Unacceptable Adverse Effects Research Articles

Multiple pharmacological and toxicological investigations on Tanacetum parthenium and Salix alba extracts: Focus on potential application as anti-migraine agents

Migraine is one of the most common neurological disorder, which has long been related to brain serotonin (5-HT) depletion and neuro-inflammation. Despite many treatment options are available, the frequent occurrence of unacceptable adverse effects further supports the research toward nutraceuticals and herbal preparations, among which Tanacetum parthenium and Salix alba showed promising anti-inflammatory and neuro-modulatory activities.The impact of extract treatment on astrocyte viability, spontaneous migration and apoptosis was evaluated. Anti-inflammatory/anti-oxidant effects were investigated on isolated rat cortexes exposed to a neurotoxic stimulus. The lactate dehydrogenase (LDH) release, nitrite levels and 5-HT turnover were evaluated, as well. A proteomic analysis was focused on specific neuronal proteins and a fingerprint analysis was carried out on selected phenolic compounds.Both extracts appeared able to exert in vitro anti-oxidant and anti-apoptotic effects. S. alba and T. parthenium extracts reduced LDH release, nitrite levels and 5-HT turnover induced by neurotoxic stimulus. The downregulation of selected proteins suggest a neurotoxicity, which could be ascribed to an elevated content of gallic acid in both S. alba and T. parthenium extracts.Concluding, both extracts exert neuroprotective effects, although the downregulation of key proteins involved in neuron physiology suggest caution in their use as food supplements.

Low‐dose ketamine provides poor analgesia for pain in redback spider envenoming

Redback spider envenoming causes severe pain lasting several days. A recent clinical trial found that antivenom is not effective. We investigated ketamine for pain in redback spider envenoming. Ten adult patients with severe pain from redback spider envenoming were administered 15mg intravenous ketamine after standard analgesia, then up to 4 oral doses of ketamine 25- 50mg. Three patients had a clinically significant improvement in pain compared to baseline after intravenous ketamine. Five patients had a minimal decrease in pain and 2 had no improvement. Eight patients received oral ketamine: 4 doses in 5 and 2 doses in 3. At 24h, 3/6 patients assessed had clinically significant improvement in pain and 4/5 patients assessed at 48h, had clinically significant improvement in pain. Six patients reported side effects, including dissociation (4) and hallucinations (2). Five patients required rescue opioids and 2 were readmitted to hospital. We found that ketamine provided no additional pain relief in redback spider envenoming, compared to standard analgesia, and resulted in unacceptable adverse effects.

Rituximab (Ritux) Maintenance Infusions in Immune Thrombocytopenia (ITP) to Prolong Remission Following Relapse after Initial Ritux Induction but Responded to a Second Course

Introduction: ITP is an autoimmune disease characterized by low platelet counts and variable bleeding. Ritux treatment of ITP patients (pts) receiving 375 mg/m2 once a week for 4 weeks results in 50-60% achieving complete responses (CR). However, most pts will relapse, usually around 1 year from initial treatment. In a previous study, 20 pts were retreated with a second round of 4 infusions of ritux and 16 (80%) had essentially the same response to retreatment with ritux with the second set of 4 infusions (Hasan A, AmJHem, 2009). Maintenance ritux infusions in Non-Hodgkin Lymphoma are now well-demonstrated to increase cure despite variable infusion schedules. This retrospective study explores ritux maintenance in pts with ITP or / and other autoimmune cytopenias who responded to but relapsed after a first induction with Ritux and who then received a 2nd to 4th induction with ritux.Methods: We enrolled 17 pts with ITP, Autoimmune hemolytic anemia (AIHA), Autoimmune Neutropenia (AIN) and/or Evans syndrome, who previously responded to but then relapsed following induction with 4 ritux infusions. Ritux was administered to relapsed pts at standard dose during weeks 1, 2, 3, and 4 of induction. During the maintenance phase, single infusions of ritux were given at 1 dose of 375 mg/m2 every 4 months for a total of 2 years or until relapse or development of unacceptable adverse effects or infections or withdrawal from the study (to become pregnant); 3 pts with shorter remission times following previous ritux were treated at 3 month intervals. 5 pts received 40mg/day of dexamethasone (Dex) with the ritux maintenance infusions: 3 4-day cycles of Dex at 2 weekly intervals (Chapin, AJH, 2016) with induction and single dose dex with each maintenance infusion. The primary endpoint was the duration of response. Secondary endpoints included safety. Statistical analysis was largely descriptive. Comparisons of first and second ritux treatments (without and with maintenance) were made using the Fisher Exact test.Results: Of the 17 pts who received ritux maintenance, 11 had ITP, 2 AIHA, and 4 had Evans syndrome. Three pts had AIN as part of their Evans syndrome. 7 had received more than 1 ritux induction (2-4) in the past. At initiation of maintenance, there were 10 males and 7 females and 13 adults and 4 children. Three had undergone splenectomy prior to starting ritux. The mean duration of response following the first cycle of 4 ritux standard infusions was 19 months, while the mean duration of response with maintenance schedule was 48 months. Fifteen of 17 patients achieved CR with ritux re-induction; of these 7 relapsed. 2 patients achieved PR, 1 relapsed. The mean duration of response with ritux maintenance was 36.8 months in adults and 63.8 months in children; it was 48 months each in males and females; it was 49 months in the 3 patients who had undergone splenectomy and also in those who had not undergone splenectomy. Fisher exact test did not show any statistical difference in clinical parameters including the type of autoimmune cytopenia. Pts with more previous ritux inductions did worse than those receiving their 2nd reinduction. Three patients developed hypogammaglobulinemia and needed IVIG prophylaxis against infections; one patient had bacteremia. One patient developed sepsis secondary to hypogammaglobulinemia requiring ICU admission. JC virus cultures were negative in all tested pts. No pts developed transaminitis or signs of renal failure.Discussion: The expectation for these 17 very difficult to treat pts was that they would have all relapsed in 1 year or less following a “routine” ritux re-induction based on past data and clinical experience. The number of pts reported who achieved lasting remission following a second or third course of ritux is very small. Dex was added to reinduction in 5 of these multiply-induced pts, but curative effects occur only in female pts treated within 1 year of diagnosis, and these were pts with years of disease so this would not explain the results. Being able to achieve lasting remission over many years in half this group appears to be a significant improvement on their expected outcomes. Hypogammaglobulinemia became clinically significant in 1 pt who stopped coming for checkups; it has been reported primarily with the combination of dex-ritux but even then in only 10% of patients. A randomized controlled trial is needed to test these exciting findings. [Display omitted] DisclosuresBussel:Prophylix: Consultancy, Research Funding; Momenta: Consultancy; Rigel: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Uptodate: Honoraria; Amgen Inc.: Consultancy, Research Funding; Protalex: Consultancy.

EFFECTS OF FORMULATION PARAMETERS ON PROPERTIES OF GASTRIC FLOATING TABLETS CONTAINING POORLY SOLUBLE DRUG: DICLOFENAC SODIUM

Objective: The objective of this study was to prepare and investigate the effects of formulation parameters on the properties of gastric floating tablets containing diclofenac sodium (DICL) as a model of poorly soluble acidic drug, sodium bicarbonate (NaHCO3) or calcium carbonate (CaCO3) as gas-forming agent, hydroxypropyl methylcellulose (HPMC) K100M or K15M as swelling polymer and sodium lauryl sulfate (SLS) as wetting agent.Methods: DICL floating tablets were prepared using direct compression method. The compressed tablets were evaluated for tablet properties, swelling index, and in vitro buoyancy. The in vitro release under non-sink condition was determined. Molecular interaction was studied using differential scanning calorimetry and fourier transform infrared spectroscopy.Results: The tablet properties of all DICL floating tablets were within the acceptance criteria. The molecular interaction between DICL and excipients in the formulation was excluded. Depends on the formulation compositions, the swelling index at 3 h (SI) ranged from 44±11 to 1158±33 %, whereas the buoyancy properties namely floating lag time (FLT) and total floating time (TFT) were 0.33±0.03 to 10.04±0.04 min and 10.0±0.0 to>12 h, respectively. NaHCO3 showed higher swelling, buoyancy and release properties compared to those of CaCO3. NaHCO3 at 20% gave sufficient swelling (SI of 1074±16 %), buoyancy (FLT of 0.39±0.03 min, TFT of>12 h) and release properties (cumulative release of 5.83±0.02 %). HPMC K100M showed better swelling property of which its initial swelling rate was 1412±25 %/h compared to HPMC K15M (1042±31 %/h). HPMC K100M at 20% showed better buoyancy and release properties compared to those obtained from HPMC K100M at 30%. The release testing under non-sink conditions was able to distinguish the effect of formulation parameters on the DICL release profiles. Incorporation of SLS at 0.25% could enhance both release rate and cumulative release of DICL from the floating tablets. Nevertheless, it showed the unacceptable adverse effect on swelling and buoyancy properties of DICL floating tablets. The TFT of DICL floating tablets containing 0.25% SLS was only 0.5±0.0 h.Conclusion: DICL floating tablets were successfully prepared. Tablets possessing suitable swelling and buoyancy properties were obtained using NaHCO3 at 20% as a gas-forming agent, with HPMC K100M at 10 and 20% as floating matrix and swelling polymer. Addition of SLS as wetting and solubilizing agent showed the unacceptable adverse effect on the swelling and buoyancy properties of DICL floating tablets. The release under sink conditions and/or in vivo pharmacokinetic studies shall be further performed.

Dipeptidyl peptidase IV Inhibitory activity of Terminalia arjuna attributes to its cardioprotective effects in experimental diabetes: In silico, in vitro and in vivo analyses

BackgroundThe marketed synthetic (Dipeptidyl peptidase-IV) DPP-IV Inhibitors are expensive antidiabetic drugs and have been reported to cause unacceptable adverse effects such as pancreatitis, angioedema, thyroid and pancreatic cancers. In this scenario research to develop novel DPP-IV Inhibitors from alternative sources is the need of the hour. Hypothesis/purposeTerminalia arjuna, a medicinal herb with antidiabetic and cardioprotective activities may represent a natural DPP-IV Inhibitor, the DPP-IV Inhibitory activity of which may translate into demonstrable therapeutic benefits in setting of diabetes with cardiovascular co-morbidities. Study designThe study type used for the present study was an experimental (In vitro, In vivo and In silico) design. MethodThe DPP-IV Inhibitory, antidiabetic and cardioprotective effects of Terminalia arjuna was evaluated in the experimental model of myocardial infarction co-existing with diabetes. To determine the active principle of Terminalia arjuna responsible for DPP-IV Inhibitory activity, the crystal structure of DPP-IV was considered as receptor which was docked against Arjunetin, Arjungenin, Arjunic acid, Arjunone, Ellagic acid, Gallic acid, Sitagliptin and Vildagliptin. The binding sites as well as affinity of various active ingredients of Terminalia arjuna for DPP- IV enzyme was elucidated using in silico studies and compared to Vildagliptin. ResultsTerminalia arjuna demonstrated significant DPP-IV Inhibitory, antidiabetic (significant reduction in HbA1C) and cardioprotective effects (restoration of myocardial CPK-MB) in the experimental model of myocardial infarction co-existing with diabetes. The cardioprotective efficacy correlated to its DPP-IV Inhibitory activity. The active ingredients of Terminalia arjuna (Arjunetin, Arjungenin, Arjunic Acid Arjunone, Ellagic acid and Gallic acid) demonstrated significant inhibition of DPP-IV enzyme. Arjunic acid and Arjunone prefers the active site pocket of DPP-IV enzyme. Compounds like Arjunetin and Vildagliptin prefers to bind near the interface region of the DPP-IV as their biological active forms are homodimer. Sitagliptin binds near the α/β hydrolase domain. ConclusionThe DPP-IV Inhibitory activity of Terminalia arjuna was found to be comparable to Vildagliptin. The DPP-IV Inhibitory activity translated into significant cardioprotective effects in the setting of diabetes. The active ingredient of Terminalia arjuna; Arjunetin, Arjungenin, Ellagic acid and Arjunic acid showed superior DPP-IV Inhibitory activity as compared to synthetic DPP-IV inhibitors (Sitagliptin and Vildagliptin) based on results of docking studies.

Indirect-acting strategy of opioid action instead of direct receptor activation: dual-acting enkephalinase inhibitors (DENKIs).

Although pain is one of the most common afflictions, it is often inadequately managed because the available analgesic options are relatively limited due to insufficient efficacy, unacceptable adverse effects or the potential for misuse or abuse. However, recent publications suggest that an alternative approach-indirect enhancement of endogenous pain-relieving pathways-might be desirable. We review this approach, in particular the dual enkephalinase inhibitors (DENKIs). Published literature and Internet sources were searched for information related to the basic science and clinical data on inhibition of metabolic pathways of endogenous analgesic agents. The identified sources were reviewed, assessed and synthesized. Emphasis was placed on the benefits of the approach, as well as on the individual agents. Inhibition of the enzymes that degrade the endogenous opioid ligands Met- and Leu-enkephalin results in an increased synaptic concentration of the enkephalins and an analgesic effect in a variety of animal models of pain and in preliminary trials in humans. The design of compounds that inhibit both of the two major enkephalin-degrading enzymes (neprilysin and aminopeptidase N) has been found to be better than those that inhibit only one of the enzymes. These dual-acting enkephalinase inhibitors yield analgesia with less adverse effects than current opioid drugs. Unlike currently available analgesics, inhibitors of the metabolic degradation of endogenous analgesic substances attempt to elicit a more "natural" and targeted analgesic effect. This indirect approach offers an opportunity for novel additions to the otherwise relatively limited choice of analgesic classes.

Tandem High-dose Chemotherapy and Autologous Stem Cell Transplantation in Children with Brain Tumors : Review of Single Center Experience.

The prognosis of brain tumors in children has improved for last a few decades. However, the prognosis remains dismal in patients with recurrent brain tumors. The outcome for infants and young children in whom the use of radiotherapy (RT) is very limited because of unacceptable long-term adverse effect of RT remains poor. The prognosis is also not satisfactory when a large residual tumor remains after surgery or when leptomeningeal seeding is present at diagnosis. In this context, a strategy using high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) has been explored to improve the prognosis of recurrent or high-risk brain tumors. This strategy is based on the hypothesis that chemotherapy dose escalation might result in improvement in survival rates. Recently, the efficacy of tandem HDCT/auto-SCT has been evaluated in further improving the outcome. This strategy is based on the hypothesis that further dose escalation might result in further improvement in survival rates. At present, the number of studies employing tandem HDCT/auto-SCT for brain tumors is limited. However, results of these pilot studies suggest that tandem HDCT/auto-SCT may further improve the outcome. In this review, we will summarize our single center experience with tandem HDCT/auto-SCT for recurrent or high-risk brain tumors.

Prevalence and patterns of anti-epileptic medication prescribing in the treatment of epilepsy in older adults with intellectual disabilities.

The prevalence of epilepsy is higher in people with intellectual disability (ID) and increases with the degree of ID. Although life expectancy for people with ID is increasing, people with ID coexisting with epilepsy have a higher mortality rate, particularly those who had recent seizures. There have been few observational studies of the prevalence and patterns of anti-epileptic prescribing among older people with ID and epilepsy. The aim of this study was to investigate prevalence and patterns of anti-epileptic prescribing in the treatment of epilepsy in a representative population of older people with ID and epilepsy. This was an observational cross-sectional study from wave 1 (2009/2010) of Intellectual Disability Supplement to the Irish Longitudinal Study on Aging, a nationally representative sample of 753 persons with ID aged between 41 and 90years. Participants and/or proxies recorded medicines used on a regular basis and reported doctor's diagnosis of epilepsy; medication data were available for 736 (98%). Prescribing of anti-epileptic drugs (AEDs) for epilepsy in those with a doctor's diagnosis of epilepsy (N=205) was the primary exposure of interest for this study. Participant exposure to these AEDs was then categorised into AED monotherapy and polytherapy. Participants/carers reported seizure frequency, when epilepsy was last reviewed and which practitioner reviewed epilepsy. In addition, medications that may lower the seizure threshold that were listed in the Maudsley prescribing guidelines in psychiatry were examined. Of the 736 participants with reported medicines use, 38.9% (n=287) were exposed to AEDs, and 30.6% (225) had a doctor's diagnosis of epilepsy. Of those with epilepsy (n=225), 90.9% (n=205) reported concurrent use of AEDs and epilepsy. Of these 205 participants, 50.3% (n=103) were exposed to AED polytherapy, and 63 different polytherapy regimes were reported. The most frequently reported AEDs were valproic acid (n=100, 48.7%), carbamazepine (n=89, 46.3%) and lamotrigine (n=57, 27.8%). In total, 13.7% had a concurrent psychotropic, which should be avoided in epilepsy, and 32.6% had a psychotropic where caution is required. Antipsychotics with potential epileptogenic potential accounted for 80% of these medications. Of those with AED polytherapy (n=103), 29.5% (28) reported being seizure free for the previous 2years. Prevalence of epilepsy was high among older people with ID, and half were exposed to two or more AEDs. Despite the use of AED therapy, over half had seizures in the previous 2years. As the primary goals of optimal AED treatment are to achieve seizure freedom without unacceptable adverse effects, this was not achievable for many older patients with ID and epilepsy. Our findings indicated that people with ID and epilepsy were often exposed to psychotropic medications that may lower the seizure threshold. Regular review of epilepsy and medicines (including medicines that may interact with AEDs or lower the seizure threshold) by multidisciplinary teams working to agreed standards may improve quality of prescribing. Improved exchange of information and coordination of care between specialists and primary care practitioners in line with expert consensus recommendations could bring substantial benefit.

Addition of an antiangiogenic therapy, bevacizumab, to gemcitabine plus oxaliplatin improves survival in advanced biliary tract cancers.

Background The prognosis of patients with metastatic carcinoma of the biliary tract (mBTC) is poor and a systemic therapy with gemcitabine and platinum-based is the gold standard. The addition of bevacizumab to the chemotherapy might increase patients' survival. Our aim was to assess and compare the efficacy of GEMOX (gemcitabine and oxaliplatin regimen) plus bevacizumab to GEMOX alone in mBTC. Methods Patients with mBTC who received the GEMOX-bevacizumab (n=32; Group A) or GEMOX (n=25; Group B) regimen as first-line treatment were compared. Treatment was repeated every two weeks until disease progression or unacceptable adverse effects occurred. The primary evaluation criterion was the progression-free survival (PFS). Results A quarter of patients (8/32) from Group A and a fifth of patients (13/25) from Group B had an objective response. The median PFS was 6.48months and 3.72months in Group A and B, respectively (p=0.049). The median OS was 11.31months and 10.34months in Group A and B, respectively. Grade 3/4 sepsis was identified in 9.4% and 12% in Group A and B, respectively, (p=0.64). Conclusion In mBTC, the addition of bevacizumab to GEMOX increased the progression-free survival and was associated with manageable toxicity. These data pave the way for further evaluation of antiangiogenic agents in mBTC.

Opioids for cancer-related pain in children and adolescents.

Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.We designed a suite of seven reviews in chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) to review the evidence for children's pain using pharmacological interventions.As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer-related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer-related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.Opioids are used worldwide for the treatment of pain. Currently available opioids include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are generally available in healthcare settings across most developed countries but access may be restricted in developing countries. To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is to start with a low dose gradually titrated to effect or unacceptable adverse effect in the child. To assess the analgesic efficacy, and adverse events, of opioids used to treat cancer-related pain in children and adolescents aged between birth and 17 years, in any setting. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid and Embase via Ovid from inception to 22 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. Randomised controlled trials (RCTs), with or without blinding, of any dose, and any route, treating cancer-related pain in children and adolescents, comparing opioids with placebo or an active comparator. Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table. No studies were identified that were eligible for inclusion in this review (very low quality evidence). Several studies tested opioids on adults with cancer-related pain, but none in participants aged from birth to 17 years.We rated the quality of evidence as very low, downgraded due to a lack of available data; no analyses could be undertaken. No conclusions can be drawn about efficacy or harm in the use of opioids to treat cancer-related pain in children and adolescents. As a result, there is no RCT evidence to support or refute the use of opioids to treat cancer-related pain in children and adolescents.

Intravenous Acetaminophen

MOST PATIENTS WHO UNDERGO surgical procedures will experience acute postoperative pain. The use of multimodal analgesia, defined as the concurrent use of various analgesic drugs or techniques that target different mechanisms of analgesia, is recommended for the management of postoperative pain. 1 Chou R. Gordon D.B. de Leon-Casasola O.A. et al. Management of postoperative pain: A clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016; 17: 131-157 Abstract Full Text Full Text PDF PubMed Scopus (1551) Google Scholar The goal of multimodal analgesia is to maximize the use of one or more scheduled (around the clock) nonopioid analgesics, as well as nonpharmacologic therapies, to minimize or eliminate the need for opioids and their often unacceptable adverse effects. The current recommendation (strong recommendation and high-quality evidence) is to provide acetaminophen and/or nonsteroidal anti-inflammatory drugs (NSAIDs) as part of multimodal analgesia for management of postoperative pain in adults and children unless contraindicated. 1 Chou R. Gordon D.B. de Leon-Casasola O.A. et al. Management of postoperative pain: A clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016; 17: 131-157 Abstract Full Text Full Text PDF PubMed Scopus (1551) Google Scholar An analgesic regimen that includes acetaminophen or an NSAID generally provides improved analgesia or less opioid consumption compared with an opioid alone. 2 Gimbel J.S. Brugger A. Zhao W. et al. Efficacy and tolerability of celecoxib versus hydrocodone/acetaminophen in the treatment of pain after ambulatory orthopedic surgery in adults. Clin Ther. 2001; 23: 228-241 Abstract Full Text PDF PubMed Scopus (132) Google Scholar , 3 Kinsella J. Moffat A.C. Patrick J.A. et al. Ketorolac trometamol for postoperative analgesia after orthopedic surgery. Br J Anaesth. 1992; 69: 19-22 Crossref PubMed Scopus (63) Google Scholar , 4 Grundmann U. Wornie C. Beidler A. et al. The efficacy of the non-opioid analgesics parecoxib, paracetamol and metamizol for postoperative pain relief after lumbar microdiscectomy. Anesth Analg. 2006; 103: 217-222 Crossref PubMed Scopus (102) Google Scholar Julie Golembiewski, PharmD, is a Clinical Associate Professor, Departments of Pharmacy Practice and Anesthesiology, University of Illinois at Chicago, Chicago, IL

A weight-of-evidence approach for deriving a level of concern for atrazine that is protective of aquatic plant communities.

Atrazine is a selective triazine herbicide widely used in the United States primarily for control of broadleaf weeds in corn and sorghum. In 2003, the US Environmental Protection Agency (USEPA) concluded that atrazine poses potential risks to sensitive aquatic species. Consequently, a surface water monitoring program was developed to assess whether measured levels of atrazine could impact aquatic plants in vulnerable watersheds. To facilitate evaluation of the monitoring data, the Agency needed to establish a level of concern (LOC) below which atrazine would not cause unacceptable adverse effects to aquatic plant communities. Several attempts at developing a community-level LOC have followed from USEPA but none have been formally accepted or endorsed by independent Scientific Advisory Panels. As part of registration review, the USEPA needs to revisit development of a community-level LOC for atrazine that will be protective of aquatic plant communities. This article reviews 4 methods that can or have been used for this purpose. Collectively, the methods take advantage of the large number of single species and mesocosm studies that have been conducted for aquatic plants exposed to atrazine. The Plant Assemblage Toxicity Index (PATI) and the Comprehensive Aquatic Systems Model for atrazine (CASMATZ2 ) incorporate single-species toxicity data but are calibrated with micro- and mesocosm study results to calculate community-level LOCs. The Brock et al. scoring system relies exclusively on mesocosm studies. Single-species toxicity data were used in a modified version of the USEPA's Water Quality Criteria (WQC) method. The 60-day LOCs calculated using the 4 methods ranged from 19.6 to 26 µg/L. A weight-of-evidence assessment indicated that the CASMATZ2 method was the most environmentally relevant and statistically reliable method. Using all 4 methods with weights based on method reliability, the weighted 60-day LOC was 23.6 µg/L. Integr Environ Assess Manag 2017;13:686-701. © 2016 SETAC.

Pharmacogenomics Can Enhance Prescribing of Psychiatric Medications.

Many psychiatric patients experience pharmaceutical intolerances, and some of them do not derive optimal efficacy from their pharmacotherapies. Clinical problems such as these may result in prolonged dysfunction, adverse consequences, and repeated changes in medication treatment regimens. Pharmacogenomics is a laboratory method that aids individualized medication selection by predicting drug efficacy and adverse effect profiles. It is a technique that involves the testing of patients' genetic makeup to improve medicinal response and tolerance. Pharmacogenomics aims to clarify pharmacokinetics and pharmacodynamics in addition to focusing on hepatic cytochrome enzyme metabolism. Ultimately, it facilitates optimal selection and adjustment of medications to enhance clinical outcomes. Pharmacogenomics is most useful in cases in which routinely prescribed pharmacotherapies are either suboptimally effective or have unacceptable adverse effects. Once there has been a failure of a therapeutic drug treatment, rather than "blindly" selecting an alternative medicine, pharmacogenomic test results can provide guidance for the selection of the most appropriate drug and its dose. The intent is to yield a greater likelihood of patient success in following a therapeutic intervention.

Association of Survival Benefit With Docetaxel in Prostate Cancer and Total Number of Cycles Administered

ImportanceThe optimal total number of docetaxel cycles in patients with metastatic castration resistant prostate cancer (mCPRC) has not been investigated yet. It is unknown whether it is beneficial for patients to continue treatment upon 6 cycles.ObjectiveTo investigate whether the number of docetaxel cycles administered to patients deriving clinical benefit was an independent prognostic factor for overall survival (OS) in a post hoc analysis of the Mainsail trial.Design, Setting, and ParticipantsThe Mainsail trial was a multinational randomized phase 3 study of 1059 patients with mCRPC receiving docetaxel, prednisone, and lenalidomide (DPL) or docetaxel, prednisone, and a placebo (DP). Study patients were treated until progressive disease or unacceptable adverse effects occurred. Median OS was found to be inferior in the DPL arm compared with the DP arm. As a result of increased toxic effects with the DPL combination, patients on DPL received fewer docetaxel cycles (median, 6) vs 8 cycles in the control group. As the dose intensity was comparable in both treatment arms, we investigated whether the number of docetaxel cycles administered to patients deriving clinical benefit on Mainsail was an independent prognostic factor for OS. We conducted primary univariate and multivariate analyses for the intention-to-treat population. Additional sensitivity analyses were done, excluding patients who stopped treatment for reasons of disease progression and those who received 4 or fewer cycles of docetaxel for other reasons, minimizing the effect of confounding factors.Main Outcomes and MeasuresTotal number of docetaxel cycles delivered as an independent factor for OS.ResultsOverall, all 1059 patients from the Mainsail trial were included (mean [SD] age, 68.7 [7.89] years). Treatment with 8 or more cycles of docetaxel was associated with superior OS (hazard ratio [HR], 1.909; 95% CI, 1.660-2.194; P < .001), irrespective of lenalidomide treatment (HR, 1.060; 95% CI, 0.924-1.215; P = .41). Likewise, in the sensitivity analysis, patients who received a greater number of docetaxel cycles had superior OS; patients who received more than 10 cycles had a median OS of 33.0 months compared with 26.9 months in patients treated with 8 to 10 cycles; and patients who received 5 to 7 cycles had a median OS of 22.8 months (P < .001).Conclusions and RelevanceThese findings suggest that continuation of docetaxel chemotherapy contributes to the survival benefit. Prospective validation is warranted.

Toward the definition of specific protection goals for the environmental risk assessment of chemicals: A perspective on environmental regulation in Europe.

This critical review examines the definition and implementation of environmental protection goals for chemicals in current European Union (EU) legislation, guidelines, and international agreements to which EU countries are party. The European chemical industry is highly regulated, and prospective environmental risk assessments (ERAs) are tailored for different classes of chemical, according to their specific hazards, uses, and environmental exposure profiles. However, environmental protection goals are often highly generic, requiring the prevention of "unacceptable" or "adverse" impacts on "biodiversity" and "ecosystems" or the "environment as a whole." This review aims to highlight working examples, challenges, solutions, and best practices for defining specific protection goals (SPGs), which are seen to be essential for refining and improving ERA. Specific protection goals hinge on discerning acceptable versus unacceptable adverse effects on the key attributes of relevant, sensitive ecological entities (ranging from organisms to ecosystems). Some isolated examples of SPGs for terrestrial and aquatic biota can be found in prospective ERA guidance for plant protection products (PPPs). However, SPGs are generally limited to environmental or nature legislation that requires environmental monitoring and retrospective ERA. This limitation is due mainly to the availability of baselines, which define acceptable versus unacceptable environmental effects on the key attributes of sentinel species, populations and/or communities, such as reproductive status, abundance, or diversity. Nevertheless, very few regulatory case examples exist in which SPGs incorporate effect magnitude, spatial extent, and temporal duration. We conclude that more holistic approaches are needed for defining SPGs, particularly with respect to protecting population sustainability, ecosystem function, and integrity, which are implicit in generic protection goals and explicit in the International Programme for Chemical Safety (IPCS) definition of "adverse effect." A possible solution, which the chemical industry is currently assessing, is wider application of the ecosystem services approach proposed by the European Food Safety Authority (EFSA) for the risk assessment of PPPs. Integr Environ Assess Manag 2017;13:17-37. © 2016 SETAC.

Malaria protection in Sierra Leone during the Ebola outbreak 2014/15; The UK military experience with malaria chemoprophylaxis Sep 14–Feb 15

The UK deployed a task force to Sierra Leone to assist in ending the 2014/15 Ebola outbreak. Malaria protection was based on existing Defence Policy which saw a wide range of bite prevention measures deployed. Atovaquone/Proguanil ("A/P"), Doxycycline ("D") and Mefloquine ("M") were the chemoprophylactic medications that were prescribed. A survey was undertaken to audit the Adverse Effect (AE) burden experienced by the population. A questionnaire based survey was administered that sought information on individuals' experiences with malaria chemoprophylaxis. 337 personnel were eligible to take part and 151 (46.3%) individuals returned questionnaires. The reported AE rates for the three drugs were "A/P" 28% of the respondents, "D" 25% and "M" 23.1%. 24 individuals (15.9%) reported 1 AE while 34 (22.5%) reported multiple AEs. Eight (5.3%) individuals changed medication (Five "A/P", two "M" and one "D") because of unacceptable AE but no significant neuro/psychological conditions were reported. The malaria attack rate for the deployed population was 0.4 cases per thousand person weeks which is very low when compared to other military deployments to the West African Area. UK Defence policy is effective in the way it balances the risk of malaria with that of AE due to chemoprophylaxis. "M" remains an acceptable chemoprophylactic agent for a section of the population.

Allergen-specific immunotherapy in pediatric allergic asthma.

Allergen-specific immunotherapy (AIT) is the only curative way that can change the immunologic response to allergens and thus can modify the natural progression of allergic diseases. There are some important criteria which contributes significantly on efficacy of AIT, such as the allergen extract used for treatment, the dose and protocol, patient selection in addition to the severity and control of asthma. The initiation of AIT in allergic asthma should be considered in intermittent, mild and moderate cases which coexisting with other allergic diseases such as allergic rhinitis, and in case of unacceptable adverse effects of medications. Two important impact of AIT; steroid sparing effect and preventing from progression to asthma should be taken into account in pediatric asthma when making a decision on starting of AIT. Uncontrolled asthma remains a significant risk factor for adverse events and asthma should be controlled both before and during administration of AIT. The evidence concerning the efficacy of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) for treatment of pediatric asthma suggested that SCIT decreases asthma symptoms and medication scores, whereas SLIT can ameliorate asthma symptoms. Although the effectiveness of SCIT has been shown for both seasonal and perennial allergens, the data for SLIT is less convincing for perennial allergies in pediatric asthma.

Switching and stopping antidepressants.

Switching from one antidepressant to another is frequently indicated due to an inadequate treatment response or unacceptable adverse effects. All antidepressant switches must be carried out cautiously and under close observation. Conservative switching strategies involve gradually tapering the first antidepressant followed by an adequate washout period before the new antidepressant is started. This can take a long time and include periods of no treatment with the risk of potentially life-threatening exacerbations of illness. Clinical expertise is needed for more rapid or cross-taper switching as drug toxicity, including serotonin syndrome, may result from inappropriate co-administration of antidepressants. Some antidepressants must not be combined. Antidepressants can cause withdrawal syndromes if discontinued abruptly after prolonged use. Relapse and exacerbation of depression can also occur. Gradual dose reduction over days to weeks reduces the risk and severity of complications.

Optimising the Use of Ruxolitinib in Inadequately Controlled Polycythaemia Vera

Polycythaemia vera (PV) is an uncommon chronic myeloproliferative neoplasm characterised by increased red-cell mass. The condition is currently managed by phlebotomy and/or palliative cytoreductive therapy, most commonly using hydroxyurea (HU). However, around 25% of patients have an inadequate response and/or unacceptable adverse effects; furthermore, patients with resistance to HU appear to have shorter survival than other patients with PV. Recently, a second-line treatment has become available. Ruxolitinib, an oral inhibitor of the Janus kinase (JAK) 1 and JAK 2 tyrosine kinases, has recently received regulatory approval for the treatment of patients with PV who are resistant to or intolerant of HU. This treatment offers the potential to significantly reduce phlebotomy requirements and improve the symptom burden. However, in order to determine which patients will benefit most from ruxolitinib, it is necessary to identify those who are inadequate responders to HU, a definition that is not currently consensual in the literature. Five patient groups, for whom ruxolitinib may be a beneficial second-line treatment option, have been proposed. These comprise patients who are at high risk and retain a high symptom burden after HU, require frequent phlebotomy, have an elevated leukocyte count, are intolerant to HU or interferon, or have palpable splenomegaly.

Vetoing Wetland Permits Under Section 404(c) of the Clean Water Act: A History of Inter-Federal Agency Controversy and Reform

For most of its four-decade history, section 404(c) of the Clean Water Act could have been considered to be a sleeper provision of environmental law. The provision authorizes the U.S. Environmental Protection Agency (EPA) to overrule permits for discharges of dredged or fill material issued by the U.S. Army Corps of Engineers (Corps) where necessary to ensure protection of fish and wildlife habitat, municipal water supplies, and recreational areas against unacceptable adverse effects. This authority of one federal agency to veto the decisions of another federal agency is quite unusual and perhaps unprecedented in environmental law. The exceptional nature of section 404(c) may explain why EPA has employed it only thirteen times in over four decades and just three times since 1990. When EPA has invoked its 404(c) authority, it has often done so to support the positions of federal and state fish and wildlife agencies and, perhaps surprisingly, Corps field-office officials. These agencies managed for eighteen years—between 1990 and 2008—to conduct the 404 permit program, one of the largest federal permit programs, without a single 404(c) veto, helped by the use of an interagency review process authorized by section 404(q) of the Act. The most recent three 404(c) actions—two involving large- scale mining operations and the other involving a large-scale flood control project—have all generated significant widespread controversy, and the fate of none of them is finally resolved. Their notoriety may disguise what we believe to be a chief lesson of having no 404(c) vetoes during the eighteen year period and just three vetoes in a quarter-century: the evolution of the Corps as an environmental agency, a notable achievement of section 404(c), since it has greatly furthered the statute’s goal of restoring and maintaining the chemical, physical, and biological integrity of the nation’ s waters.