, immigration status, or socioeconomic status.

An understanding of the risks, benefits, and relative value of glatiramer acetate (GA) in multiple sclerosis (MS) has been evolving based on recently completed head-to-head studies: REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease); BEYOND (Betaseron Efficacy Yielding Outcomes of a New Dose); and BECOME (BEtaseron vs COpaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-Tesla MRI Endpoints). Outcomes in the primary endpoints of these trials showed no significant differences between GA and high-dose beta-interferons (IFNbetas). Results of the PreCISe (Early GA Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis [CDMS] in Subjects Presenting With a Clinically Isolated Syndrome [CIS]) trial led to the US Food and Drug Administration approval of GA in patients with a CIS. Furthermore, the ongoing follow-up study to the original pivotal GA trial, now extending beyond 15 years, continues to support the safety of GA. Currently, GA and IFNbetas are no longer the only immunomodulators available for MS. Introduction of the monoclonal antibody, natalizumab (Tysabri((R)); Biogen Idec, Inc., Cambridge, MA, USA) provides an alternative immunomodulator for MS and has changed the therapeutic landscape dramatically. However, the rare but serious cases of progressive multifocal leukoencephalopathy that have occurred with natalizumab have raised concerns among clinicians and patients about using this agent and some of the emerging agents. The potential risks and benefits of the emerging therapies (cladribine, alemtuzumab, rituximab, fingolimod, laquinimod, teriflunomide, and dimethyl fumarate) based on phase II/III trials, as well as their use for indications other than MS, will be presented. This review provides available data on GA, natalizumab, and the emerging agents to support new developments in our understanding of GA and how its long-standing role as a first-line therapy in MS will evolve within the increasingly complex MS therapeutic landscape.

N-acetylglutamate synthase (NAGS) deficiency is a rare inborn error of metabolism affecting ammonia detoxification in the urea cycle. The product of NAGS is N-acetylglutamate which is the absolutely required allosteric activator of the first urea cycle enzyme carbamoylphosphate synthetase 1. In defects of NAGS, the urea cycle function can be severely affected resulting in fatal hyperammonemia in neonatal patients or at any later stage in life. NAGS deficiency can be treated with a structural analog of N-acetylglutamate, N-carbamyl-L-glutamate, which is available for enteral use as a licensed drug. Since NAGS deficiency is an extremely rare disorder, reports on the use of N-carbamyl-L-glutamate are mainly based on single patients. According to these, the drug is very effective in treating acute hyperammonemia by avoiding the need for detoxification during the acute metabolic decompensation. Also during long-term treatment, N-carbamyl-L-glutamate is effective in maintaining normal plasma ammonia levels and avoiding the need for additional drug therapy or protein-restricted diet. Open questions remain which concern the optimal dosage in acute and long-term use of N-carbamyl-L-glutamate and potential additional disorders in which the drug might also be effective in treating acute hyperammonemia. This review focuses on the role of N-carbamyl-L-glutamate for the treatment of acute hyperammonemia due to primary NAGS deficiency but will briefly discuss the current knowledge on the role of N-carbamyl-L-glutamate for treatment of secondary NAGS deficiencies.

Ceftaroline is a novel broad-spectrum cephalosporin β-lactam antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA) as well as multidrug-resistant Streptococcus pneumoniae among other routine Gram positive and Gram negative organisms. It has been approved by the US Food and Drug Administration for treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections (ABSSSIs). Ceftaroline is approved for treatment of ABSSSI due to MRSA, however currently there are no data for pneumonia due to MRSA in humans. Herein we review the major clinical trials as well as ceftaroline microbiology, pharmacokinetics, and safety, followed by a look at further directions for investigation of this new agent.

Prescriptions for opioid analgesics to manage moderate-to-severe chronic noncancer pain have increased markedly over the last decade, as have postmarketing reports of adverse events associated with opioids. As an unintentional consequence of greater prescription opioid utilization, there has been the parallel increase in misuse, abuse, and overdose, which are serious risks associated with all opioid analgesics. In response to these concerns, the Food and Drug Administration announced the requirement for a class-wide Risk Evaluation and Mitigation Strategy (REMS) for long-acting and extended-release (ER) opioid analgesics in April 2011. An understanding of the details of this REMS will be of particular importance to primary care providers. The class-wide REMS is focused on educating health care providers and patients on appropriate prescribing and safe use of ER opioids. Support from primary care will be necessary for the success of this REMS, as these clinicians are the predominant providers of care and the main prescribers of opioid analgesics for patients with chronic pain. Although currently voluntary, future policy will likely dictate that providers undergo mandatory training to continue prescribing medications within this class. This article outlines the elements of the class-wide REMS for ER opioids and clarifies the impact on primary care providers with regard to training, patient education, and clinical practice.

Bipolar affective disorder is a disabling illness with substantial morbidity and many management challenges. Traditional mood stabilizers such as lithium, valproate, and carbamazepine are often inadequate in controlling symptoms both during the acute and maintenance phase of treatment. Aripiprazole is a second-generation antipsychotic with a unique mechanism of action. Evidence suggests that it is effective in acute manic and mixed states. There are limited data to suggest its efficacy as a maintenance agent. Future studies will be needed to better define the role of aripiprazole relative to other traditional pharmacologic agents.

Ticagrelor is a novel P2Y₁₂ receptor antagonist which, like clopidogrel and prasugrel, functions by blocking adenosine diphosphate-mediated platelet aggregation. However, unlike the aforementioned agents, the binding of ticagrelor to this receptor is reversible. Ticagrelor is also believed to mediate some of its beneficial effects by augmenting the effects of adenosine, which is another unique pharmacologic property of this drug. In terms of antiplatelet effect, ticagrelor is more potent than clopidogrel and produces a faster and stronger inhibition of platelet aggregation. This may also be an advantage of ticagrelor over prasugrel, but this has not been adequately studied. Due to the reversible nature of the binding of ticagrelor to the platelet receptor, ticagrelor has a relatively fast offset of effect, with platelet aggregation approaching pretreatment levels about 3 days after discontinuation of therapy. This has advantages in patients requiring invasive procedures, but also makes medication adherence very important in order to be able to maintain an effective antiplatelet effect. Ticagrelor has been shown to be clinically superior to clopidogrel when given to patients with an acute coronary syndrome, resulting in significantly lower rates of myocardial infarction and vascular death. However, ticagrelor is indicated to be administered with aspirin, and the clinical benefits of ticagrelor may be less when daily dosages of aspirin exceed 100 mg. As expected, bleeding is the most common adverse effect with ticagrelor, although it occurs at rates comparable with those seen for clopidogrel with the exception of noncoronary artery bypass graft-related major bleeding and fatal intracranial bleeds, the latter of which occurs only rarely. Dyspnea is another common adverse effect with ticagrelor, although this is usually not severe and resolves with drug discontinuation. Unlike clopidogrel, there are no known pharmacogenomic concerns with ticagrelor, and emerging data suggest ticagrelor to be effective in patients resistant to clopidogrel, although more study is needed on this topic. While preliminary data suggest ticagrelor to be cost effective when compared with generic clopidogrel, the acquisition cost of ticagrelor is not insignificant and this will likely be an issue for many health care organizations. Currently, ticagrelor is well positioned to assume an active role in the treatment of coronary artery disease due to an impressive efficacy profile and reasonable safety. Its ultimate role in therapy will continue to evolve as studies on this drug continue eg, (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin, PEGASUS) and more information hopefully becomes available on its use in clopidogrel nonresponders and relative safety and efficacy compared with prasugrel.

Drug efficacy might differ from clinical trial results when performed in clinical daily conditions. Therefore, it is mandatory to conduct trials about effectiveness to improve external validity. This post-authorization, open-label, noncontrolled, prospective, multicenter, observational, and naturalistic trial was designed to search for factors influencing the racecadotril overall effect on childhood acute watery diarrhea in a real-world setting of Venezuela. There were 3,873 children with acute watery diarrhea treated with racecadotril, an enkephalin breakdown blocker plus oral rehydration therapy by 97 pediatricians. Evaluations were carried out daily until emission of two consecutive formed stools or absence of watery bowel movements for 24 hours. The primary end-point was time-to-relief, defined as the time from first racecadotril dose to the last watery bowel movement time. Age, gender, nursing type, nursing status during diarrhea, diarrhea severity, and co-medication were considered as factors in the statistical analysis. The primary end-point was evaluated by factors using UNIANOVA, and post-hoc tests were done. A multiple regression analysis was carried out to identify factors affecting drug performance, racecadotril effectiveness and tolerability overall assessment was searched by physicians and patients, and inter-observer agreement was evaluated by kappa statistics. The mean time-to-relief was 18.5 +/- 12.5 hours [95% confidence interval 17.9-19.0] and the diarrhea severity was the only variable with significant and independent weight on racecadotril effectiveness explaining 23% of time-to-relief variance, but even in severe diarrhea cases this time was less than 24 hours. High agreement about satisfactory perception on effectiveness and tolerability was reached among physicians and patients. In conclusion, the racecadotril overall effect, evaluated in a real-world setting of Venezuela, was in agreement with results of some earlier controlled trials. It was only influenced by severity of diarrhea episode, as well as being considered an effective and well tolerated treatment by physicians and patients.

Type 2 diabetes is associated with decreased incretin hormone response to an oral glucose load, and a progressive decline in postprandial glucagon-like peptide-1 (GLP-1) secretion. Incretin-based therapies offer a new option for treatment of type 2 diabetes. Saxagliptin, a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor specifically designed for extended inhibition of the DPP-4 enzyme, causes increased endogenous GLP-1 concentration. In a phase 3 clinical trials program of 24 weeks duration, saxagliptin was studied in 6 multicenter, multinational, randomized, controlled studies and in combination with 3 of the most commonly administered oral antidiabetic drugs: metformin, glyburide and a thiozolidinedione (TZD). Saxagliptin provided significant reductions in hemoglobin HbA(1c) when given with metformin, glyburide, a TZD, or as monotherapy. Saxagliptin also reduced fasting plasma glucose and 2-hour post-prandial glucose in each of these studies, and was weight and lipid neutral. Saxagliptin was well tolerated and had a low risk of hypoglycemia when used as monotherapy.

Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder characterized by atypical levels of inattention, hyperactivity, and impulsivity that impair daily living activities. Although commonly associated with children and adolescents, current literature and practice now demonstrate the impairment the disorder may impose on adults as well. Central nervous system (CNS) stimulant medications are the first-line therapy for ADHD. CNS stimulants include methylphenidate and amphetamine derivatives. Longer-acting formulations used once daily are often preferred to avoid medication administration during school or work as well as to avoid side effects associated with rapid fluctuations in serum concentrations associated with multiple daily dosing. Lisdexamfetamine, a new, novel amphetamine product, has been shown to provide efficacy upwards of 12 hours in children and adults with a side effect profile similar to those of other longer-acting amphetamine products. Owing to its unique prodrug composition and the need for oral administration to activate the medication, lisdexamfetamine may offer advantages in clinical situations where stimulant abuse is a concern.

Eslicarbazepine is a new dibenzazepine antiepileptic agent. It is a high affinity antagonist of the voltage-gated sodium channel. It is closely related to both carbamazepine and oxcarbazepine. Eslicarbazepine has similar affinity to inactivated sodium channels (channels in just activated neurons) as carbamazepine, and greater efficacy in animal models of seizure than oxcarbazepine. In human placebo-controlled trials of a single daily dose of eslicarbazepine added to other anti-epileptic agents, significant seizure reductions occurred with 800 and 1200 mg daily, with nearly half of the patients experiencing a greater than 50% reduction in seizure frequency. Adverse events (AEs) occurred in over 50% of patients receiving therapeutic doses of eslicarbazepine (compared to 31.4%-44.7% of placebo-treated subjects), but were generally mild or moderate. Eight to 19.6% of eslicarbazepine treated patients discontinued due to AEs (compared to 3.9%-8.5% of placebo-treated subjects). In these patients receiving combination anticonvulsant therapy, the most common AEs were dizziness, nausea and vomiting, somnolence, and diplopia. Eslicarbazepine is an effective and reasonably well-tolerated adjunct in patients with suboptimal control of their partial seizures.

Poor reporting of adverse drug reactions (ADRs) by doctors is a major hindrance to successful pharmacovigilance. The present study was designed to assess first-year residents' knowledge of ADR reporting. First-year postgraduate doctors at a private medical college completed a structured questionnaire. The responses were analyzed by nonparametric methods. All doctors were aware of the term "adverse drug reactions." Fifty percent of the doctors reported being taught about ADR reporting during their undergraduate teaching, and 50% had witnessed ADRs in their internship training. Ten percent of patients suffering an ADR observed and reported by doctors required prolonged hospitalization for treatment as a result. Only 40% of interns reported the ADRs that they observed, while 60% did not report them. Twenty-eight percent reported ADRs to the head of the department, 8% to an ADR monitoring committee, and 4% to the pharmacovigilance center. Eighty-six percent of the doctors surveyed felt that a good knowledge of undergraduate clinical pharmacology therapeutics would have improved the level of ADR reporting. The knowledge of first-year doctors regarding ADR reporting is quite poor. There is a dire need to incorporate ADR reporting into undergraduate teaching, and to reinforce this during internships and periodically thereafter.

Aquacel Ag((R)) (ConvaTec, Princeton, NJ, USA) is a new hydrofiber wound dressing consisting of soft non-woven sodium carboxymethylcellulose fibers integrated with ionic silver. It is a moisture-retention dressing, which forms a gel on contact with wound fluid and has antimicrobial properties of ionic silver. We present a current literature review on Aquacel Ag((R)), of both in vitro and in vivo efficacy and clinical applications. In vitro and in vivo studies have demonstrated the wide antimicrobial properties of Aquacel Ag((R)), and additionally demonstrated the cytotoxicity of ionic silver to keratinocytes and fibroblasts that cause delay in wound re-epithelialization. Clinical studies confirmed that Aquacel Ag((R)) is an effective and safe dressing for a variety of wound types, both acute and chronic. Incorporation of ionic silver into the hydrofibers does not cause undue alteration in the performance properties of the base dressing, which continues to provide favorable wound moisture and exudate management. The addition of ionic silver reduces local pain and dressing changes, and provides significant broad-spectrum antimicrobial properties, with no delay in wound healing.

Recently, multiple C1 inhibitor (C1-INH) replacement products have been approved for the treatment of hereditary angioedema (HAE). This review summarizes HAE and its current treatment modalities and focuses on findings from bench to bedside trials of a new C1-INH replacement, conestat alfa. Conestat alfa is unique among the other C1-INH replacement products because it is produced from transgenic rabbits rather than derived from human plasma donors, which can potentially allow an unlimited source of drug without any concern of infectious transmission. The clinical trial data generated to date indicate that conestat alfa is safe and effective for the treatment of acute HAE attacks.

The most common of the neuropathies associated with diabetes mellitus, diabetic sensorimotor polyneuropathy (DSPN) is a syndrome of diffuse, length-dependent, symmetric nerve dysfunction. The condition is linked with substantial morbidity, frequent healthcare utilization, and compromised quality of life due to related discomfort. Correspondingly, antidepressants, anticonvulsants, and opioids are regularly prescribed with the goal of pain control. However, the agents rarely provide complete pain relief and fail to address progression of the disorder. Whereas strict blood glucose control can slow the onset and worsening of DSPN, near-normoglycemia is not easily attainable. Evidence implicating oxidative processes in the pathogenesis of DSPN offers one potentially important therapeutic avenue. Due to its properties as a potent antioxidant, alpha lipoic acid (ALA) could mitigate the development of DSPN and attenuate resultant symptoms and signs. Approved for treatment of DSPN in Germany, the agent is not more widely used due to uncertainty about its efficacy and reported adverse effects. Here we review the effectiveness and tolerability of ALA in the treatment of symptomatic DSPN. The MEDLINE, EMBASE, and Cochrane Library databases were searched for English-language literature on the topic. Randomized, blinded studies comparing parenteral and oral ALA with placebo in the treatment of peripheral neuropathy in diabetic adults were selected. Analysis included studies with a level of evidence of at least 2b. The current appraisal summarizes data from 1160 participants in the ALADIN, SYDNEY, ORPIL, SYDNEY 2, and ALADIN III trials. In four of the studies, ALA provided significant improvement in manifestations of DSPN. Treatment with ALA 600 mg iv daily for 3 weeks represents a well-tolerated and effective therapy for DSPN. An oral dose of 600 mg daily administered for up to 5 weeks could offer benefits in symptoms and signs of DSPN without significant side effects.

Shailendra KapoorMechanicsville, Richmond, VA, USAThe recent article by Villesen et al in a recent issue of your journal was most interesting.1 Recent studies show that the potency of morphine in efficacious pain control may be influenced greatly by polymorphisms of certain genes.View original paper by Villesen and colleagues.

The purpose of this paper was to demonstrate the use of an online service for conducting a systematic review and meta-analysis of the efficacy of topical prostaglandin analogs in reducing intraocular pressure (IOP) in glaucoma and ocular hypertension. An online service provider (Doctor Evidence) reviewed and extracted data from the peer-reviewed literature through September 2009. Randomized controlled studies of at least three months' duration assessing at least two prostaglandin analogs in patients with primary open-angle glaucoma, ocular hypertension, or normal-tension glaucoma were included. The primary endpoint was mean IOP. Summary estimates were created using random-effects models. The Q Chi-square test was used to assess statistical heterogeneity. Sixteen studies satisfied the inclusion criteria and were analyzed. On average, greater IOP-lowering was seen with bimatoprost relative to latanoprost (1 mmHg, P = 0.025) and travoprost (0.8 mmHg, P = 0.033) based on mean IOP after 12-26 weeks of treatment. No statistical difference was observed in IOP-lowering between latanoprost and travoprost (P = 0.841). Findings were similar to previously published meta-analyses of topical prostaglandin analogs. Systematic reviews relying on meta-analytic techniques to create summary statistics are considered to be the "gold standard" for synthesizing evidence to support clinical decision-making. However, the process is time-consuming, labor-intensive, and outside the capability of most formulary managers. We have demonstrated the effectiveness of a commercial service that facilitates the process of conducting such reviews.

Osteoarthritis is common in patients ≥65 years of age. Although nonsteroidal anti-inflammatory drugs (NSAIDs) are often prescribed for osteoarthritis pain, they pose age-related cardiovascular, renal, and gastrointestinal risks. Two topical NSAIDs, diclofenac sodium 1% gel (DSG) and diclofenac sodium 1.5% in 45.5% dimethylsulfoxide solution (D-DMSO), are approved in the US for the treatment of osteoarthritis pain. Topical NSAIDs have shown efficacy and safety in knee (DSG, D-DMSO) and hand (DSG) osteoarthritis. Analyses of data from randomized controlled trials of DSG in hand and knee osteoarthritis demonstrate significant improvement of pain and function in both younger patients (<65 years) and older patients (≥65 years) and suggest good safety and tolerability. However, long-term safety data in older patients are limited. Topical NSAIDs can ease medication administration and help address barriers to pain management in older patients, such as taking multiple medications and inability to swallow, and are a valuable option for long-term care providers.

Parenteral anticoagulation followed by warfarin has been conventionally used for the treatment of venous thromboembolism (VTE). However, there are numerous troublesome characteristics of warfarin that prompted the development of novel oral anticoagulants (NOACs) for the treatment of VTE. Asians are reported to be at an increased risk of bleeding with warfarin, and while the reported incidence of VTE in Asians is lower than in Caucasians, the annual rate of VTE in Asia is rising along with the need for better oral anticoagulant options. Recently, several Phase III clinical trials with NOACs for the treatment and prevention of VTE recurrence have been published. For the treatment of VTE, the four NOACs - dabigatran, rivaroxaban, apixaban, and edoxaban - each showed comparable efficacy outcomes while resulting in better safety outcomes when compared with conventional treatment. In these trials, Asian patients had comparable efficacy and safety outcomes as other races, except in the edoxaban trial, in which the Asian subgroup had better safety profiles than other races, although further confirmation is necessary. For secondary prevention, dabigatran was compared with conventional treatment and showed similar efficacy and safety outcomes. When NOACs were compared with placebo for secondary prevention of VTE, they showed superior efficacy and increased bleeding except for apixaban, which showed comparable major bleeding and composite of major and clinically relevant nonmajor bleeding rates as placebo. No significant differences in the outcomes based on race were observed in the Asian subgroups for secondary prevention. Therefore, NOACs can be used with similar efficacy and at least similar or superior safety compared with conventional treatment in the treatment of VTE, and at no increased risk in Asian patients.

Fungi are a frequent cause of nosocomial infections, with an incidence that has increased significantly in recent years, especially among critically ill patients who require intensive care unit (ICU) admission. Among ICU patients, postsurgical patients have a higher risk of Candida infections in the bloodstream. In consideration of the high incidence of fungal infections in these patients, their strong impact on mortality rate, and of the difficulties in Candida diagnosis, some experts suggest the use of antifungal prophylaxis in critically ill surgical patients. A clinical benefit from this strategy has been demonstrated, but the economic impact of the use of antifungal prophylaxis in surgical patients has not been systematically evaluated, and its cost-benefit ratio has not been defined. Whereas the costs associated with treating fungal infections are very high, the cost of antifungal drugs varies from affordable (ie, the older azoles) to expensive (ie, echinocandins, polyenes, and the newer azoles). Adverse drug-related effects and the possibly increased incidence of fluconazole resistance and of isolates other than Candida albicans must also be taken into account. From the published studies of antifungal prophylaxis in surgical patients, a likely economic benefit of this strategy could be inferred, but its usefulness and cost-benefits should be evaluated in light of local data, because the available evidence does not permit general recommendations.

Recently, multiple C1 inhibitor (C1-INH) replacement products have been approved for the treatment of hereditary angioedema (HAE). This review summarizes HAE and its current treatment modalities and focuses on findings from bench to bedside trials of a new C1-INH replacement, conestat alfa. Conestat alfa is unique among the other C1-INH replacement products because it is produced from transgenic rabbits rather than derived from human plasma donors, which can potentially allow an unlimited source of drug without any concern of infectious transmission. The clinical trial data generated to date indicate that conestat alfa is safe and effective for the treatment of acute HAE attacks.

The most common of the neuropathies associated with diabetes mellitus, diabetic sensorimotor polyneuropathy (DSPN) is a syndrome of diffuse, length-dependent, symmetric nerve dysfunction. The condition is linked with substantial morbidity, frequent healthcare utilization, and compromised quality of life due to related discomfort. Correspondingly, antidepressants, anticonvulsants, and opioids are regularly prescribed with the goal of pain control. However, the agents rarely provide complete pain relief and fail to address progression of the disorder. Whereas strict blood glucose control can slow the onset and worsening of DSPN, near-normoglycemia is not easily attainable. Evidence implicating oxidative processes in the pathogenesis of DSPN offers one potentially important therapeutic avenue. Due to its properties as a potent antioxidant, alpha lipoic acid (ALA) could mitigate the development of DSPN and attenuate resultant symptoms and signs. Approved for treatment of DSPN in Germany, the agent is not more widely used due to uncertainty about its efficacy and reported adverse effects. Here we review the effectiveness and tolerability of ALA in the treatment of symptomatic DSPN. The MEDLINE, EMBASE, and Cochrane Library databases were searched for English-language literature on the topic. Randomized, blinded studies comparing parenteral and oral ALA with placebo in the treatment of peripheral neuropathy in diabetic adults were selected. Analysis included studies with a level of evidence of at least 2b. The current appraisal summarizes data from 1160 participants in the ALADIN, SYDNEY, ORPIL, SYDNEY 2, and ALADIN III trials. In four of the studies, ALA provided significant improvement in manifestations of DSPN. Treatment with ALA 600 mg iv daily for 3 weeks represents a well-tolerated and effective therapy for DSPN. An oral dose of 600 mg daily administered for up to 5 weeks could offer benefits in symptoms and signs of DSPN without significant side effects.

Shailendra KapoorMechanicsville, Richmond, VA, USAThe recent article by Villesen et al in a recent issue of your journal was most interesting.1 Recent studies show that the potency of morphine in efficacious pain control may be influenced greatly by polymorphisms of certain genes.View original paper by Villesen and colleagues.

The purpose of this paper was to demonstrate the use of an online service for conducting a systematic review and meta-analysis of the efficacy of topical prostaglandin analogs in reducing intraocular pressure (IOP) in glaucoma and ocular hypertension. An online service provider (Doctor Evidence) reviewed and extracted data from the peer-reviewed literature through September 2009. Randomized controlled studies of at least three months' duration assessing at least two prostaglandin analogs in patients with primary open-angle glaucoma, ocular hypertension, or normal-tension glaucoma were included. The primary endpoint was mean IOP. Summary estimates were created using random-effects models. The Q Chi-square test was used to assess statistical heterogeneity. Sixteen studies satisfied the inclusion criteria and were analyzed. On average, greater IOP-lowering was seen with bimatoprost relative to latanoprost (1 mmHg, P = 0.025) and travoprost (0.8 mmHg, P = 0.033) based on mean IOP after 12-26 weeks of treatment. No statistical difference was observed in IOP-lowering between latanoprost and travoprost (P = 0.841). Findings were similar to previously published meta-analyses of topical prostaglandin analogs. Systematic reviews relying on meta-analytic techniques to create summary statistics are considered to be the "gold standard" for synthesizing evidence to support clinical decision-making. However, the process is time-consuming, labor-intensive, and outside the capability of most formulary managers. We have demonstrated the effectiveness of a commercial service that facilitates the process of conducting such reviews.

Osteoarthritis is common in patients ≥65 years of age. Although nonsteroidal anti-inflammatory drugs (NSAIDs) are often prescribed for osteoarthritis pain, they pose age-related cardiovascular, renal, and gastrointestinal risks. Two topical NSAIDs, diclofenac sodium 1% gel (DSG) and diclofenac sodium 1.5% in 45.5% dimethylsulfoxide solution (D-DMSO), are approved in the US for the treatment of osteoarthritis pain. Topical NSAIDs have shown efficacy and safety in knee (DSG, D-DMSO) and hand (DSG) osteoarthritis. Analyses of data from randomized controlled trials of DSG in hand and knee osteoarthritis demonstrate significant improvement of pain and function in both younger patients (<65 years) and older patients (≥65 years) and suggest good safety and tolerability. However, long-term safety data in older patients are limited. Topical NSAIDs can ease medication administration and help address barriers to pain management in older patients, such as taking multiple medications and inability to swallow, and are a valuable option for long-term care providers.

Parenteral anticoagulation followed by warfarin has been conventionally used for the treatment of venous thromboembolism (VTE). However, there are numerous troublesome characteristics of warfarin that prompted the development of novel oral anticoagulants (NOACs) for the treatment of VTE. Asians are reported to be at an increased risk of bleeding with warfarin, and while the reported incidence of VTE in Asians is lower than in Caucasians, the annual rate of VTE in Asia is rising along with the need for better oral anticoagulant options. Recently, several Phase III clinical trials with NOACs for the treatment and prevention of VTE recurrence have been published. For the treatment of VTE, the four NOACs - dabigatran, rivaroxaban, apixaban, and edoxaban - each showed comparable efficacy outcomes while resulting in better safety outcomes when compared with conventional treatment. In these trials, Asian patients had comparable efficacy and safety outcomes as other races, except in the edoxaban trial, in which the Asian subgroup had better safety profiles than other races, although further confirmation is necessary. For secondary prevention, dabigatran was compared with conventional treatment and showed similar efficacy and safety outcomes. When NOACs were compared with placebo for secondary prevention of VTE, they showed superior efficacy and increased bleeding except for apixaban, which showed comparable major bleeding and composite of major and clinically relevant nonmajor bleeding rates as placebo. No significant differences in the outcomes based on race were observed in the Asian subgroups for secondary prevention. Therefore, NOACs can be used with similar efficacy and at least similar or superior safety compared with conventional treatment in the treatment of VTE, and at no increased risk in Asian patients.

Fungi are a frequent cause of nosocomial infections, with an incidence that has increased significantly in recent years, especially among critically ill patients who require intensive care unit (ICU) admission. Among ICU patients, postsurgical patients have a higher risk of Candida infections in the bloodstream. In consideration of the high incidence of fungal infections in these patients, their strong impact on mortality rate, and of the difficulties in Candida diagnosis, some experts suggest the use of antifungal prophylaxis in critically ill surgical patients. A clinical benefit from this strategy has been demonstrated, but the economic impact of the use of antifungal prophylaxis in surgical patients has not been systematically evaluated, and its cost-benefit ratio has not been defined. Whereas the costs associated with treating fungal infections are very high, the cost of antifungal drugs varies from affordable (ie, the older azoles) to expensive (ie, echinocandins, polyenes, and the newer azoles). Adverse drug-related effects and the possibly increased incidence of fluconazole resistance and of isolates other than Candida albicans must also be taken into account. From the published studies of antifungal prophylaxis in surgical patients, a likely economic benefit of this strategy could be inferred, but its usefulness and cost-benefits should be evaluated in light of local data, because the available evidence does not permit general recommendations.

Niacin is a B-complex vitamin which has been used for decades for the management of mixed dyslipidemias and primary hypercholesterolemia. It decreases the risk of cardiovascular events either when used as a monotherapy or in combination with other lipid lowering medications. However, a major limitation to its use is niacin-induced flushing occurring even with the extended-release formulations. Laropiprant, a selective prostaglandin-2 receptor inhibitor, specifically targets the cascade of events causing the flushing. It has been recently used in combination with extended-release niacin. This article will review the early experience with this combination with focus on efficacy, safety, tolerability and current place in therapy. Early data are promising and suggest that more patients in clinical practice will benefit from niacin combined with laropiprant. Ongoing clinical trials will provide a better insight on the long-term safety of the drug and its efficacy for reducing cardiovascular events.

A utilization study was performed in a 2200-bed tertiary care teaching hospital. Data mining was performed on all nasogastric medication prescriptions for patients hospitalized in 2011. Nurses were interviewed by questionnaire. A PDCA (Plan-Do-Check-Act) cycle was used for continuous quality improvement. The proportion of patients with nasogastric tubes (NGT) was 3.2%. A large number of medical orders (n = 6261) involved nasogastric medications with a package insert particularly noting that they should not be crushed or opened (group 1) or medications without a specific formulation recommendation in the package insert but having evidence discouraging NGT dosing (group 2). Of the nasogastrically administered sustained-release or controlled-release formulations, a sustained-release sodium valproate tablet formulation was the most prescribed drug and a sustained-release 2.5 mg felodipine tablet was prescribed with the highest proportion of NGT dosing [NGT/(NGT + oral) = 12.3%]. Among the nasogastrically administered enteric-coated formulations, a myrtol-standardized enteric-coated capsule formulation was the most prescribed drug and a pantoprazole tablet formulation was prescribed with the highest proportion of NGT dosing [NGT/(NGT + oral) = 19.3%]. Proportions of NGT dosing for amiodarone and carbamazepine (group 2) were 4.8% and 6.3%, respectively. The percentage of nurses with adequate knowledge about pharmaceutical dosage formulations was 60%. The rate of answering correctly as to whether medications in group 1 could be crushed or opened was only 30%. Awareness of evidence discouraging NGT dosing of medications in group 2 was zero. Most nurses (90%) left physicians and pharmacists with the entire responsibility for knowledge and decision-making concerning route of drug administration. After a 3-month preliminary intervention, irrational medical orders involving nasogastric administration of medications in group 1 were successfully abolished. The rate of answering correctly as to whether medications in group 1 could be crushed or opened increased to 100%. This utilization study indicates poor awareness concerning nasogastric administration of medication on the part of physicians and nurses, and preliminary intervention measures were efficient in improving knowledge through team cooperation and effort.

This study retrospectively compared the continuous epidural infusion of morphine with a single epidural injection of extended-release morphine for postoperative pain control after arthroplasty. Medical records were reviewed for subjects who had total knee or hip arthroplasty (THA) under spinal anesthesia and received either a continuous epidural infusion of morphine (Group EPID; n = 101) or an extended-release epidural morphine (Group EREM; n = 109) for postoperative pain. Data were collected for three postoperative days (POD) on: pain scores; supplemental opioids; medications for respiratory depression, nausea, and pruritus, and distance ambulated during physical therapy. Pain scores were similar until subjects were transitioned to another analgesic approach on POD 2; after that time, pain scores increased in Group EPID, although they decreased in Group EREM. Supplemental opioids were used more on POD1 in Group EREM than in Group EPID, although time to first opioid and total daily morphine equivalents were similar. Naloxone and antiemetics, not antipruritics, were used more in Group EREM. Distance ambulated after THA was greater in Group EREM than in Group EPID. These results suggest that EREM is associated with better postoperative ambulation and analgesia during the transition to oral or intravenous analgesics, although a higher incidence of side-effects was evident.

Trichosporon asahii is an emerging opportunistic pathogen that is life-threatening particularly for immunosuppressed patients. Only a few studies have described Trichosporon infection in kidney transplant recipients. This study reports a 67-year-old male kidney transplant recipient who developed fatal fungemia and pneumonia caused by T. asahii during caspofungin treatment. Although funguria is benign, kidney transplant recipients are still at risk of T. asahii fungemia and invasive T. asahii infection even if they are under antifungal therapy, particularly echinocandins.

Multifactor cardiovascular disease is the leading cause of death; besides well-known cardiovascular risk factors, several emerging factors such as mental stress, diet type, and physical inactivity, have been associated to cardiovascular disease. To date, preventive strategies are based on the concept of absolute risk calculated by different algorithms and scoring systems. However, in general practice the patient's data collection represents a critical issue. A new multipurpose computer-based program has been developed in order to:1) easily calculate and compare the absolute cardiovascular risk by the Framingham, Procam, and Progetto Cuore algorithms; 2) to design a web-based computerized tool for prospective collection of structured data; 3) to support the doctor in the decision-making process for patients at risk according to recent international guidelines. During a medical consultation the doctor utilizes a common computer connected by Internet to a medical server where all the patient's data and software reside. The program evaluates absolute and relative cardiovascular risk factors, personalized patient's goals, and multiparametric trends, monitors critical parameter values, and generates an automated medical report. In a pilot study on 294 patients (47% males; mean age 60 ± 12 years [±SD]) the global time to collect data at first consultation was 13 ± 11 minutes which declined to 8 ± 7 minutes at the subsequent consultation. In 48.2% of cases the program revealed 2 or more primary risk factor parameters outside guideline indications and gave specific clinical suggestions to return altered parameters to target values. The web-based system proposed here may represent a feasible and flexible tool for clinical management of patients at risk of cardiovascular disease and for epidemiological research.

Ciclesonide is a nonhalogenated synthetic inhaled corticosteroid (ICS) that has been approved by the US Food and Drug Administration for the treatment of all severities of persistent asthma. It is available as a hydrofluroalkane pressurized metered-dose inhaler in two strengths, 80 mcg/activation and 160 mcg/activation, with the recommenced dosage being two inhalations twice-daily. It is a prodrug that is converted in the lung to its active form, which possesses 100-fold greater glucocorticoid-receptor-binding affinity than the parent compound. Its relative receptor affinity is similar to budesonide. In clinical studies, ciclesonide was effective in improving pulmonary function, reducing asthma symptoms, and reducing or eliminating the need for oral corticosteroids (OCSs). Patients with severe asthma dependent on OCSs and high doses of ICSs were able to achieve greater asthma control and reduce or even eliminate the use of OCSs when switched to ciclesonide. In comparison with fluticasone propionate and budesonide, ciclesonide was demonstrated to be at least as effective in maintaining pulmonary function and asthma control. In clinical trials, ciclesonide was well tolerated, with the majority of adverse events considered mild or moderate in intensity. It had low systemic bioavailability and no clinically significant hypothalamic-pituitary-adrenal axis suppression at therapeutic doses. Its safety profile establishes ciclesonide as an important addition to the currently available ICSs.

Leishmaniasis is an important vector-borne disease, and it is classified as one of the most important tropical fly-borne infections. This disease can cause two types of clinical manifestations: cutaneous forms and visceral forms. Visceral leishmaniasis, which is also called kala-azar, is a very serious infection that can be fatal. The management of visceral leishmaniasis requires informed diagnostic and therapeutic approaches. Continuous research and development regarding the treatment of visceral leishmaniasis had led to many improvements. Paromomycin is a relatively new antibiotic drug that has been used for the treatment of visceral leishmaniasis for several years. This article reviews and discusses the use of paromomycin for visceral leishmaniasis therapy.

Naftopidil, approved only in Japan, is an α1-adrenergic receptor antagonist (α1-blocker) used to treat lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). Different from tamsulosin hydrochloride and silodosin, in that it has higher and extremely higher affinity respectively, for the α1A-adrenergic receptor subtype than for the α1D type, naftopidil has distinct characteristics because it has a three times greater affinity for the α1D-adrenergic receptor subtype than for the α1A subtype. Although well-designed large-scale randomized controlled studies are lacking and the optimal dosage of naftopidil is not always completely determined, previous reports from Japan have shown that naftopidil has superior efficacy to a placebo and comparable efficacy to other α1-blockers such as tamsulosin. On the other hand, the incidences of ejaculatory disorders and intraoperative floppy iris syndrome induced by naftopidil may be lower than for tamsulosin and silodosin having high affinity for the α1A-adrenergic receptor subtype. However, it remains unknown if the efficacy and safety of naftopidil in Japanese is applicable to white, black and Hispanic men having LUTS/BPH in western countries.

Occasionally, urologists may see patients requiring temporary bladder irrigation at hospitals without stocks of specialist irrigation apparatus. One option is to transfer the patient to a urology ward, but often there are outstanding medical issues that require continued specialist input. Here, we describe an improved system for delivering temporary bladder irrigation by utilizing readily available components and the novel modification of a sphygmomanometer blub. This option is good for bladder irrigation in patients with moderate or severe gross hematuria due to various causes. In this prospective study from March 2007 to April 2009, we used our new system in eligible cases. In this system, an irrigant bag with 1 L of normal saline was suspended 80 cm above the indwelled 3-way Foley catheter, and its drainage tube was inserted into the irrigant port of the catheter. To increase the flow rate of the irrigant system, we inserted a traditional sphygmomanometer bulb at the top of the irrigant bag. This closed system was used for continuous bladder irrigation (CBI) in patients who underwent open prostatectomy, transurethral resection of the prostate (TURP), or transurethral resection of the bladder (TURB). This high-pressure system is also used for irrigation during cystourethroscopy, internal urethrotomy, and transurethral lithotripsy. Our 831 eligible cases were divided into two groups: group 1 were endourologic cases and group 2 were open prostatectomy, TURP, and TURB cases. The maximum and average flow rates were evaluated. The efficacy of our new system was compared prospectively with the previous traditional system used in 545 cases. In group 1, we had clear vision at the time of endourologic procedures. The success rate of this system was 99.5%. In group 2, the incidence of clot retention decreased two fold in comparison to traditional gravity-dependent bladder flow system. These changes were statistically significant (P = 0.001). We did not observe any adverse effects such as bladder perforation due to our high-pressure, high-flow system. A pressurized irrigant system has better visualization during endourologic procedures, and prevents clot formation after open prostatectomy, TURP, and TURB without any adverse effects.

This retrospective cohort study evaluated whether manual lymphatic drainage (MLD) therapy increases the risk of recurrence of breast cancer. We analyzed 1,106 women who were diagnosed with stage 0-3 breast cancer between 2007 and 2011 and experienced remission after surgery and adjuvant therapy. The patients were divided into two groups: group A (n=996), in which patients did not participate in any MLD therapy, regardless of whether they developed breast cancer-related lymphedema (BCRL) after cancer treatment; and group B (n=110), in which patients participated in MLD therapy for BCRL. All patients were monitored until October 2013 to determine whether breast cancer recurrence developed, including local or regional recurrence and distant metastasis. Patients who developed cancer recurrence prior to MLD therapy were excluded from analysis. Risk factors associated with cancer recurrence were evaluated using Cox proportional hazards models. During the monitoring period, 166 patients (15.0%) developed cancer recurrence, including 154 (15.5%) in group A and 12 (10.9%) in group B. The median period from surgery to cancer recurrence was 1.85 (interquartile range 1.18-2.93) years. Independent risk factors for cancer recurrence were tumor histological grading of grade 3, high number (≥3) of axillary lymph node invasion, and a large tumor size (>5 cm). Factors protecting against recurrence were positive progesterone receptor status and receiving radiation therapy. Receiving MLD therapy was not an outcome factor in multivariate analyses (hazard ratio 0.71, 95% confidence interval 0.39-1.29, P=0.259). MLD is a gentle procedure that does not increase the risk of breast cancer recurrence in patients who develop BCRL.

Nearly all patients with end-stage renal disease develop hyperphosphatemia. These patients typically require oral phosphate binders for life-long phosphorus management, in addition to dietary restrictions and maintenance dialysis. Recently, niacin, a traditional antilipemic agent, drew attention as an experimental treatment for hyperphosphatemia. The purpose of this article was to report on new findings regarding niacin's novel effects and to review the possibility of repurposing niacin for hyperphosphatemia treatment in dialysis patients by elucidating its safety and efficacy profiles along with its synergistic clinical benefits. Following approval from the Institutional Review Board, we tracked the yearly trends of order frequency of niacin in comparison with statins and sevelamer in a tertiary care hospital. Also, a Cochrane Library and PubMed literature search was performed to capture prospective clinical trials on niacin's hypophosphatemic effects in dialysis patients. Niacin use in clinical settings has been on the wane, and the major contribution to that originates from the wide use of statins. Niacin use rates have further plummeted following a trial failure which prompted the suspension of the niacin-laropiprant (a flushing blocker) combination product in the global market. Our literature search identified ten relevant articles. Overall, all studies demonstrated that niacin or nicotinamide (the metabolite form) reduced serum phosphorus levels as well as Ca-P products significantly. Additive beneficial effects on lipid parameters were also observed. Sevelamer appeared superior to niacin in a comparative study, but the study design had several limitations. The intervention dosage for niacin ranged from 375 to 1,500 mg/day, with the average daily dose of approximately 1,000-1,500 mg. Niacin can be a patient-convenient and inexpensive alternative or adjunctive therapy for phosphorus management in dialysis patients. Further well-designed, large-scale, long-term, comparative trials are needed to successfully repurpose niacin for the new indication.

Persons with Down syndrome (DS) have reduced peak and submaximal exercise capacity. Because ambulation is one predictor of survival among adults with DS, a review of the current knowledge of the causes, effects, and management of reduced exercise capacity in these individuals would be important. Available data suggest that reduced exercise capacity in persons with DS results from an interaction between low peak oxygen uptake (VO(2peak)) and poor exercise economy. Of several possible explanations, chronotropic incompetence has been shown to be the primary cause of low VO(2peak) in DS. In contrast, poor exercise economy is apparently dependent on disturbed gait kinetics and kinematics resulting from joint laxity and muscle hypotonia. Importantly, there is enough evidence to suggest that such low levels of physical fitness (reduced exercise capacity and muscle strength) limit the ability of adults with DS to perform functional tasks of daily living. Consequently, clinical management of reduced exercise capacity in DS seems important to ensure that these individuals remain productive and healthy throughout their lives. However, few prospective studies have examined the effects of structured exercise training in this population. Existent data suggest that exercise training is beneficial for improving exercise capacity and physiological function in persons with DS. This article reviews the current knowledge of the causes, effects, and management of reduced exercise capacity in DS. This review is limited to the acute and chronic responses to submaximal and peak exercise intensities because data on supramaximal exercise capacity of persons with DS have been shown to be unreliable.

The purpose of this study is to investigate the distribution and antimicrobial susceptibility of pathogenic bacteria in inpatients with pulmonary infection in the neurological intensive care unit (NICU). A total of 947 sputum specimens of 428 inpatients from May 2007 to May 2008 in the NICU were enrolled in the study, and bacterial identification and antibiotic susceptibility tests were analyzed using a VITEK 2 system. A total of 400 positive bacterial strains were separated from 947 sputum specimens, with Gram-negative bacteria accounting for 69.0% of the total strains collected. The most common strain of Gram-negative bacteria was Klebsiella pneumoniae (20.5%). Gram-positive bacteria accounted for 10.0% of the total strains, with the most common strain being Staphylococcus aureus (2.5%). Fungal species accounted for 21.0% of the total strains, and the most common strain collected was Candida albicans (12.25%). Imipenem was the most effective antibiotic against Gram-positive and Gram-negative bacteria. The drug resistance rate of Gram-positive bacteria to penicillin G was 100%, and the Gram-positive bacteria were 100% sensitive to teicoplanin, vancomycin, and linezolid. Gram-negative bacterial infections account for the majority of pulmonary infections in the NICU, with fungal infections being the second most common infection type observed. In addition, fungal infections seem to be related to mortality in the NICU.

Naftopidil, approved only in Japan, is an α1-adrenergic receptor antagonist (α1-blocker) used to treat lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). Different from tamsulosin hydrochloride and silodosin, in that it has higher and extremely higher affinity respectively, for the α1A-adrenergic receptor subtype than for the α1D type, naftopidil has distinct characteristics because it has a three times greater affinity for the α1D-adrenergic receptor subtype than for the α1A subtype. Although well-designed large-scale randomized controlled studies are lacking and the optimal dosage of naftopidil is not always completely determined, previous reports from Japan have shown that naftopidil has superior efficacy to a placebo and comparable efficacy to other α1-blockers such as tamsulosin. On the other hand, the incidences of ejaculatory disorders and intraoperative floppy iris syndrome induced by naftopidil may be lower than for tamsulosin and silodosin having high affinity for the α1A-adrenergic receptor subtype. However, it remains unknown if the efficacy and safety of naftopidil in Japanese is applicable to white, black and Hispanic men having LUTS/BPH in western countries.

Occasionally, urologists may see patients requiring temporary bladder irrigation at hospitals without stocks of specialist irrigation apparatus. One option is to transfer the patient to a urology ward, but often there are outstanding medical issues that require continued specialist input. Here, we describe an improved system for delivering temporary bladder irrigation by utilizing readily available components and the novel modification of a sphygmomanometer blub. This option is good for bladder irrigation in patients with moderate or severe gross hematuria due to various causes. In this prospective study from March 2007 to April 2009, we used our new system in eligible cases. In this system, an irrigant bag with 1 L of normal saline was suspended 80 cm above the indwelled 3-way Foley catheter, and its drainage tube was inserted into the irrigant port of the catheter. To increase the flow rate of the irrigant system, we inserted a traditional sphygmomanometer bulb at the top of the irrigant bag. This closed system was used for continuous bladder irrigation (CBI) in patients who underwent open prostatectomy, transurethral resection of the prostate (TURP), or transurethral resection of the bladder (TURB). This high-pressure system is also used for irrigation during cystourethroscopy, internal urethrotomy, and transurethral lithotripsy. Our 831 eligible cases were divided into two groups: group 1 were endourologic cases and group 2 were open prostatectomy, TURP, and TURB cases. The maximum and average flow rates were evaluated. The efficacy of our new system was compared prospectively with the previous traditional system used in 545 cases. In group 1, we had clear vision at the time of endourologic procedures. The success rate of this system was 99.5%. In group 2, the incidence of clot retention decreased two fold in comparison to traditional gravity-dependent bladder flow system. These changes were statistically significant (P = 0.001). We did not observe any adverse effects such as bladder perforation due to our high-pressure, high-flow system. A pressurized irrigant system has better visualization during endourologic procedures, and prevents clot formation after open prostatectomy, TURP, and TURB without any adverse effects.

This retrospective cohort study evaluated whether manual lymphatic drainage (MLD) therapy increases the risk of recurrence of breast cancer. We analyzed 1,106 women who were diagnosed with stage 0-3 breast cancer between 2007 and 2011 and experienced remission after surgery and adjuvant therapy. The patients were divided into two groups: group A (n=996), in which patients did not participate in any MLD therapy, regardless of whether they developed breast cancer-related lymphedema (BCRL) after cancer treatment; and group B (n=110), in which patients participated in MLD therapy for BCRL. All patients were monitored until October 2013 to determine whether breast cancer recurrence developed, including local or regional recurrence and distant metastasis. Patients who developed cancer recurrence prior to MLD therapy were excluded from analysis. Risk factors associated with cancer recurrence were evaluated using Cox proportional hazards models. During the monitoring period, 166 patients (15.0%) developed cancer recurrence, including 154 (15.5%) in group A and 12 (10.9%) in group B. The median period from surgery to cancer recurrence was 1.85 (interquartile range 1.18-2.93) years. Independent risk factors for cancer recurrence were tumor histological grading of grade 3, high number (≥3) of axillary lymph node invasion, and a large tumor size (>5 cm). Factors protecting against recurrence were positive progesterone receptor status and receiving radiation therapy. Receiving MLD therapy was not an outcome factor in multivariate analyses (hazard ratio 0.71, 95% confidence interval 0.39-1.29, P=0.259). MLD is a gentle procedure that does not increase the risk of breast cancer recurrence in patients who develop BCRL.

Nearly all patients with end-stage renal disease develop hyperphosphatemia. These patients typically require oral phosphate binders for life-long phosphorus management, in addition to dietary restrictions and maintenance dialysis. Recently, niacin, a traditional antilipemic agent, drew attention as an experimental treatment for hyperphosphatemia. The purpose of this article was to report on new findings regarding niacin's novel effects and to review the possibility of repurposing niacin for hyperphosphatemia treatment in dialysis patients by elucidating its safety and efficacy profiles along with its synergistic clinical benefits. Following approval from the Institutional Review Board, we tracked the yearly trends of order frequency of niacin in comparison with statins and sevelamer in a tertiary care hospital. Also, a Cochrane Library and PubMed literature search was performed to capture prospective clinical trials on niacin's hypophosphatemic effects in dialysis patients. Niacin use in clinical settings has been on the wane, and the major contribution to that originates from the wide use of statins. Niacin use rates have further plummeted following a trial failure which prompted the suspension of the niacin-laropiprant (a flushing blocker) combination product in the global market. Our literature search identified ten relevant articles. Overall, all studies demonstrated that niacin or nicotinamide (the metabolite form) reduced serum phosphorus levels as well as Ca-P products significantly. Additive beneficial effects on lipid parameters were also observed. Sevelamer appeared superior to niacin in a comparative study, but the study design had several limitations. The intervention dosage for niacin ranged from 375 to 1,500 mg/day, with the average daily dose of approximately 1,000-1,500 mg. Niacin can be a patient-convenient and inexpensive alternative or adjunctive therapy for phosphorus management in dialysis patients. Further well-designed, large-scale, long-term, comparative trials are needed to successfully repurpose niacin for the new indication.

Persons with Down syndrome (DS) have reduced peak and submaximal exercise capacity. Because ambulation is one predictor of survival among adults with DS, a review of the current knowledge of the causes, effects, and management of reduced exercise capacity in these individuals would be important. Available data suggest that reduced exercise capacity in persons with DS results from an interaction between low peak oxygen uptake (VO(2peak)) and poor exercise economy. Of several possible explanations, chronotropic incompetence has been shown to be the primary cause of low VO(2peak) in DS. In contrast, poor exercise economy is apparently dependent on disturbed gait kinetics and kinematics resulting from joint laxity and muscle hypotonia. Importantly, there is enough evidence to suggest that such low levels of physical fitness (reduced exercise capacity and muscle strength) limit the ability of adults with DS to perform functional tasks of daily living. Consequently, clinical management of reduced exercise capacity in DS seems important to ensure that these individuals remain productive and healthy throughout their lives. However, few prospective studies have examined the effects of structured exercise training in this population. Existent data suggest that exercise training is beneficial for improving exercise capacity and physiological function in persons with DS. This article reviews the current knowledge of the causes, effects, and management of reduced exercise capacity in DS. This review is limited to the acute and chronic responses to submaximal and peak exercise intensities because data on supramaximal exercise capacity of persons with DS have been shown to be unreliable.

The purpose of this study is to investigate the distribution and antimicrobial susceptibility of pathogenic bacteria in inpatients with pulmonary infection in the neurological intensive care unit (NICU). A total of 947 sputum specimens of 428 inpatients from May 2007 to May 2008 in the NICU were enrolled in the study, and bacterial identification and antibiotic susceptibility tests were analyzed using a VITEK 2 system. A total of 400 positive bacterial strains were separated from 947 sputum specimens, with Gram-negative bacteria accounting for 69.0% of the total strains collected. The most common strain of Gram-negative bacteria was Klebsiella pneumoniae (20.5%). Gram-positive bacteria accounted for 10.0% of the total strains, with the most common strain being Staphylococcus aureus (2.5%). Fungal species accounted for 21.0% of the total strains, and the most common strain collected was Candida albicans (12.25%). Imipenem was the most effective antibiotic against Gram-positive and Gram-negative bacteria. The drug resistance rate of Gram-positive bacteria to penicillin G was 100%, and the Gram-positive bacteria were 100% sensitive to teicoplanin, vancomycin, and linezolid. Gram-negative bacterial infections account for the majority of pulmonary infections in the NICU, with fungal infections being the second most common infection type observed. In addition, fungal infections seem to be related to mortality in the NICU.

Characteristics of nephrotic syndrome (NS) in children varies in different geographical areas based on genetic and environmental factors. The aim of this study is to evaluate the steroid response pattern and outcome of idiopathic NS (INS) in a pediatric referral hospital in northwest Iran. Medical records of all admitted children under 14 years of age with INS in the Children's Hospital of Tabriz, Iran, from 1999 to 2010 were studied retrospectively. Demographics, pattern of response to medications, recurrence rate, histopathology, and outcome were documented. A total of 165 patients with INS, with a mean age of 4.98 ± 2.61 years were studied. Male to female ratio was 2:1. Duration of follow-up was 5.36 ± 2.2 years (1-10 years). A total of 124 patients (75.2%) responded to steroids, and 41 patients (24.8%) were steroid resistant. Frequency of hematuria (P = 0.01) and steroid resistance (P = 0.005) in girls was significantly higher than boys. Patients with steroid resistance had a higher frequency of hematuria (P = 0.001) and a higher mean age (P = 0.017) in comparison with steroid responders. Renal biopsy carried out in 49 patients (29.7%) revealed minimal change in NS in 20 (40.8%), focal segmental glomerulosclerosis in 16 (32.7%), and mesangial proliferation in 11 (22.5%) patients. Twenty-two steroid resistant patients (13%) achieved remission with other immunosupressives. Nineteen patients (11.5%) were resistant to all treatment modalities; of these, nine (5.4%) progressed to end-stage renal disease, and 10 (6%) continued nephrotic range proteinuria. Seven patients (4.2%) died. Of the 146 patients who achieved remission with any one of the treatment modalities, 91 patients (62.3%) experienced at least one recurrence episode, 15 patients (10.3%) were frequent relapsers, and 12 patients (8.2%) were steroid dependent. Higher age at onset of NS was associated with lower relapse rate (P = 0.04). Demographics, histological features, and outcome of INS in our area were similar to western countries. In the present study, risk of steroid resistance was higher in girls than boys.