Panning for SNuRMs: using cofactor profiling for the rational discovery of selective nuclear receptor modulators.

PubMed

Kremoser, Claus; Albers, Michael; Burris, Thomas P; Deuschle, Ulrich; Koegl, Manfred

2007-10-01

Drugs that target nuclear receptors are clinically, as well as commercially, successful. Their widespread use, however, is limited by an inherent propensity of nuclear receptors to trigger beneficial, as well as adverse, pharmacological effects upon drug activation. Hence, selective drugs that display reduced adverse effects, such as the selective estrogen receptor modulator (SERM) Raloxifene, have been developed by guidance through classical cell culture assays and animal trials. Full agonist and selective modulator nuclear receptor drugs, in general, differ by their ability to recruit certain cofactors to the receptor protein. Hence, systematic cofactor profiling is advancing into an approach for the rationally guided identification of selective NR modulators (SNuRMs) with improved therapeutic ratio.

Advising Consumption of Green Vegetables, Beef, and Full-Fat Dairy Products Has No Adverse Effects on the Lipid Profiles in Children.

PubMed

van der Gaag, Ellen José; Wieffer, Romy; van der Kraats, Judith

2017-05-19

In children, little is known about lipid profiles and the influence of dietary habits. In the past, we developed a dietary advice for optimizing the immune system, which comprised green vegetables, beef, whole milk, and full-fat butter. However, there are concerns about a possible negative influence of the full-fat dairy products of the diet on the lipid profile. We investigated the effect of the developed dietary advice on the lipid profile and BMI (body mass index)/BMI- z -score of children. In this retrospective cohort study, we included children aged 1-16 years, of whom a lipid profile was determined in the period between June 2011 and November 2013 in our hospital. Children who adhered to the dietary advice were assigned to the exposed group and the remaining children were assigned to the unexposed group. After following the dietary advice for at least three months, there was a statistically significant reduction in the cholesterol/HDL (high-density lipoproteins) ratio ( p < 0.001) and non-HDL-cholesterol ( p = 0.044) and a statistically significant increase in the HDL-cholesterol ( p = 0.009) in the exposed group, while there was no difference in the BMI and BMI z -scores. The dietary advice has no adverse effect on the lipid profile, BMI, and BMI z -scores in children, but has a significant beneficial effect on the cholesterol/HDL ratio, non-HDL-cholesterol, and the HDL-cholesterol.

Behavioral, emotional and neurobiological determinants of coronary heart disease risk in women☆

PubMed Central

Vaccarino, Viola; Bremner, J. Douglas

2016-01-01

Women have more of the stress-related behavioral profile that has been linked to cardiovascular disease than men. For example, women double the rates of stress-related mental disorders such as depression and posttraumatic stress disorder (PTSD) than men, and have higher rates of exposure to adversity early in life. This profile may increase women's long-term risk of cardiometabolic conditions linked to stress, especially coronary heart disease (CHD). In addition to having a higher prevalence of psychosocial stress-ors, women may be more vulnerable to the adverse effects of these stressors on CHD, perhaps through altered neurobiological physiology. Emerging data suggest that young women are disproportionally susceptible to the adverse effects of stress on the risk of cardiovascular disease, both in terms of initiating the disease as well as worsening the prognosis in women who have already exhibited symptoms of the disease. Women's potential vulnerability to psychosocial stress could also help explain their higher propensity toward abnormal coronary vasomotion and microvascular disease compared with men. PMID:27496672

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

EPA Pesticide Factsheets

Background: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies.Objective: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system.Methods: We used U.S. EPA??s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA??s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. Results: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. Conclusion: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarch

Is the use of colloids for fluid replacement harmless in children?

PubMed

Saudan, Sonja

2010-06-01

Albumin has been regarded as the gold standard for maintaining adequate colloid osmotic pressure in children, but increased cost, the lack of clear-cut benefits for survival, and fear of transmission of unknown viruses have contributed to its replacement by hydroxyethyl starch and gelatin preparations. Each of the synthetic colloids has unique physicochemical characteristics that determine their likely efficacy and adverse effect profile. This review will examine the advantages and disadvantages of the use of different colloid solutions in children with a particular focus on their safety profile. Dextrans are rarely used because of their negative effects on coagulation and potential for anaphylactic reactions. Gelatin and albumin have little effect on hemostasis, but the disadvantages of gelatin include its high anaphylactoid potential and limited beneficial volume effect. Tetrastarches have significantly fewer adverse effects on coagulation and renal function than the older hydroxyethyl starches and are now approved for children. Dissolving tetrastarches in a plasma-adapted, balanced solution rather than in saline further improves safety with regard to coagulation and acid-base balance. Tetrastarches offer the best currently available compromise between cost-effectiveness and safety profile in children with preexisting normal renal function and coagulation.

Severity of mental illness as a result of multiple childhood adversities: US National Epidemiologic Survey.

PubMed

Curran, Emma; Adamson, Gary; Stringer, Maurice; Rosato, Michael; Leavey, Gerard

2016-05-01

To examine patterns of childhood adversity, their long-term consequences and the combined effect of different childhood adversity patterns as predictors of subsequent psychopathology. Secondary analysis of data from the US National Epidemiologic Survey on alcohol and related conditions. Using latent class analysis to identify childhood adversity profiles; and using multinomial logistic regression to validate and further explore these profiles with a range of associated demographic and household characteristics. Finally, confirmatory factor analysis substantiated initial latent class analysis findings by investigating a range of mental health diagnoses. Latent class analysis generated a three-class model of childhood adversity in which 60 % of participants were allocated to a low adversity class; 14 % to a global adversities class (reporting exposures for all the derived latent classes); and 26 % to a domestic emotional and physical abuse class (exposed to a range of childhood adversities). Confirmatory Factor analysis defined an internalising-externalising spectrum to represent lifetime reporting patterns of mental health disorders. Using logistic regression, both adversity groups showed specific gender and race/ethnicity differences, related family discord and increased psychopathology. We identified underlying patterns in the exposure to childhood adversity and associated mental health. These findings are informative in their description of the configuration of adversities, rather than focusing solely on the cumulative aspect of experience. Amelioration of longer-term negative consequences requires early identification of psychopathology risk factors that can inform protective and preventive interventions. This study highlights the utility of screening for childhood adversities when individuals present with symptoms of psychiatric disorders.

Mycophenolate mofetil in erosive genital lichen planus: a case and review of the literature.

PubMed

Deen, Kristyn; McMeniman, Erin

2015-03-01

Erosive genital lichen planus is a disabling, inflammatory mucocutaneous condition that can cause significant patient morbidity and loss of function. Treatment initially involves topical corticosteroids but some patients can have severe treatment-resistant courses requiring systemic immunosuppression. With potentially unfavorable adverse effect profiles and subsequent intolerance of these agents by patients, erosive lichen planus can ultimately be a challenging condition to treat effectively. We present a case of a 66-year-old woman with treatment-resistant erosive genital lichen planus who was successfully managed with mycophenolate mofetil. Although there is only weak evidence for this agent in this condition, its role in dermatology is growing due to its efficacy and advantageous adverse effect profile and should therefore be considered in patients with treatment-resistant erosive genital lichen planus. © 2015 Japanese Dermatological Association.

One size fits one: pharmacogenetics in gastroenterology.

PubMed

Porayette, Prashanth; Flockhart, David; Gupta, Sandeep K

2014-04-01

Individual variability in response and development of adverse effects to drugs is a major challenge in clinical practice. Pharmacogenomics refers to the aspect of personalized medicine where the patient's genetic information instructs the selection and dosage of therapy while also predicting its adverse effects profile. Sequencing of the entire human genome has given us the opportunity to study commonly used drugs as well as newer therapeutic agents in a new light, opening up opportunities for better drug efficacy and decreased adverse effects. This article highlights developments in pharmacogenomics, relates these to practice of gastroenterology, and outlines roadblocks in translation of this knowledge into clinical practice. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

The impact of old versus new antiepileptic drugs on costs and patient reported outcomes among older adults.

PubMed

Almalag, Haya M; Alzahrani, Huda; Al-Hussain, Fawaz; Alsemari, Abdulaziz; De Vol, Edward B; Almarzouqi, Manal Rashed; AlRuthia, Yazed S

2018-05-30

The aim of this prospective questionnaire-based cross-sectional study was to examine whether the new generation of Antiepileptic drugs (AEDs) with higher acquisition cost generate lower adverse effects than the old AEDs among a sample of 102 Arabic-speaking older adults (60 years of age or older) with seizure disorders. The mean scores of the Arabic version of the Liverpool Adverse Events Profile (LAEP), which assessed the adverse effects of the AEDs, did not differ between patients taking the old and new generations of AEDs. Despite their 4-fold higher cost, the new generation of AEDs were not characterized by lower LAEP scores of adverse effects. However, higher LAEP scores were associated with better health literacy. In conclusion, the use of new AEDs was not associated with lower self-reported adverse effects scores among Arabic-speaking older adults with seizure disorders despite their higher acquisition costs. Copyright © 2018 Elsevier Inc. All rights reserved.

Food and Insulin Effect on QT/QTC Interval of ECG

ClinicalTrials.gov

2014-08-19

Effects of Different Meals on the QT/QTc Interval; Insulin and Oral Hypoglycemic [Antidiabetic] Drugs Causing Adverse Effects in Therapeutic Use; C-Peptide Effects on the QT/QTc Interval; Moxifloxacin ECG Profile in Fed and Fasted State; Japanese vs. Caucasian TQT Comparison

Blood transcriptomics: applications in toxicology

PubMed Central

Joseph, Pius; Umbright, Christina; Sellamuthu, Rajendran

2015-01-01

The number of new chemicals that are being synthesized each year has been steadily increasing. While chemicals are of immense benefit to mankind, many of them have a significant negative impact, primarily owing to their inherent chemistry and toxicity, on the environment as well as human health. In addition to chemical exposures, human exposures to numerous non-chemical toxic agents take place in the environment and workplace. Given that human exposure to toxic agents is often unavoidable and many of these agents are found to have detrimental human health effects, it is important to develop strategies to prevent the adverse health effects associated with toxic exposures. Early detection of adverse health effects as well as a clear understanding of the mechanisms, especially at the molecular level, underlying these effects are key elements in preventing the adverse health effects associated with human exposure to toxic agents. Recent developments in genomics, especially transcriptomics, have prompted investigations into this important area of toxicology. Previous studies conducted in our laboratory and elsewhere have demonstrated the potential application of blood gene expression profiling as a sensitive, mechanistically relevant and practical surrogate approach for the early detection of adverse health effects associated with exposure to toxic agents. The advantages of blood gene expression profiling as a surrogate approach to detect early target organ toxicity and the molecular mechanisms underlying the toxicity are illustrated and discussed using recent studies on hepatotoxicity and pulmonary toxicity. Furthermore, the important challenges this emerging field in toxicology faces are presented in this review article. PMID:23456664

Analysis of pharmacology data and the prediction of adverse drug reactions and off-target effects from chemical structure.

PubMed

Bender, Andreas; Scheiber, Josef; Glick, Meir; Davies, John W; Azzaoui, Kamal; Hamon, Jacques; Urban, Laszlo; Whitebread, Steven; Jenkins, Jeremy L

2007-06-01

Preclinical Safety Pharmacology (PSP) attempts to anticipate adverse drug reactions (ADRs) during early phases of drug discovery by testing compounds in simple, in vitro binding assays (that is, preclinical profiling). The selection of PSP targets is based largely on circumstantial evidence of their contribution to known clinical ADRs, inferred from findings in clinical trials, animal experiments, and molecular studies going back more than forty years. In this work we explore PSP chemical space and its relevance for the prediction of adverse drug reactions. Firstly, in silico (computational) Bayesian models for 70 PSP-related targets were built, which are able to detect 93% of the ligands binding at IC(50) < or = 10 microM at an overall correct classification rate of about 94%. Secondly, employing the World Drug Index (WDI), a model for adverse drug reactions was built directly based on normalized side-effect annotations in the WDI, which does not require any underlying functional knowledge. This is, to our knowledge, the first attempt to predict adverse drug reactions across hundreds of categories from chemical structure alone. On average 90% of the adverse drug reactions observed with known, clinically used compounds were detected, an overall correct classification rate of 92%. Drugs withdrawn from the market (Rapacuronium, Suprofen) were tested in the model and their predicted ADRs align well with known ADRs. The analysis was repeated for acetylsalicylic acid and Benperidol which are still on the market. Importantly, features of the models are interpretable and back-projectable to chemical structure, raising the possibility of rationally engineering out adverse effects. By combining PSP and ADR models new hypotheses linking targets and adverse effects can be proposed and examples for the opioid mu and the muscarinic M2 receptors, as well as for cyclooxygenase-1 are presented. It is hoped that the generation of predictive models for adverse drug reactions is able to help support early SAR to accelerate drug discovery and decrease late stage attrition in drug discovery projects. In addition, models such as the ones presented here can be used for compound profiling in all development stages.

An update of safety of clinically used atypical antipsychotics.

PubMed

Orsolini, L; Tomasetti, C; Valchera, A; Vecchiotti, R; Matarazzo, I; Vellante, F; Iasevoli, F; Buonaguro, E F; Fornaro, M; Fiengo, A L C; Martinotti, G; Mazza, M; Perna, G; Carano, A; De Bartolomeis, A; Di Giannantonio, M; De Berardis, D

2016-10-01

The atypical antipsychotic (APs) drugs have become the most widely used agents to treat a variety of psychoses because of their superiority with regard to safety and tolerability profile compared to conventional/'typical' APs. We aimed at providing a synthesis of most current evidence about the safety and tolerability profile of the most clinically used atypical APs so far marketed. Qualitative synthesis followed an electronic search made inquiring of the following databases: MEDLINE, Embase, PsycINFO and the Cochrane Library from inception until January 2016, combining free terms and MESH headings for the topics of psychiatric disorders and all atypical APs as following: ((safety OR adverse events OR side effects) AND (aripiprazole OR asenapine OR quetiapine OR olanzapine OR risperidone OR paliperidone OR ziprasidone OR lurasidone OR clozapine OR amisulpride OR iloperidone)). A critical issue in the treatment with atypical APs is represented by their metabolic side effect profile (e.g. weight gain, lipid and glycaemic imbalance, risk of diabetes mellitus and diabetic ketoacidosis) which may limit their use in particular clinical samples. Electrolyte imbalance, ECG abnormalities and cardiovascular adverse effects may recommend a careful baseline and periodic assessments.

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

PubMed Central

Leung, Maxwell C.K.; Phuong, Jimmy; Baker, Nancy C.; Sipes, Nisha S.; Klinefelter, Gary R.; Martin, Matthew T.; McLaurin, Keith W.; Setzer, R. Woodrow; Darney, Sally Perreault; Judson, Richard S.; Knudsen, Thomas B.

2015-01-01

Background: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies. Objective: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system. Methods: We used U.S. EPA’s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA’s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. Results: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. Conclusion: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s. Citation: Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050–1061; http://dx.doi.org/10.1289/ehp.1510385 PMID:26662846

Comparison of tolerability and adverse symptoms in oxcarbazepine and carbamazepine in the treatment of trigeminal neuralgia and neuralgiform headaches using the Liverpool Adverse Events Profile (AEP).

PubMed

Besi, E; Boniface, D R; Cregg, R; Zakrzewska, J M

2015-01-01

Adverse effects of drugs are poorly reported in the literature . The aim of this study was to examine the frequency of the adverse events of antiepileptic drugs (AEDs), in particular carbamazepine (CBZ) and oxcarbazepine (OXC) in patients with neuralgiform pain using the psychometrically tested Liverpool Adverse Events Profile (AEP) and provide clinicians with guidance as to when to change management. The study was conducted as a clinical prospective observational exploratory survey of 161 patients with idiopathic trigeminal neuralgia and its variants of whom 79 were on montherapy who attended a specialist clinic in a London teaching hospital over a period of 2 years. At each consultation they completed the AEP questionnaire which provides scores of 19-76 with toxic levels being considered as scores >45. The most common significant side effects were: tiredness 31.3 %, sleepiness 18.2 %, memory problems 22.7 %, disturbed sleep 14.1 %, difficulty concentrating and unsteadiness 11.6 %. Females reported significantly more side effects than males. Potential toxic dose for females is approximately 1200 mg of OXC and 800 mg of CBZ and1800mg of OXC and 1200 mg of CBZ for males. CBZ and OXC are associated with cognitive impairment. Pharmacokinetic and pharmacodynamic differences are likely to be the reason for gender differences in reporting side effects. Potentially, females need to be prescribed lower dosages in view of their tendency to reach toxic levels at lower dosages. Side effects associated with AED could be a major reason for changing drugs or to consider a referral for surgical management.

Comparison on the Effects and Safety of Tualang Honey and Tribestan in Sperm Parameters, Erectile Function, and Hormonal Profiles among Oligospermic Males

PubMed Central

Ismail, Shaiful Bahari; Bakar, Mohd. Bustamanizan; Nik Hussain, Nik Hazlina; Sulaiman, Siti Amrah; Jaafar, Hasnan; Draman, Samsul; Ramli, Roszaman; Wan Yusoff, Wan Zahanim

2014-01-01

Introduction. This study aims to evaluate the effectiveness of Tualang honey on sperm parameters, erectile function, and hormonal and safety profiles. Methodology. A randomized control trial was done using Tualang honey (20 grams) and Tribestan (750 mg) over a period of 12 weeks. Sperm parameters including sperm concentration, motility, and morphology were analyzed and erectile function was assessed using IIEF-5 questionnaire. Hormonal profiles of testosterone, FSH, and LH were studied. The volunteers were randomized into two groups and the outcomes were analyzed using SPSS version 18. Results. A total of 66 participants were involved. A significant increment of mean sperm concentration (P < 0.001), motility (P = 0.015) and morphology (P = 0.008) was seen in Tualang honey group. In Tribestan group, a significant increment of mean sperm concentration (P = 0.007), and morphology (P = 0.009) was seen. No significant differences of sperm concentration, motility, and morphology were seen between Tualang honey and Tribestan group and similar results were also seen in erectile function and hormonal profile. All safety profiles were normal and no adverse event was reported. Conclusion. Tualang honey effect among oligospermic males was comparable with Tribestan in improving sperm concentration, motility, and morphology. The usage of Tualang honey was also safe with no reported adverse event. PMID:25505918

A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly

PubMed Central

Wongrakpanich, Supakanya; Wongrakpanich, Amaraporn; Melhado, Katie; Rangaswami, Janani

2018-01-01

NSAIDs, non-steroidal anti-inflammatory drugs, are one of the most commonly prescribed pain medications. It is a highly effective drug class for pain and inflammation; however, NSAIDs are known for multiple adverse effects, including gastrointestinal bleeding, cardiovascular side effects, and NSAID induced nephrotoxicity. As our society ages, it is crucial to have comprehensive knowledge of this class of medication in the elderly population. Therefore, we reviewed the pharmacodynamics and pharmacokinetics, current guidelines for NSAIDs use, adverse effect profile, and drug interaction of NSAIDs and commonly used medications in the elderly. PMID:29392089

Electrical stimulation for gastroesophageal reflux disease: current state of the art.

PubMed

Kim, Sharon E; Soffer, Edy

2016-01-01

Patients with gastroesophageal reflux disease (GERD) who are not satisfied with acid suppression therapy can benefit primarily from fundoplication, a surgical intervention. Fundoplication has been the standard surgical procedure for GERD. It is effective but is associated with adverse effects, resulting in a declining number of interventions, creating a need for alternative interventions that are effective, yet have a better adverse effect profile. One such alternative involves the application of electrical stimulation to the lower esophageal sphincter. A number of animal studies showed that such stimulation can increase resting lower esophageal sphincter pressure. An acute human study confirmed this effect, and was followed by two open-label studies, with a follow-up of up to 3 years. Results thus far show that the therapy is associated with a significant improvement in symptoms, a significant reduction in esophageal acid exposure, and a very good safety profile. This review will describe the evolution of electrical stimulation therapy for GERD, as well as the safety and efficacy of this intervention.

Adverse effect profile of lidocaine injections for occipital nerve block in occipital neuralgia.

PubMed

Sahai-Srivastava, Soma; Subhani, Dawood

2010-12-01

To determine whether there are differences in the adverse effect profile between 1, 2 and 5% Lidocaine when used for occipital nerve blocks (ONB) in patients with occipital neuralgia. Occipital neuralgia is an uncommon cause of headaches. Little is known regarding the safety of Lidocaine injections for treatment in larger series of patients. Retrospective chart analysis of all ONB was performed at our headache clinic during a 6-year period on occipital neuralgia patients. 89 consecutive patients with occipital neuralgia underwent a total of 315 ONB. All the patients fulfilled the IHS criteria for Occipital Neuralgia. Demographic data were collected including age, gender, and ethnicity. The average age of this cohort was 53.25 years, and the majority of patients were females 69 (78%). Ethnicity of patients was diverse, with Caucasian 48(54%), Hispanics 31(35%), and others 10 (11%). 69 patients had 1%, 18 patients had 2% and 29 patient were given 5% Lidocaine. All Lidocaine injections were given with 20 mg Depo-medrol and the same injection technique and location were used for all the procedures. Eight patients (9%)had adverse effects to the Lidocaine and Depo-medrol injections, of which 5 received 5% and 3 received 1% Lidocaine. Majority of patients who had adverse effects were female 7(87%), and had received bilateral blocks (75%). ONB is a safe procedure with 1% Lidocaine; however, caution should be exerted with 5% in elderly patients, 70 or older, especially when administering bilateral injections.

Effect of scalp blocks with levobupivacaine on recovery profiles after craniotomy for aneurysm clipping: a randomized, double-blind, and controlled study.

PubMed

Hwang, Jin-Young; Bang, Jae-Seung; Oh, Chang-Wan; Joo, Jin-Deok; Park, Seong-Joo; Do, Sang-Hwan; Yoo, Yong-Jae; Ryu, Jung-Hee

2015-01-01

This study was conducted to evaluate the effect of scalp blocks using levobupivacaine on recovery profiles including postoperative pain, patient-controlled analgesia (PCA) consumption, postoperative nausea and vomiting (PONV), and other adverse events in patients undergoing frontoparietal craniotomy for aneurysm clipping. Fifty-two patients scheduled for elective frontoparietal craniotomy for unruptured aneurysm clipping were enrolled. After surgery, scalp blocks were performed using normal saline (group C, n = 26) or 0.75% levobupivacaine (group L, n = 26). Postoperative pain scores and PCA consumption were recorded for 72 hours after recovery of consciousness. The time from patient recovery to the first use of PCA drug and rescue analgesics, the requirement for vasoactive agents, and adverse effects related to PCA and local anesthetics also were recorded. Postoperative pain scores and PCA consumption in group L were lower than in group C (P < .05). The time intervals from patient recovery to the first use of PCA drug (P < .001) and rescue analgesics (P = .038) was longer in group L than in group C. Additionally, less antihypertensive agent was required (P = .017), and PONV occurred less frequently (P = .039) in group L than in group C. Scalp blocks with 0.75% levobupivacaine improved recovery profiles in that it effectively lowered postoperative pain and PCA consumption without severe adverse events and also reduced the requirement for a postoperative antihypertensive agent and the incidence of PONV in patients who underwent frontoparietal craniotomy for aneurysm clipping. Copyright © 2015 Elsevier Inc. All rights reserved.

A review on adverse event profiles of epidermal growth factor receptor-tyrosine kinase inhibitors in nonsmall cell lung cancer patients.

PubMed

Biswas, B; Ghadyalpatil, N; Krishna, M V; Deshmukh, J

2017-12-01

The epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of EGFR-mutant nonsmall cell lung cancer (NSCLC). These EGFR TKIs demonstrate a different adverse event (AE) profile as compared to conventional chemotherapy agents. They are more commonly associated with cutaneous AEs and diarrhea while hematological AEs occurred commonly with chemotherapy agents. These AEs are the extension of pharmacological effect and occur as a result of blockade of EGFR-regulated pathways in the skin and gastrointestinal tract. This review article sheds light on the safety profile of first-, second-, and third-generation EGFR TKIs based on data obtained from several clinical trials conducted in NSCLC patients and highlights trials comparing these agents with the conventional chemotherapy agents. The strategies to manage EGFR TKI-related AEs are also reviewed.

Updated recommendations on the use of hydroxychloroquine in dermatologic practice.

PubMed

Fernandez, Anthony P

2017-06-01

Hydroxychloroquine has unique immunomodulatory properties and an attractive adverse effect profile. Over the past 10 years, research has led to significant updates in clinical recommendations concerning the optimal use of hydroxychloroquine and monitoring of patients taking it. We discuss updated recommendations concerning hydroxychloroquine daily dosing, retinopathy screening, serologic monitoring, use in smokers, use in pregnant women, and adverse effect risk and monitoring. This review can hopefully serve as an aid to dermatologists and help ensure they continue using hydroxychloroquine safely and effectively. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

CYP3A-Mediated Generation of Aldehyde and Hydrazine in Atazanavir MetabolismS⃞

PubMed Central

Li, Feng; Lu, Jie; Wang, Laiyou

2011-01-01

Atazanavir (ATV) is an antiretroviral drug of the protease inhibitor class. Multiple adverse effects of ATV have been reported in clinical practice, such as jaundice, nausea, abdominal pain, and headache. The exact mechanisms of ATV-related adverse effects are unknown. It is generally accepted that a predominant pathway of drug-induced toxicity is through the generation of reactive metabolites. Our current study was designed to explore reactive metabolites of ATV. We used a metabolomic approach to profile ATV metabolism in mice and human liver microsomes. We identified 5 known and 13 novel ATV metabolites. Three potential reactive metabolites were detected and characterized for the first time: one aromatic aldehyde, one α-hydroxyaldehyde, and one hydrazine. These potential reactive metabolites were primarily generated by CYP3A. Our results provide a clue for studies on ATV-related adverse effects from the aspect of metabolic activation. Further studies are suggested to illustrate the impact of these potential reactive metabolites on ATV-related adverse effects. PMID:21148252

Comparative Effectiveness of Treatment Choices for Graves' Hyperthyroidism: A Historical Cohort Study.

PubMed

Sundaresh, Vishnu; Brito, Juan P; Thapa, Prabin; Bahn, Rebecca S; Stan, Marius N

2017-04-01

The optimum therapy for Graves' disease (GD) is chosen following discussion between physician and patient regarding benefits, drawbacks, potential side effects, and logistics of the various treatment options, and it takes into account patient values and preferences. This cohort study aimed to provide useful information for this discussion regarding the usage, efficacy, and adverse-effect profile of radioactive iodine (RAI), antithyroid drugs (ATDs), and thyroidectomy in a tertiary healthcare facility. The cohort included consecutive adults diagnosed with GD from January 2002 to December 2008, who had complete follow-up after treatment at the Mayo Clinic, Rochester, Minnesota. Data on treatment modalities, disease relapses, and adverse effects were extracted manually and electronically from the electronic medical records. Kaplan-Meier analyses were performed to evaluate the association of treatments with relapse-free survival. The cohort included 720 patients with a mean age of 49.3 years followed for a mean of 3.3 years. Of these, 76.7% were women and 17.1% were smokers. The initial therapy was RAI in 75.4%, ATDs in 16.4%, and thyroidectomy in 2.6%, while 5.6% opted for observation. For the duration of follow-up, ATDs had an overall failure rate of 48.3% compared with 8% for RAI (hazard ratio = 7.6; p < 0.0001). Surgery had a 100% success rate; 80% of observed patients ultimately required therapy. Adverse effects developed in 43 (17.3%) patients treated with ATDs, most commonly dysgeusia (4.4%), rash (2.8%), nausea/gastric distress (2.4%), pruritus (1.6%), and urticaria (1.2%). Eight patients treated with RAI experienced radiation thyroiditis (1.2%). Thyroidectomy resulted in one (2.9%) hematoma and one (2.85%) superior laryngeal nerve damage, with no permanent hypocalcemia. RAI was the most commonly used modality within the cohort and demonstrated the best efficacy and safety profile. Surgery was also very effective and relatively safe in the hands of experienced surgeons. While ATDs allow preservation of thyroid function, a high relapse rate combined with a significant adverse-effect profile was documented. These data can inform discussion between physician and patient regarding choice of therapy for GD.

The effectiveness and adverse effects profile of "burst" ketamine in refractory cancer pain: The VCOG PM 1-00 study.

PubMed

Jackson, Kate; Ashby, Michael; Howell, Deb; Petersen, Jennifer; Brumley, David; Good, Phillip; Pisasale, Maria; Wein, Simon; Woodruff, Roger

2010-01-01

This multi-centre study of adjuvant "burst" ketamine in palliative care in-patients documents its effectiveness, duration of pain relief, and adverse effects (AE) profile. Patients received a three-to-five day continuous subcutaneous infusion (CSCI) of ketamine escalated from 100 to 300 to 500 mg/24 hours if required. When the effective or maximum tolerated dose was attained, the infusion was continued for three days and each patient assessed as a responder or non-responder using strict criteria. The response rate was 22/44 (50 percent), with 4 (9 percent) becoming pain-free. Pain relief lasting two or more weeks was documented in 50 percent of responders. AEs were documented daily using the National Cancer Institute (NCI) Common Toxicity Criteria 0-4 scales. There were 11 grade 3 and 4 neurological AEs. However, no responders elected to cease treatment early due to neurological AEs. We concluded that this protocol in the controlled environment of an in-patient PC unit is relatively safe and simple with reasonable effectiveness.

Corrigendum: Childhood Adversity, Self-Esteem, and Diurnal Cortisol Profiles Across the Life Span.

PubMed

2018-01-01

Original article: Zilioli, S., Slatcher, R. B., Chi, P., Li, X., Zhao, J., & Zhao, G. (2016). Childhood adversity, self-esteem, and diurnal cortisol profiles across the life span. Psychological Science, 27, 1249-1265. doi:10.1177/0956797616658287.

Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells

EPA Science Inventory

Plasticizers with estrogenic activity, such as bisphenol A (BPA), have potential adverse health effects in humans. Due to mounting evidence of these health effects, BPA is being phased out and replaced by other bisphenol variants in “BPA-free” products. We have compared estrogeni...

Bosutinib, dasatinib, imatinib, nilotinib, and ponatinib differentially affect the vascular molecular pathways and functionality of human endothelial cells.

PubMed

Gover-Proaktor, Ayala; Granot, Galit; Pasmanik-Chor, Metsada; Pasvolsky, Oren; Shapira, Saar; Raz, Oshrat; Raanani, Pia; Leader, Avi

2018-05-09

The tyrosine kinase inhibitors (TKIs), nilotinib, ponatinib, and dasatinib (but not bosutinib or imatinib), are associated with vascular adverse events (VAEs) in chronic myeloid leukemia (CML). Though the mechanism is inadequately understood, an effect on vascular cells has been suggested. We investigated the effect of imatinib, nilotinib, dasatinib, bosutinib, and ponatinib on tube formation, cell viability, and gene expression of human vascular endothelial cells (HUVECs). We found a distinct genetic profile in HUVECs treated with dasatinib, ponatinib, and nilotinib compared to bosutinib and imatinib, who resembled untreated samples. However, unique gene expression and molecular pathway alterations were detected between dasatinib, ponatinib, and nilotinib. Angiogenesis/blood vessel-related pathways and HUVEC function (tube formation/viability) were adversely affected by dasatinib, ponatinib, and nilotinib but not by imatinib or bosutinib. These results correspond to the differences in VAE profiles of these TKIs, support a direct effect on vascular cells, and provide direction for future research.

Oral Health in Electroconvulsive Therapy: A Neglected Topic.

PubMed

Muzyka, Brian C; Glass, Magdalena; Glass, Oliver M

2017-03-01

Psychiatric medications may have serious and untoward adverse effects such as blurred vision, restlessness, agranulocytosis, muscle rigidity, and tremors. When compared to medications, electroconvulsive therapy (ECT) is becoming a more acceptable treatment due to its efficacy, tolerability, and minimal adverse effect profile. Oral trauma can be an ECT-related adverse effect. We reviewed the published literature on oral health and dental protection in patients undergoing ECT, and found that there are deficits in all guidelines on dental protection during ECT. Dental assessment and treatment before and after ECT is warranted. Given the increased risk of poor oral health in psychiatric patients, and the continued evolution of ECT as a mainstay treatment, it is important that studies be conducted to determine the optimal method of oral protection. If adequate care can be ensured, the risks of ECT-induced oral trauma will be minimized.

Adverse drug reactions induced by valproic acid.

PubMed

Nanau, Radu M; Neuman, Manuela G

2013-10-01

Valproic acid is a widely-used first-generation antiepileptic drug, prescribed predominantly in epilepsy and psychiatric disorders. VPA has good efficacy and pharmacoeconomic profiles, as well as a relatively favorable safety profile. However, adverse drug reactions have been reported in relation with valproic acid use, either as monotherapy or polytherapy with other antiepileptic drugs or antipsychotic drugs. This systematic review discusses valproic acid adverse drug reactions, in terms of hepatotoxicity, mitochondrial toxicity, hyperammonemic encephalopathy, hypersensitivity syndrome reactions, neurological toxicity, metabolic and endocrine adverse events, and teratogenicity. Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Ibrutinib (Imbruvica). Relapsed chronic lymphocytic leukaemia and mantle cell lymphoma: uncertain impact on survival.

PubMed

January

2016-04-01

codynamic interactions are also likely in view of its adverse effect profile. There is no consensus on the treatment of patients with refractory or relapsed mantle cell lymphoma, or for patients with relapsed or possibly refractory chronic lymphocytic leukaemia. Ibrutinib inhibits an enzyme involved in regulating B lymphocyte activity. It has been authorised in the European Union for these conditions. Clinical evaluation of ibrutinib in mantle cell lymphoma is based on a single non-comparative trial in 111 patients, in which the median overall survival time was 22.5 months. Clinical evaluation of ibrutinib in chronic lymphocytic leukaemia is based on two randomised trials. One unblinded trial compared ibrutinib versus ofatumumab and involved 391 patients, most of whom were sufficiently fit to receive anticancer combination therapy. Ibrutinib was more effective than ofatumumab, but the choice of this comparator might not have been appropriate for most of the patients who received it. The other double-blind, placebo-controlled trial involved 578 patients with relapsed or refractory chronic lymphocytic leukaemia. Ibrutinib was added to the bendamustine + rituximab combination. No significant difference in mortality was observed between the two groups. The main adverse effects of ibrutinib were: gastrointestinal disorders such as diarrhoea; life-threatening infections and bleeding disorders; and cardiac disorders, including atrial fibrillation. Ibrutinib carries a risk of multiple pharmacokinetic interactions. Pharmacodynamic interactions are also likely in view of its adverse effect profile.

Intermittent calorie restriction largely counteracts the adverse health effects of a moderate-fat diet in aging C57BL/6J mice.

PubMed

Rusli, Fenni; Lute, Carolien; Boekschoten, Mark V; van Dijk, Miriam; van Norren, Klaske; Menke, Aswin L; Müller, Michael; Steegenga, Wilma T

2017-05-01

Calorie restriction (CR) has been shown to extend life- and health-span in model species. For most humans, a life-long CR diet is too arduous to adhere to. The aim of this study was to explore whether weekly intermittent CR can (1) provide long-term beneficial effects and (2) counteract diet-induced obesity in male aging mice. In this study, we have exposed C57Bl/6J mice for 24 months to an intermittent (INT) diet, alternating weekly between CR of a control diet and ad libitum moderate-fat (MF) feeding. This weekly intermittent CR significantly counteracted the adverse effects of the MF diet on mortality, body weight, and liver health markers in 24-month-old male mice. Hepatic gene expression profiles of INT-exposed animals appeared much more comparable to CR- than to MF-exposed mice. At 12 months of age, a subgroup of MF-exposed mice was transferred to the INT diet. Gene expression profiles in the liver of the 24-month-old diet switch mice were highly similar to the INT-exposed mice. However, a small subset of genes was consistently changed by the MF diet during the first phase of life. Weekly intermittent CR largely, but not completely, reversed adverse effects caused by a MF diet. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Childhood adversity profiles and adult psychopathology in a representative Northern Ireland study.

PubMed

McLafferty, Margaret; Armour, Cherie; McKenna, Aine; O'Neill, Siobhan; Murphy, Sam; Bunting, Brendan

2015-10-01

Childhood adversities are key aetiological factors in the onset and persistence of psychopathology. The aims of this study were to identify childhood adversity profiles, and investigate the relationship between the adversity classes and psychopathology in Northern Ireland. The study utilized data from the Northern Ireland Study of Health and Stress, an epidemiological survey (N=1986), which used the CIDI to examine mental health disorders and associated risk factors. Latent Class Analysis revealed 3 distinct typologies; a low risk class (n=1709; 86%), a poly-adversity class (n=122; 6.1%), and an economic adversity class (n=155; 7.8%). Logistic Regression models revealed that individuals in the economic adversity class had a heightened risk of anxiety and substance disorders, with individuals in the poly-adversity class more likely to have a range of mental health problems and suicidality. The findings indicate the importance of considering the impact of co-occurring childhood adversities when planning treatment, prevention, and intervention programmes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Adverse Effects of Grape Seed Extract Supplement: A Clinical Case and Long-Term Follow-Up.

PubMed

Berry, Andrew C; Nakshabendi, Rahman; Abidali, Hussein; Atchaneeyasakul, Kunakorn; Dholaria, Kevin; Johnson, Cassandra; Kishore, Varsha A; Baltz, Aaron C

2016-01-01

Grape seed extract (GSE) supplement use is becoming more popular today for its potential chemopreventive and chemotherapeutic role. We report a 49-year-old male who presented with recurrent nausea, vomiting, diarrhea, and acute weakness following GSE use. A thorough medical workup ensued and no causes were identified clinically, procedurally, or with imaging. Symptoms resolved after GSE discontinuation and the patient remained symptom-free 5 years later. This case illustrates the paucity of documented detailed clinical cases and lack of controlled trials detailing a thorough and reproducible adverse effect profile of GSE supplement.

Metabolites as Biomarkers of Adverse Reactions Following Vaccination: A Pilot Study using Nuclear Magnetic Resonance Metabolomics

PubMed Central

McClenathan, Bruce M.; Stewart, Delisha A.; Spooner, Christina E.; Pathmasiri, Wimal W.; Burgess, Jason P.; McRitchie, Susan L.; Choi, Y. Sammy; Sumner, Susan C.J.

2017-01-01

An Adverse Event Following Immunization (AEFI) is an adverse reaction to a vaccination that goes above and beyond the usual side effects associated with vaccinations. One serious AEFI related to the smallpox vaccine is myopericarditis. Metabolomics involves the study of the low molecular weight metabolite profile of cells, tissues, and biological fluids, and provides a functional readout of the phenotype. Metabolomics may help identify a particular metabolic signature in serum of subjects who are predisposed to developing AEFIs. The goal of this study was to identify metabolic markers that may predict the development of adverse events following smallpox vaccination. Serum samples were collected from military personnel prior to and following receipt of smallpox vaccine. The study population included five subjects who were clinically diagnosed with myopericarditis, 30 subjects with asymptomatic elevation of troponins, and 31 subjects with systemic symptoms following immunization, and 34 subjects with no AEFI, serving as controls. Two-hundred pre- and post-smallpox vaccination sera were analyzed by untargeted metabolomics using 1H nuclear magnetic resonance (NMR) spectroscopy. Baseline (pre-) and post-vaccination samples from individuals who experienced clinically verified myocarditis or asymptomatic elevation of troponins were more metabolically distinguishable pre- and post-vaccination compared to individuals who only experienced systemic symptoms, or controls. Metabolomics profiles pre- and post-receipt of vaccine differed substantially when an AEFI resulted. This study is the first to describe pre- and post-vaccination metabolic profiles of subjects who developed an adverse event following immunization. The study demonstrates the promise of metabolites for determining mechanisms associated with subjects who develop AEFI and the potential to develop predictive biomarkers. PMID:28169076

Metabolites as biomarkers of adverse reactions following vaccination: A pilot study using nuclear magnetic resonance metabolomics.

PubMed

McClenathan, Bruce M; Stewart, Delisha A; Spooner, Christina E; Pathmasiri, Wimal W; Burgess, Jason P; McRitchie, Susan L; Choi, Y Sammy; Sumner, Susan C J

2017-03-01

An Adverse Event Following Immunization (AEFI) is an adverse reaction to a vaccination that goes above and beyond the usual side effects associated with vaccinations. One serious AEFI related to the smallpox vaccine is myopericarditis. Metabolomics involves the study of the low molecular weight metabolite profile of cells, tissues, and biological fluids, and provides a functional readout of the phenotype. Metabolomics may help identify a particular metabolic signature in serum of subjects who are predisposed to developing AEFIs. The goal of this study was to identify metabolic markers that may predict the development of adverse events following smallpox vaccination. Serum samples were collected from military personnel prior to and following receipt of smallpox vaccine. The study population included five subjects who were clinically diagnosed with myopericarditis, 30 subjects with asymptomatic elevation of troponins, and 31 subjects with systemic symptoms following immunization, and 34 subjects with no AEFI, serving as controls. Two-hundred pre- and post-smallpox vaccination sera were analyzed by untargeted metabolomics using 1 H nuclear magnetic resonance (NMR) spectroscopy. Baseline (pre-) and post-vaccination samples from individuals who experienced clinically verified myocarditis or asymptomatic elevation of troponins were more metabolically distinguishable pre- and post-vaccination compared to individuals who only experienced systemic symptoms, or controls. Metabolomics profiles pre- and post-receipt of vaccine differed substantially when an AEFI resulted. This study is the first to describe pre- and post-vaccination metabolic profiles of subjects who developed an adverse event following immunization. The study demonstrates the promise of metabolites for determining mechanisms associated with subjects who develop AEFI and the potential to develop predictive biomarkers. Published by Elsevier Ltd.

Are selective serotonin reuptake inhibitors safe for drivers? What is the evidence?

PubMed

Ravera, Silvia; Ramaekers, Johannes G; de Jong-van den Berg, Lolkje T W; de Gier, Johan J

2012-05-01

Selective serotonin reuptake inhibitors (SSRIs) are widely used medications to treat several psychiatric diseases and, above all, depression. They seem to be as effective as older antidepressants but have a different adverse effect profile. Despite their favorable safety profile, little is known about their influence on traffic safety. To conduct a literature review to summarize the current evidence on the role of SSRIs in traffic safety, particularly concerning undesirable effects that could potentially impair fitness to drive, experimental and pharmacoepidemiologic studies on driving impairment, 2 existing categorization systems for driving-impairing medications, and the European legislative procedures for assessing fitness to drive before issuing a driver's license and driving under the influence of medicines. The article search was performed in the following electronic databases: MEDLINE, PsycINFO, ScienceDirect, and SafetyLit. The English-language scientific literature was searched using key words such as SSRIs and psychomotor performance, car crash or traffic accident, and adverse effects. For inclusion in this review, papers had to be full-text articles, refer to possible driving-related adverse effects, and be experimental or pharmacoepidemiologic studies on SSRIs and traffic accident risks. No restrictions concerning publication year were applied. Ten articles were selected as background information on driving-related adverse effects, and 15 articles were selected regarding experimental and pharmacoepidemiologic work. Regarding SSRI adverse effects, the most reported undesirable effects referring to driving impairment were anxiety, agitation, sleep disturbances, headache, increased risk of suicidal behavior, and deliberate self-harm. Regarding the remaining issues addressed in this article, inconsistencies were found between the outcomes of the selected experimental and epidemiologic studies and between the 2 existing categorization systems under evaluation. Some pitfalls of the current legislative scenario were identified as well. Based on the current evidence, it was concluded that more experimental and epidemiologic research is needed to elucidate the relationship between SSRI use and traffic safety. Furthermore, a revision of the existing categorization systems and harmonized European legislation in the field of medication use and driving were highly recommended. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

More effective assessment of adverse effects and comorbidities in epilepsy: results of a Phase II communication study.

PubMed

Stern, John M; Labiner, David M; Gilliam, Frank G; Penovich, Patricia E; Onofrey, Meaghan; Eagan, Corey A; Holmes, Gregory L

2011-11-01

Research was conducted to evaluate conversations about epilepsy between community-based neurologists and patients. Adverse effects of antiepileptic drugs and mood/behavioral issues were infrequently discussed, and neurologists and patients disagreed about these issues postvisit. Follow-up research was conducted to assess the impact of a previsit assessment tool on discussions of epilepsy. Twenty neurologists reviewed a tool incorporating questions from validated instruments (Adverse Events Profile [AEP] and Neurological Disorders Depression Inventory for Epilepsy [NDDI-E]). Naturally occurring interactions between neurologists and 60 patients were recorded. Neurologists and patients were interviewed separately. All components were transcribed and analyzed using sociolinguistics. Using the previsit assessment tool increased the number of discussions about adverse effects and mood/behavioral issues and increased neurologist-patient agreement about issues postvisit. Visit length did not increase significantly when the tool was used. Ten months after follow-up research, 50% of neurologists reported continuing to use the tool in everyday practice with patients with epilepsy. Copyright © 2011 Elsevier Inc. All rights reserved.

Environmental Assessment: T-6 Aircraft Basing and Operation

DTIC Science & Technology

2004-06-01

The operating characteristics of the T -6 are similar to the T-37. Thus, the T-6 traffic pattern aircraft ground tracks, profiles , and airspeeds are...low-income populations.” Adverse is defined by the Federal Interagency Working Group on Environmental Justice as “having a deleterious effect on...types of aircraft (i.e., large and trainer) was considered a significant safety issue. Safety concerns include mixing the flight profiles of two

Physician access to drug profiles to reduce adverse reactions

NASA Astrophysics Data System (ADS)

Yasnoff, William A.; Tomkins, Edward L.; Dunn, Louise M.

1995-10-01

Adverse drug reactions (ADRs) are a major source of preventable morbidity and mortality, especially among the elderly, who use more drugs and are more sensitive to them. The insurance industry has recently addressed this problem through the implementation of drug interaction alerts to pharmacists in conjunction with immediate online claims adjudication for almost 60% of prescriptions (expected to reach 90% within 5 years). These alerts are based on stored patient drug profiles maintained by pharmacy benefit managers (PBMs) which are updated whenever prescriptions are filled. While these alerts are very helpful, the pharmacist does not prescribe, resulting in time-consuming and costly delays to contact the physician and remedy potential interactions. We have developed and demonstrated the feasibility of the PINPOINT (Pharmaceutical Information Network for prevention of interactions) system for making the drug profile and interaction information easily available to the physician before the prescription is written. We plan to test the cost-effectiveness of the system in a prospective controlled clinical trial.

Vagus nerve stimulation therapy in partial epilepsy: a review.

PubMed

Panebianco, Mariangela; Zavanone, Chiara; Dupont, Sophie; Restivo, Domenico A; Pavone, Antonino

2016-09-01

Epilepsy is a chronic neurological disorder characterized by recurrent, unprovoked epileptic seizures. The majority of people given a diagnosis of epilepsy have a good prognosis, but 20-30 % will develop drug-resistant epilepsy. Vagus nerve stimulation (VNS) is a neuromodulatory treatment that is used as an adjunctive therapy for treating people with medically refractory epilepsy. It consists of chronic intermittent electrical stimulation of the vagus nerve, delivered by a programmable pulse generator (Neuro-Cybernetic Prosthesis). In 1997, the Food and Drug Administration approved VNS as adjunctive treatment for medically refractory partial-onset seizures in adults and adolescents. This article reviews the literature from 1988 to nowadays. We discuss thoroughly the anatomy and physiology of vagus nerve and the potential mechanisms of actions and clinical applications involved in VNS therapy, as well as the management, safety, tolerability and effectiveness of VNS therapy. VNS for partial seizures appears to be an effective and well tolerated treatment in adult and pediatric patients. People noted improvements in feelings of well-being, alertness, memory and thinking skills, as well as mood. The adverse effect profile is substantially different from the adverse effect profile associated with antiepileptic drugs, making VNS a potential alternative for patients with difficulty tolerating antiepileptic drug adverse effects. Despite the passing years and the advent of promising neuromodulation technologies, VNS remains an efficacy treatment for people with medically refractory epilepsy. Past and ongoing investigations in other indications have provided signals of the therapeutic potential in a wide variety of conditions.

Antidepressant-Induced Female Sexual Dysfunction.

PubMed

Lorenz, Tierney; Rullo, Jordan; Faubion, Stephanie

2016-09-01

Because 1 in 6 women in the United States takes antidepressants and a substantial proportion of patients report some disturbance of sexual function while taking these medications, it is a near certainty that the practicing clinician will need to know how to assess and manage antidepressant-related female sexual dysfunction. Adverse sexual effects can be complex because there are several potentially overlapping etiologies, including sexual dysfunction associated with the underlying mood disorder. As such, careful assessment of sexual function at the premedication visit followed by monitoring at subsequent visits is critical. Treatment of adverse sexual effects can be pharmacological (dose reduction, drug discontinuation or switching, augmentation, or using medications with lower adverse effect profiles), behavioral (exercising before sexual activity, scheduling sexual activity, vibratory stimulation, psychotherapy), complementary and integrative (acupuncture, nutraceuticals), or some combination of these modalities. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Comparison of gene expression profiles induced by coarse, fine, and ultrafile particulate matter

EPA Science Inventory

Coarse, fine, and ultrafine particulate matter (PM) fractions possess different physical properties and chemical compositions and may produce different adverse health effects. Studies were undertaken to determine whether or not gene expression patterns may be used to discriminate...

Metabolic Profiles Predict Adverse Events Following Coronary Artery Bypass Grafting

PubMed Central

Shah, Asad A.; Craig, Damian M.; Sebek, Jacqueline K.; Haynes, Carol; Stevens, Robert C.; Muehlbauer, Michael J.; Granger, Christopher B.; Hauser, Elizabeth R.; Newby, L. Kristin; Newgard, Christopher B.; Kraus, William E.; Hughes, G. Chad; Shah, Svati H.

2012-01-01

Objectives Clinical models incompletely predict outcomes following coronary artery bypass grafting. Novel molecular technologies may identify biomarkers to improve risk stratification. We examined whether metabolic profiles can predict adverse events in patients undergoing coronary artery bypass grafting. Methods The study population comprised 478 subjects from the CATHGEN biorepository of patients referred for cardiac catheterization who underwent coronary artery bypass grafting after enrollment. Targeted mass spectrometry-based profiling of 69 metabolites was performed in frozen, fasting plasma samples collected prior to surgery. Principal-components analysis and Cox proportional hazards regression modeling were used to assess the relation between metabolite factor levels and a composite outcome of post-coronary artery bypass grafting myocardial infarction, need for percutaneous coronary intervention, repeat coronary artery bypass grafting, or death. Results Over a mean follow-up of 4.3 ± 2.4 years, 126 subjects (26.4%) suffered an adverse event. Three principal-components analysis-derived factors were significantly associated with adverse outcome in univariable analysis: short-chain dicarboxylacylcarnitines (factor 2, P=0.001); ketone-related metabolites (factor 5, P=0.02); and short-chain acylcarnitines (factor 6, P=0.004). These three factors remained independently predictive of adverse outcome after multivariable adjustment: factor 2 (adjusted hazard ratio 1.23; 95% confidence interval [1.10-1.38]; P<0.001), factor 5 (1.17 [1.01-1.37], P=0.04), and factor 6 (1.14 [1.02-1.27], P=0.03). Conclusions Metabolic profiles are independently associated with adverse outcomes following coronary artery bypass grafting. These profiles may represent novel biomarkers of risk that augment existing tools for risk stratification of coronary artery bypass grafting patients and may elucidate novel biochemical pathways that mediate risk. PMID:22306227

Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: Myocardial and infectious adverse reactions as application cases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Kejian, E-mail: kejian.wang.bio@gmail.com; Weng, Zuquan; Sun, Liya

Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure–activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. Inmore » the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. - Highlights: • Drugs causing common toxicity lead to similar in vitro gene expression changes. • We built a model to predict drug toxicity with drug-specific expression profiles. • Drugs with FDA black box warnings were effectively identified by our model. • In vitro assay can detect severe toxicity in the early stage of drug development.« less

Children's Autonomic Nervous System Reactivity Moderates the Relations between Family Adversity and Sleep Problems in Latino 5-Year Olds in the CHAMACOS Study.

PubMed

Alkon, Abbey; Boyce, W Thomas; Neilands, Torsten B; Eskenazi, Brenda

2017-01-01

Sleep problems are common for young children especially if they live in adverse home environments. Some studies investigate if young children may also be at a higher risk of sleep problems if they have a specific biological sensitivity to adversity. This paper addresses the research question, does the relations between children's exposure to family adversities and their sleep problems differ depending on their autonomic nervous system's sensitivity to challenges? As part of a larger cohort study of Latino, low-income families, we assessed the cross-sectional relations among family demographics (education, marital status), adversities [routines, major life events (MLE)], and biological sensitivity as measured by autonomic nervous system (ANS) reactivity associated with parent-rated sleep problems when the children were 5 years old. Mothers were interviewed in English or Spanish and completed demographic, family, and child measures. The children completed a 15-min standardized protocol while continuous cardiac measures of the ANS [respiratory sinus arrhythmia (RSA), preejection period (PEP)] were collected during resting and four challenge conditions. Reactivity was defined as the mean of the responses to the four challenge conditions minus the first resting condition. Four ANS profiles, co-activation, co-inhibition, reciprocal low RSA and PEP reactivity, and reciprocal high RSA and PEP reactivity, were created by dichotomizing the reactivity scores as high or low reactivity. Logistic regression models showed there were significant main effects for children living in families with fewer daily routines having more sleep problems than for children living in families with daily routines. There were significant interactions for children with low PEP reactivity and for children with the reciprocal, low reactivity profiles who experienced major family life events in predicting children's sleep problems. Children who had a reciprocal, low reactivity ANS profile had more sleep problems if they also experienced MLE than children who experienced fewer MLE. These findings suggest that children who experience family adversities have different risks for developing sleep problems depending on their biological sensitivity. Interventions are needed for young Latino children that support family routines and reduce the impact of family adversities to help them develop healthy sleep practices.

ENDOTHELIAL INJURY IN PARTICULATE MATTER (PM)-INDUCED CARDIOVASCULAR INJURY: KINETIC ANALYSIS OF GENE EXPRESSION PROFILES

EPA Science Inventory

Numerous epidemiological studies established positive associations between ambient fine PM and cardiovascular morbidity and mortality. The biological basis for these adverse health effects is yet to be elucidated. Cardiovascular toxicity of fine PM and its toxic constituents may ...

PROTEOMICS IN ECOTOXICOLOGY: PROTEIN EXPRESSION PROFILING TO SCREEN CHEMICALS FOR ENDOCRINE ACTIVITY

EPA Science Inventory

Abstract for poster.

Current endocrine testing methods are animal intensive and lack the throughput necessary to screen large numbers of environmental chemicals for adverse effects. In this study, Matrix Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry...

Childhood Adversity, Self-Esteem, and Diurnal Cortisol Profiles across the Lifespan

PubMed Central

Zilioli, Samuele; Slatcher, Richard B.; Chi, Peilian; Li, Xiaoming; Zhao, Junfeng; Zhao, Guoxiang

2016-01-01

Childhood adversity is associated with poor health outcomes in adulthood; the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a crucial biological intermediary of these long-term effects. Here we tested whether childhood adversity was associated with diurnal cortisol parameters, and whether this link was partially explained by self-esteem. In both adults and children, childhood adversity was associated with lower levels of cortisol at awakening and this association was partially driven by low self-esteem. Further, we found a significant indirect pathway through which greater adversity during childhood was linked to a flatter cortisol slope via self-esteem. Lastly, those youth who had a caregiver with high self-esteem experienced a steeper decline in cortisol throughout the day compared to those youth whose caregiver reported low self-esteem. We conclude that self-esteem is a plausible psychological mechanism through which childhood adversity may get embedded in the activity of the HPA axis across the lifespan. PMID:27481911

Childhood Adversity, Self-Esteem, and Diurnal Cortisol Profiles Across the Life Span.

PubMed

Zilioli, Samuele; Slatcher, Richard B; Chi, Peilian; Li, Xiaoming; Zhao, Junfeng; Zhao, Guoxiang

2016-09-01

Childhood adversity is associated with poor health outcomes in adulthood; the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a crucial biological intermediary of these long-term effects. Here, we tested whether childhood adversity was associated with diurnal cortisol parameters and whether this link was partially explained by self-esteem. In both adults and youths, childhood adversity was associated with lower levels of cortisol at awakening, and this association was partially driven by low self-esteem. Further, we found a significant indirect pathway through which greater adversity during childhood was linked to a flatter cortisol slope via self-esteem. Finally, youths who had a caregiver with high self-esteem experienced a steeper decline in cortisol throughout the day compared with youths whose caregiver reported low self-esteem. We conclude that self-esteem is a plausible psychological mechanism through which childhood adversity may get embedded in the activity of the HPA axis across the life span. © The Author(s) 2016.

Gene expression profiles in the cerebellum and hippocampus following exposure to a neurotoxicant, Aroclor 1254: Developmental effects.

EPA Science Inventory

The developmental consequences of exposure to the polychlorinated biphenyls (PCBs) have been widely studied, making PCBs a unique model to understand issues related to environmental mixture of persistent chemicals. PCB exposure in humans adversely affects neurocognitive developm...

Perturbational Metabolic Profiling of Human Breast Cancer Cells

EPA Science Inventory

A major goal of toxicity testing is to obtain toxicity data for protecting public health and the environment from adverse effects that may be caused by exposure to environmental agents in the air, water, soil and food. The current toxicological studies that target human health ef...

CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects.

PubMed

Franco, Valentina; Perucca, Emilio

2015-01-01

Phenytoin, a widely prescribed old-generation antiepileptic drug, requires careful individualization of dosage to compensate for its prominent pharmacokinetic variability. This article reviews the contribution of genetic polymorphisms affecting the activity of CYP2C9, the main enzyme responsible for phenytoin metabolism, to the variation in phenytoin clearance and susceptibility to adverse effects. Comprehensive and critical review of available evidence concerning the influence of CYP2C9 genetic polymorphism on phenytoin pharmacokinetic and safety profile. There is extensive evidence that CYP2C9 polymorphisms are an important determinant of the rate of phenytoin metabolism, although other factors including expression of other enzymes such as CYP2C19 and the influence of drug interactions, physiological and disease-related factors may also play a role. Patients carrying CYP2C9 genotypes associated with reduced phenytoin clearance are at greater risk of developing CNS adverse effects as well as serious cutaneous adverse reactions when given usual dosages of phenytoin. The clinical value and cost-effectiveness of CYP2C9 genotyping in improving the safety of phenytoin therapy, however, have not been clearly established and require formal testing in well-designed prospective studies.

Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential?

PubMed

Albert-Vartanian, A; Boyd, M R; Hall, A L; Morgado, S J; Nguyen, E; Nguyen, V P H; Patel, S P; Russo, L J; Shao, A J; Raffa, R B

2016-08-01

Optimal utilization of opioid analgesics is significantly limited by the central nervous system adverse effects and misuse/abuse potential of currently available drugs. It has been postulated that opioid-associated adverse effects and abuse potential would be greatly reduced if opioids could be excluded from reaching the brain. We review the basic science and clinical evidence of one such approach - peripherally restricted kappa-opioid receptor (KOR) agonists (pKORAs). Published and unpublished literature, websites and other sources were searched for basic science and clinical information related to the potential benefits and development of peripherally restricted kappa-opioid receptor agonists. Each source was summarized, reviewed and assessed. The historical development of pKORAs can be traced from the design of increasingly KOR-selective agonists, elucidation of the pharmacologic attributes of such compounds and strategies to restrict passage across the blood-brain barrier. Novel compounds are under development and have progressed to clinical trials. The results from recent clinical trials suggest that peripherally restricted opioids can be successfully designed and that they can retain analgesic efficacy with a more favourable adverse effect profile. © 2016 John Wiley & Sons Ltd.

Adverse drug event profile associated with pregabalin among patients with and without cancer: analysis of a spontaneous reporting database.

PubMed

Kose, Eiji

2018-03-25

Pregabalin is used for the relief of neuropathic pain in patients with and without cancer. However, no report has examined whether there is a difference in the adverse drug event (ADE) profile of pregabalin in each context. We aimed to establish whether pregabalin's ADE profile was different between patients with and without cancer. This study was based on the Japanese Adverse Drug Event Report (JADER) database, which is a spontaneous reporting database. Reports obtained from the JADER database were analysed from April 2004 to December 2016 for ADEs, using reporting odds ratios (RORs), a method of disproportionality analysis. We evaluated the association between the RORs and ADEs of pregabalin and compared the age, dosage and time at which ADEs occurred in patients with and without cancer. The primary outcome was RORs. Secondary outcomes were expression age and time-to-onset of ADE among patients with and without cancer. In total, 426 216 reports from the JADER database were analysed. The major side effects associated with pregabalin among both patient groups were interstitial pneumonia, renal failure, liver failure, altered consciousness, heart failure and rhabdomyolysis. The pregabalin dose was significantly higher in patients with cancer than in those without cancer. Furthermore, the times to reporting of interstitial pneumonia, altered consciousness and liver failure were significantly shorter in patients with cancer than in those without cancer. The ADE profiles of pregabalin were broadly similar among patients with and without cancer, but time-to-onset and type of some ADEs may be different. © 2018 John Wiley & Sons Ltd.

CHANGES IN PROTEOMIC PROFILES OF CEREBELLUM FOLLOWING DEVELOPMENTAL EXPOSURE TO AROCLOR 1254 OR DE-71.

EPA Science Inventory

Chronic low level exposure to polychlorinated biphenyls (PCBs) has been shown to adversely affect human health, including learning and memory. Polybromiated diphenyl ethers (PBDEs) are structurally similar to PCBs and have been shown to have neurotoxic effects in vitro and in viv...

ALTERED GENE EXPRESSION PROFILES OF RAT LUNG IN RESPONSE TO AN EMISSION PARTICULATE AND ITS METAL CONSTITUENTS

EPA Science Inventory

Comprehensive and systematic approaches are needed to understand the molecular basis for the proposed adverse health effects of PM exposure reported in epidemiological studies. Due to the complex nature of the pollutant and the altered physiological conditions in the predisposed...

Pharmacodynamic effects of pilocarpine eye drop enhanced by decreasing its volume of instillation.

PubMed

Lal, A; Kataria, V; Rajpal, A; Khanna, N

1995-07-01

Previous studies have proved that as the volume of the drug solution instilled into the eye is decreased, the fraction of the dose absorbed into the ocular tissue is increased and the adverse drug reactions lowered. The present study investigated the acute effects of different drop volumes (10 microliters, 20 microliters, 40 microliters, and 80 microliters) of pilocarpine nitrate (2%) on pupil diameter, heart rate, and adverse reaction profile, in 12 healthy human volunteers. The drop volumes of 10 microliters and 20 microliters produced more miosis and less side effects than 40 microliters and 80 microliters drop volumes. This may be due to more penetration of the drug into the ocular tissue and less drainage into the nasolacrimal system.

Donepezil dosing strategies: pharmacokinetic considerations.

PubMed

Gomolin, Irving H; Smith, Candace; Jeitner, Thomas M

2011-10-01

Donepezil (Aricept) is a cholinesterase inhibitor approved for the treatment of Alzheimer's disease. Immediate release formulations of 5- and 10-mg tablets were approved by the Food and Drug Administration in the United States in 1996. In July 2010, the Food and Drug Administration approved a 23-mg sustained release (SR) formulation. The SR formulation may provide additional benefit to patients receiving 10 mg daily but the incidence of adverse reactions is increased. We derived plasma concentration profiles for higher dose immediate-release formulations (15 mg once daily, 10 mg twice daily, and 20 mg once daily) and for the profile anticipated to result from the 23-mg SR formulation. Our model predicts similar steady-state concentration profiles for 10 mg twice daily, 20 mg once daily, and 23 mg SR once daily. This provides the theoretical basis for incremental immediate release dose escalation to minimize the emergence of adverse reactions and the potential to offer a cost-effective alternative to the SR formulation with currently approved generic immediate release formulations. Copyright © 2011 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.

Non-Clinical Safety Studies of IMT504, a Unique Non-CpG Oligonucleotide

PubMed Central

Franco, Raúl; Rodriguez, Juan M.; Elías, Fernanda; Hernando-Insúa, Andrés; Fló, Juan; López, Ricardo; Nagle, Carlos; Lago, Néstor; Zorzopulos, Jorge; Horn, David L.

2014-01-01

IMT504 is a non-CpG 24-mer oligodeoxynucleotide (ODN) with immunomodulatory as well as tissue repair activity. IMT504 has been previously proven to be effective in animal models of vaccine potency, chronic lymphocytic leukemia, tissue regeneration, and sepsis. Here, we assessed the safety, including pharmacokinetics and toxicity studies in rats and monkeys, of IMT504 in a single- or repeated-dose administration by the subcutaneous (SC) or intravenous (IV) routes. In rats, the maximum tolerated dose was determined to be 50 mg/kg when administered SC. Adverse effects at 50 mg/kg were mild and reversible liver injury, revealed as lobular inflammation, focal necrosis, and small changes in the transaminase profile. Dose-dependent splenomegaly and lymphoid hyperplasia, most probably associated with immune stimulation, were commonly observed. Rats and monkeys were also IV injected with a single dose of 10 or 3.5 mg/kg, and no adverse effects were observed. Rats injected IV with 10 mg/kg showed a transient increase in spleen weight, together with a slight increase in the marginal zone of the white pulp and in leukocyte count 2 days post-administration. In monkeys, this dosage caused slight changes in total serum complement and leukocyte count on day 14. No adverse effects were observed at 3.5 mg/kg IV in rats or monkeys. Therefore, this dose was defined as the “no observed adverse effect level” for this route. Furthermore, repeated-dose toxicity studies were performed in these species using 3.5 or 0.35 mg/kg/day IV for 6 weeks. A transient increase in the spleen and liver weight was observed at 3.5 mg/kg/day only in female rats. No changes in clotting time and activation of the alternative complement pathway were observed. The toxicity profile of IMT504 herein reported suggests a dose range in which IMT504 can be used safely in clinical trials. PMID:24720569

Profiles of childhood adversities in pathological gamblers - A latent class analysis.

PubMed

Lotzin, Annett; Ulas, Mehmet; Buth, Sven; Milin, Sascha; Kalke, Jens; Schäfer, Ingo

2018-06-01

Despite of high rates of adverse childhood experiences (ACEs) in pathological gamblers, researchers have rarely studied which types of ACEs often co-occur and how these profiles of ACEs are related to current psychopathology. We aimed to identify profiles of ACEs in pathological gamblers and examined how these profiles were related to gambling-related characteristics and current general psychopathology. In 329 current or lifetime pathological gamblers, diagnosed with the Composite Diagnostic Interview for DSM-IV, 10 types of ACEs were measured using the Adverse Childhood Experiences Questionnaire. Global psychopathology was assessed using the Symptom Checklist SCL-27. ACE profiles were identified using latent class analysis. Differences between ACE profiles in gambling-related characteristics and global psychopathology were analyzed using MANOVA. We found that four out of five gamblers (n=257, 78.1%) reported at least one ACE. Four distinct ACE profiles were identified: 'Low ACE', 'High ACE', 'Physical and emotional abuse', and 'Neglect'. The number of the fulfilled pathological gambling criteria and the severity of current global psychopathology differed between the ACE profiles: Gamblers with a 'High ACE' profile fulfilled more pathological gambling criteria and showed a more severe current psychopathology than gamblers of the 'Low ACE' profile. Gamblers with a 'Physical and emotional abuse' or an 'Emotion neglect' profile showed an intermediate severity of psychopathology. Our findings indicate that four different ACE profiles can be distinguished in pathological gamblers that differed in their gambling-related characteristics and current psychopathology. Systematic assessment of profiles of ACEs in pathological gamblers may inform about the severity of current global psychopathology that might be important to be addressed in addition to gambling-specific treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

Sugammadex to Reverse Neuromuscular Blockade in a Child with a Past History of Cardiac Transplantation

PubMed Central

Miller, Karen; Hall, Brian; Tobias, Joseph D

2017-01-01

Sugammadex is a novel agent for the reversal of neuromuscular blockade. The speed and efficacy of reversal with sugammadex are significantly faster than acetylcholinesterase inhibitors, such as neostigmine. Sugammadex also has a limited adverse profile when compared with acetylcholinesterase inhibitors, specifically in regard to the incidence of bradycardia. This adverse effect may be particularly relevant in the setting of a heart transplant recipient with a denervated heart. The authors present a case of an 8-year-old child, status postcardiac transplantation, who required anesthetic care for laparoscopy and lysis of intra-abdominal adhesions. Sugammadex was used to reverse neuromuscular blockade and avoid the potential adverse effects of neostigmine. The unique mechanism of action of sugammadex is discussed, previous reports of its use in this unique patient population are reviewed, and its potential benefits compared to traditional acetylcholinesterase inhibitors are presented. PMID:28701612

Sugammadex to reverse neuromuscular blockade in a child with a past history of cardiac transplantation.

PubMed

Miller, Karen; Hall, Brian; Tobias, Joseph D

2017-01-01

Sugammadex is a novel agent for the reversal of neuromuscular blockade. The speed and efficacy of reversal with sugammadex are significantly faster than acetylcholinesterase inhibitors, such as neostigmine. Sugammadex also has a limited adverse profile when compared with acetylcholinesterase inhibitors, specifically in regard to the incidence of bradycardia. This adverse effect may be particularly relevant in the setting of a heart transplant recipient with a denervated heart. The authors present a case of an 8-year-old child, status postcardiac transplantation, who required anesthetic care for laparoscopy and lysis of intra-abdominal adhesions. Sugammadex was used to reverse neuromuscular blockade and avoid the potential adverse effects of neostigmine. The unique mechanism of action of sugammadex is discussed, previous reports of its use in this unique patient population are reviewed, and its potential benefits compared to traditional acetylcholinesterase inhibitors are presented.

Summarizing the incidence of adverse events using volcano plots and time intervals.

PubMed

Zink, Richard C; Wolfinger, Russell D; Mann, Geoffrey

2013-01-01

Adverse event incidence analyses are a critical component for describing the safety profile of any new intervention. The results typically are presented in lengthy summary tables. For therapeutic areas where patients have frequent adverse events, analysis and interpretation are made more difficult by the sheer number and variety of events that occur. Understanding the risk in these instances becomes even more crucial. We describe a space-saving graphical summary that overcomes the limitations of traditional presentations of adverse events and improves interpretability of the safety profile. We present incidence analyses of adverse events graphically using volcano plots to highlight treatment differences. Data from a clinical trial of patients experiencing an aneurysmal subarachnoid hemorrhage are used for illustration. Adjustments for multiplicity are illustrated. Color is used to indicate the treatment with higher incidence; bubble size represents the total number of events that occur in the treatment arms combined. Adjustments for multiple comparisons are displayed in a manner to indicate clearly those events for which the difference between treatment arms is statistically significant. Furthermore, adverse events can be displayed by time intervals, with multiple volcano plots or animation to appreciate changes in adverse event risk over time. Such presentations can emphasize early differences across treatments that may resolve later or highlight events for which treatment differences may become more substantial with longer follow-up. Treatment arms are compared in a pairwise fashion. Volcano plots are space-saving tools that emphasize important differences between the adverse event profiles of two treatment arms. They can incorporate multiplicity adjustments in a manner that is straightforward to interpret and, by using time intervals, can illustrate how adverse event risk changes over the course of a clinical trial.

Upper bound on the slope of steady water waves with small adverse vorticity

NASA Astrophysics Data System (ADS)

So, Seung Wook; Strauss, Walter A.

2018-03-01

We consider the angle of inclination (with respect to the horizontal) of the profile of a steady 2D inviscid symmetric periodic or solitary water wave subject to gravity. There is an upper bound of 31.15° in the irrotational case [1] and an upper bound of 45° in the case of favorable vorticity [13]. On the other hand, if the vorticity is adverse, the profile can become vertical. We prove here that if the adverse vorticity is sufficiently small, then the angle still has an upper bound which is slightly larger than 45°.

Profiles of Kindergarten Classroom and Elementary School Contexts: Associations with the First-Grade Outcomes of Children Transitioning from Head Start

PubMed Central

Lee, Phyllis; Bierman, Karen L.

2018-01-01

Poor quality classroom and school contexts may impede the academic and behavioral adjustment of low-income students when they transition into kindergarten. Several studies have examined the impact of teacher-student interactions on student progress, whereas others have explored the impact of school-level adversity (e.g., student poverty, school achievement levels). Expanding on prior findings, this study used latent profile analysis to characterize kindergarten contexts in terms of both classroom teacher-student interaction quality and school-level adversity. Following 164 children longitudinally and accounting for functioning in Head Start prior to kindergarten entry, associations between kindergarten context profiles and first grade outcomes revealed that children who experienced dual-risk contexts in kindergarten (classrooms with poor quality teacher-student interactions in schools with high levels of adversity) demonstrated the greatest aggression and social difficulties in first grade. Associations between kindergarten context profiles and first grade academic outcomes were less clear. PMID:29731516

Airborne Wind Profiling Algorithms for the Pulsed 2-Micron Coherent Doppler Lidar at NASA Langley Research Center

NASA Technical Reports Server (NTRS)

Beyon, Jeffrey Y.; Koch, Grady J.; Kavaya, Michael J.; Ray, Taylor J.

2013-01-01

Two versions of airborne wind profiling algorithms for the pulsed 2-micron coherent Doppler lidar system at NASA Langley Research Center in Virginia are presented. Each algorithm utilizes different number of line-of-sight (LOS) lidar returns while compensating the adverse effects of different coordinate systems between the aircraft and the Earth. One of the two algorithms APOLO (Airborne Wind Profiling Algorithm for Doppler Wind Lidar) estimates wind products using two LOSs. The other algorithm utilizes five LOSs. The airborne lidar data were acquired during the NASA's Genesis and Rapid Intensification Processes (GRIP) campaign in 2010. The wind profile products from the two algorithms are compared with the dropsonde data to validate their results.

Current Strategies in Anesthesia and Analgesia for Total Knee Arthroplasty.

PubMed

Moucha, Calin Stefan; Weiser, Mitchell C; Levin, Emily J

2016-02-01

Total knee arthroplasty is associated with substantial postoperative pain that may impair mobility, reduce the ability to participate in rehabilitation, lead to chronic pain, and reduce patient satisfaction. Traditional general anesthesia with postoperative epidural and patient-controlled opioid analgesia is associated with an undesirable adverse-effect profile, including postoperative nausea and vomiting, hypotension, urinary retention, respiratory depression, delirium, and an increased infection rate. Multimodal anesthesia--incorporating elements of preemptive analgesia, neuraxial perioperative anesthesia, peripheral nerve blockade, periarticular injections, and multimodal oral opioid and nonopioid medications during the perioperative and postoperative periods--can provide superior pain control while minimizing opioid-related adverse effects, improving patient satisfaction, and reducing the risk of postoperative complications.

Countermeasures for space radiation induced adverse biologic effects

NASA Astrophysics Data System (ADS)

Kennedy, A. R.; Wan, X. S.

2011-11-01

Radiation exposure in space is expected to increase the risk of cancer and other adverse biological effects in astronauts. The types of space radiation of particular concern for astronaut health are protons and heavy ions known as high atomic number and high energy (HZE) particles. Recent studies have indicated that carcinogenesis induced by protons and HZE particles may be modifiable. We have been evaluating the effects of proton and HZE particle radiation in cultured human cells and animals for nearly a decade. Our results indicate that exposure to proton and HZE particle radiation increases oxidative stress, cytotoxicity, cataract development and malignant transformation in in vivo and/or in vitro experimental systems. We have also shown that these adverse biological effects can be prevented, at least partially, by treatment with antioxidants and some dietary supplements that are readily available and have favorable safety profiles. Some of the antioxidants and dietary supplements are effective in preventing radiation induced malignant transformation in vitro even when applied several days after the radiation exposure. Our recent progress is reviewed and discussed in the context of the relevant literature.

Fludarabine plus alemtuzumab (FA) front-line treatment in young patients with chronic lymphocytic leukemia (CLL) and an adverse biologic profile.

PubMed

Mauro, Francesca R; Molica, Stefano; Laurenti, Luca; Cortelezzi, Agostino; Carella, Angelo M; Zaja, Francesco; Chiarenza, Annalisa; Angrilli, Francesco; Nobile, Francesco; Marasca, Roberto; Musolino, Caterina; Brugiatelli, Maura; Piciocchi, Alfonso; Vignetti, Marco; Fazi, Paola; Gentile, Giuseppe; De Propris, Maria S; Della Starza, Irene; Marinelli, Marilisa; Chiaretti, Sabina; Del Giudice, Ilaria; Nanni, Mauro; Albano, Francesco; Cuneo, Antonio; Guarini, Anna; Foà, Robin

2014-02-01

In 45, ≤ 60 years old patients with CLL and an adverse biologic profile, a front-line treatment with Fludarabine and Campath (Alemtuzumab(®)) was given. The overall response rate was 75.5%, the complete response rate (CR) 24.4% with the lowest CR rates, 16.7% and 8.3%, in 11q and 17p deleted cases. The 3-year progression-free survival (PFS) and overall survival were 42.5% and 79.9%, respectively. PFS was significantly influenced by CLL duration, beta2-microglobulin, and improved by post-remissional stem cell transplantation. Front-line fludarabine and alemtuzumab showed a manageable safety profile and evidence of a benefit in a small series of CLL patients with adverse biologic features. Copyright © 2013 Elsevier Ltd. All rights reserved.

Gender Differences in the Physical and Psychological Manifestation of Childhood Trauma and/or Adversity in People with Psychosis.

PubMed

Sweeney, Shaun; Air, Tracy; Zannettino, Lana; Galletly, Cherrie

2015-01-01

The link between childhood trauma and/or adversity and risk of psychosis is well known. Our aim was to determine the prevalence of childhood trauma and/or adversity in people who have psychotic disorders and to investigate the association between childhood trauma and/or adversity and a range of social and health measures. Participants (n = 391, 42% male) were specifically asked about any experience of childhood trauma and/or adversity. Respondents provided information about education, employment, physical health, and health service utilization. Univariate analyses revealed that childhood trauma and/or adversity was associated with poorer levels of self-reported physical health and social problems. This includes the experience of chronic pain, headaches, arthritis, asthma, and victimization/stigma in men. Participants with a childhood trauma and/or adversity history indicated higher rates of lifetime suicide attempts with women reporting more lifetime depressive symptoms. Multivariate analyses revealed differing profiles in relation to physical and psychological health variable between males and females. Males with the experience of childhood trauma and/or adversity were significantly more likely to report cardiovascular/stroke issues, migraines and anhedonia. Females with the experience of childhood trauma and/or adversity were more likely to report a lifetime history of elevated mood and to be married or in a de facto relationship. There has been very little research into the assessment and treatment of the effects of childhood trauma and/or adversity in adults with psychosis. Childhood trauma and/or adversity may contribute to higher rates of self-reported poor health in men and is associated with increased depression in women. Our findings suggest that interventions to address the effects of past trauma are urgently needed.

Nomegestrol acetate-17b-estradiol for oral contraception

PubMed Central

Burke, Anne

2013-01-01

Oral contraceptives remain a popular method of contraception over 50 years after their introduction. While safe and effective for many women, the failure rate of oral contraception is about 8%. Concerns about the risk of venous thromboembolism continue to drive the search for the safest oral contraceptive formulations. The oral contraceptive NOMAC-E2 contains nomegestrol acetate (NOMAC) 2.5 mg + 17b-estradiol (E2) 1.5 mg. The approved dosing regimen is 24 days of active hormone, followed by a 4-day hormone-free interval. NOMAC is a progestin derived from testosterone, which has high bioavailability, rapid absorption, and a long half-life. Estradiol, though it has a lower bioavailability, has been successfully combined with NOMAC in a monophasic oral contraceptive. Two recently published randomized controlled trials demonstrate that NOMAC-E2 is an effective contraceptive, with a Pearl Index less than one pregnancy per 100 woman-years. The bleeding pattern on NOMAC-E2 is characterized by fewer bleeding/spotting days, shorter withdrawal bleeds, and a higher incidence of amenorrhea than the comparator oral contraceptive containing drospirenone and ethinyl estradiol. The adverse event profile appears to be acceptable. Few severe adverse events were reported in the randomized controlled trials. The most common adverse events were irregular bleeding, acne, and weight gain. Preliminary studies suggest that NOMAC-E2 does not seem to have negative effects on hemostatic and metabolic parameters. While no one oral contraceptive formulation is likely to be the optimum choice for all women, NOMAC-E2 is a formulation with effectiveness comparable with that of other oral contraceptives, and a reassuring safety profile. PMID:23836965

Drug formulary review process for sargramostim and filgrastim: focus on analysis of adverse drug reactions.

PubMed

Kellihan, M J

1993-01-01

Selection of a drug for formulary inclusion involves evaluation of safety, efficacy, and cost. The colony-stimulating factors (CSFs) sargramostim and filgrastim have a broad range of potential indications and represent a costly formulary addition when acquisition price alone is considered; their comparative safety is unclear. These factors suggest that the CSFs should be closely scrutinized prior to formulary addition. In the absence of direct comparative studies, an assessment of the safety of CSFs involves evaluation of information provided in the product circular, official drug compendia, adverse biologic reports submitted to the United States Food and Drug Administration, and data from key clinical trials. Data in the product circulars report on adverse events in small numbers of patients treated for chemotherapy-induced neutropenia (filgrastim) or neutropenia subsequent to bone marrow transplantation (sargramostim). The official compendia and clinical trials include experience with CSFs produced in a variety of expression systems; these data are not limited to sargramostim and filgrastim. Importantly, there was a similar incidence of adverse events in patients who received sargramostim or filgrastim and in those who took placebo reported in the product circulars and the pivotal trials, suggesting that the underlying disease may have an important role in determining the side-effect profile of these agents. Adverse biologic reports represent experience with sargramostim and filgrastim obtained under actual clinical conditions and suggest that the same types of adverse events are seen with sargramostim as with filgrastim. This analysis suggests that a decision to select filgrastim over sargramostim for formulary inclusion based on the safety profile is not appropriate because currently available data are equivocal and that such decisions would more appropriately be based on efficacy and cost.

Safety Profile of Eslicarbazepine Acetate as Add-On Therapy in Adults with Refractory Focal-Onset Seizures: From Clinical Studies to 6 Years of Post-Marketing Experience.

PubMed

Gama, Helena; Vieira, Mariana; Costa, Raquel; Graça, Joana; Magalhães, Luís M; Soares-da-Silva, Patrício

2017-12-01

Eslicarbazepine acetate was first approved in the European Union in 2009 as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization. The objective of this study was to review the safety profile of eslicarbazepine acetate analyzing the data from several clinical studies to 6 years of post-marketing surveillance. We used a post-hoc pooled safety analysis of four phase III, double-blind, randomized, placebo-controlled studies (BIA-2093-301, -302, -303, -304) of eslicarbazepine acetate as add-on therapy in adults. Safety data of eslicarbazepine acetate in special populations of patients aged ≥65 years with partial-onset seizures (BIA-2093-401) and subjects with moderate hepatic impairment (BIA-2093-111) and renal impairment (BIA-2093-112) are also considered. The incidences of treatment-emergent adverse events, treatment-emergent adverse events leading to discontinuation, and serious adverse events were analyzed. The global safety database of eslicarbazepine acetate was analyzed for all cases from post-marketing surveillance from 1 October, 2009 to 21 October, 2015. From a pooled analysis of four phase III studies, it was concluded that the incidence of treatment-emergent adverse events, treatment-emergent adverse events leading to discontinuation, and adverse drug reactions were dose dependent. Dizziness, somnolence, headache, and nausea were the most common treatment-emergent adverse events (≥10% of patients) and the majority were of mild-to-moderate intensity. No dose-dependent trend was observed for serious adverse events and individual serious adverse events were reported in less than 1% of patients. Hyponatremia was classified as a possibly related treatment-emergent adverse event in phase III studies (1.2%); however, after 6 years of post-marketing surveillance it represents the most frequently (10.2%) reported adverse drug reaction, with more than half of these cases occurring with eslicarbazepine acetate at daily doses of 1200 mg. Other adverse drug reactions reported in post-marketing surveillance are seizure (5.8%), dizziness (4.1%), rash (2.6%), and fatigue (2.1%). The safety profile of eslicarbazepine acetate in renal and hepatic impairment subjects (phase I studies) and in elderly patients (phase III study) did not raise any specific concern. After 6 years of post-marketing surveillance, eslicarbazepine acetate maintains a similar safety profile to that observed in pivotal clinical studies.

Efficacy and safety profile of xanthines in COPD: a network meta-analysis.

PubMed

Cazzola, Mario; Calzetta, Luigino; Barnes, Peter J; Criner, Gerard J; Martinez, Fernando J; Papi, Alberto; Gabriella Matera, Maria

2018-06-30

Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline. Therefore, we performed a quantitative synthesis to compare the efficacy and safety profile of different xanthines in COPD.The primary end-point of this meta-analysis was the impact of xanthines on lung function. In addition, we assessed the risk of adverse events by normalising data on safety as a function of person-weeks. Data obtained from 998 COPD patients were selected from 14 studies and meta-analysed using a network approach.The combined surface under the cumulative ranking curve (SUCRA) analysis of efficacy (change from baseline in forced expiratory volume in 1 s) and safety (risk of adverse events) showed that doxofylline was superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety), and theophylline (comparable efficacy and significantly better safety).Considering the overall efficacy/safety profile of the investigated agents, the results of this quantitative synthesis suggest that doxofylline seems to be the best xanthine for the treatment of COPD. Copyright ©ERS 2018.

Children’s Autonomic Nervous System Reactivity Moderates the Relations between Family Adversity and Sleep Problems in Latino 5-Year Olds in the CHAMACOS Study

PubMed Central

Alkon, Abbey; Boyce, W. Thomas; Neilands, Torsten B.; Eskenazi, Brenda

2017-01-01

Sleep problems are common for young children especially if they live in adverse home environments. Some studies investigate if young children may also be at a higher risk of sleep problems if they have a specific biological sensitivity to adversity. This paper addresses the research question, does the relations between children’s exposure to family adversities and their sleep problems differ depending on their autonomic nervous system’s sensitivity to challenges? As part of a larger cohort study of Latino, low-income families, we assessed the cross-sectional relations among family demographics (education, marital status), adversities [routines, major life events (MLE)], and biological sensitivity as measured by autonomic nervous system (ANS) reactivity associated with parent-rated sleep problems when the children were 5 years old. Mothers were interviewed in English or Spanish and completed demographic, family, and child measures. The children completed a 15-min standardized protocol while continuous cardiac measures of the ANS [respiratory sinus arrhythmia (RSA), preejection period (PEP)] were collected during resting and four challenge conditions. Reactivity was defined as the mean of the responses to the four challenge conditions minus the first resting condition. Four ANS profiles, co-activation, co-inhibition, reciprocal low RSA and PEP reactivity, and reciprocal high RSA and PEP reactivity, were created by dichotomizing the reactivity scores as high or low reactivity. Logistic regression models showed there were significant main effects for children living in families with fewer daily routines having more sleep problems than for children living in families with daily routines. There were significant interactions for children with low PEP reactivity and for children with the reciprocal, low reactivity profiles who experienced major family life events in predicting children’s sleep problems. Children who had a reciprocal, low reactivity ANS profile had more sleep problems if they also experienced MLE than children who experienced fewer MLE. These findings suggest that children who experience family adversities have different risks for developing sleep problems depending on their biological sensitivity. Interventions are needed for young Latino children that support family routines and reduce the impact of family adversities to help them develop healthy sleep practices. PMID:28713808

The Effect of Exercise Training on Serum Lipids in the Elderly.

PubMed

Ades, Philip A.; Poehlman, Eric T.

1996-10-01

Numerous intervention trials in young subjects suggest that aerobic exercise training exerts favorable effects on specific lipid subfractions, in particular serum triglycerides and high density lipoprotein (HDL) cholesterol. Cross sectional studies in older individuals suggest that active individuals have more favorable lipid profiles than inactive individuals. However, it remains controversial as to whether leisure time activity or fitness levels per se are independent predictors of lipid measures in the elderly versus their intermediate effects on body composition and body fat distribution. That is, a greater deposition of abdominal fat in the least fit individuals is associated with adverse lipid profiles. Short-term (8-weeks) aerobic exercise in elders is not associated with any significant changes in lipid profiles, however, longer term programs, particularly if associated with improvements in body fat distribution and/or weight loss, have been demonstrated to yield significant improvements in lipid subfractions, in particular triglycerides and HDL cholesterol.

Relationship of land uses with occurrence of contaminants of emerging concern in streams of southeastern Minnesota

USDA-ARS?s Scientific Manuscript database

Endocrine disrupting compounds (EDC), pharmaceuticals, and other contaminants of emerging concern (CEC) have been detected in surface waters, including compounds suspected or known to cause adverse human or ecological effects. Goals of the project are to (1) characterize CEC profiles and land uses a...

High temperature storage characteristics of lithium sulfur dioxide cells

NASA Technical Reports Server (NTRS)

Watson, T.

1980-01-01

Hermetically sealed SO2 cells were developed to eliminate SO2 diffusion and its adverse effects on shelf life. A two part barrier coating material was applied to the internal surface of the glass seal and cured under a predetermined thermal profile in order to prevent the self discharge associated with glass seal corrosion.

Proteome Profiling Reveals Potential Toxicity and Detoxification Pathways Following Exposure of BEAS-2B Cells to Engineered Nanoparticle Titanium Dioxide

EPA Science Inventory

Identification of toxicity pathways linked to chemical -exposure is critical for a better understanding of biological effects of the exposure, toxic mechanisms, and for enhancement of the prediction of chemical toxicity and adverse health outcomes. To identify toxicity pathways a...

Safety of Sculptra: a review of clinical trial data.

PubMed

Engelhard, Peter; Humble, Gail; Mest, Douglas

2005-12-01

The development of facial lipoatrophy as a result of highly active antiretroviral therapy (HAART) used to treat patients with human immunodeficiency virus (HIV) has adversely affected patient quality of life and compliance with therapy. Thanks to modern pharmacotherapies, HIV can now be viewed as a chronic disease; however, this welcome change has exacerbated the effect of facial lipoatrophy since HIV-infected patients can now expect to live longer and healthier lives but remain subject to public scrutiny of their ongoing disease state. Sculptra (Dermik Laboratories, Berwyn, PA, USA) has recently been introduced in the USA for correction of the appearance of facial lipoatrophy. The device affords long-lasting restoration while still being non-permanent, thus providing an extended but adjustable cosmetic effect. The safety profile of this product has been observed in four investigator-initiated clinical trials of more than 250 HIV patients and in numerous investigator reports, with no serious adverse events or infections deemed associated with the product. Maintenance of the excellent safety profile for this injectable device requires adherence to a novel technique and appreciation of its unique attributes.

Mode of action characterization for adverse effect of propranolol in Daphnia magna based on behavior and physiology monitoring and metabolite profiling.

PubMed

Jeong, Tae-Yong; Yoon, Dahye; Kim, Suhkmann; Kim, Hyun Young; Kim, Sang Don

2018-02-01

Studies are underway to gather information about the mode of action (MOA) of emerging pollutants that could guide practical environmental decision making. Previously, we showed that propranolol, an active pharmaceutical ingredient, had adverse effects on Daphnia magna that were similar to its pharmaceutical action. In order to characterize the mode of action of propranolol in D. magna, which is suspected to be organ-specific pharmaceutical action or baseline toxicity, we performed time-series monitoring of behavior along with heart rate measurements and nuclear magnetic resonance (NMR) based metabolite profiling. Principle component analysis (PCA) and hierarchical clustering were used to categorize the mode of action of propranolol among 5 chemicals with different modes of action. The findings showed that the mode of action of propranolol in D. magna is organ-specific and vastly different from those of narcotics, even though metabolite regulation is similar between narcotic and non-narcotic candidates. The method applied in this study seems applicable to rapid characterization of the MOA of other cardiovascular pharmaceutical ingredients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Drug safety evaluation of naltrexone/bupropion for the treatment of obesity.

PubMed

Verpeut, Jessica L; Bello, Nicholas T

2014-06-01

Obesity is a known health risk for the development of several preventable diseases. Obesity-related metabolic alterations negatively impact different physiological mechanisms, which supports the rationale for the use of combined drug therapy. Naltrexone is an opioid antagonist for the treatment of opioid and alcohol dependency, whereas bupropion is a norepinephrine/dopamine reuptake inhibitor used to treat depression and smoking cessation. Although not effective as individual monotherapies for obesity, naltrexone and bupropion in combination produce weight loss and a metabolic profile beneficial for the potential treatment of obesity. This review examines the safety and antiobesity effects of naltrexone and bupropion alone and in combination. It reviews the results of four Phase III clinical trials of a novel fixed dose of sustained-released naltrexone/bupropion. Naltrexone/bupropion has a greater weight loss efficacy than two FDA-approved medications, orlistat and lorcaserin. Although the weight loss produced by phentermine/topiramate is superior to naltrexone/bupropion, the safety profile of naltrexone/bupropion has less severe adverse effects. In addition, naltrexone/bupropion is well tolerated, with nausea being the most reported adverse event. Unlike other centrally acting medications, lorcaserin and phentermine/topiramate, naltrexone/bupropion has no abuse potential.

Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease.

PubMed

Dean, Marissa; Sung, Victor W

2018-01-01

Deutetrabenazine was recently approved for the treatment of chorea in Huntington's disease (HD) and is the first deuterated medication that has been US Food and Drug Administration (FDA)-approved for therapeutic use. In this article, we review deutetrabenazine's drug design, pharmacokinetics, drug interactions, efficacy, adverse events, comparison with tetrabenazine, dosage, and administration. Deutetrabenazine is a deuterated form of tetrabenazine and is a vesicular monoamine transporter 2 (VMAT2) inhibitor. The substitution of deuterium for hydrogen at key positions in the tetrabenazine molecule allows a longer drug half-life and less frequent daily dosing. Deutetrabenazine is administered twice daily up to a maximum daily dose of 48 mg, which corresponds to a similar daily dose of 100 mg of tetrabenazine. In a Phase III clinical trial (First-HD), there was a statistically significant improvement of chorea in HD subjects, as well as improvements in global impression of change as assessed by both patients and clinicians. This improvement was seen without significant adverse effects as the overall tolerability profile of deutetrabenazine was similar to placebo. Somnolence was the most commonly reported symptom in the deutetrabenazine group. In a study where subjects converted from tetrabenazine to deutetrabenazine in an open-label fashion (ARC-HD) and indirect comparison studies between tetrabenazine and deutetrabenazine, there is a suggestion that while efficacy for chorea is similar, the data may slightly favor tetrabenazine, but adverse effects and tolerability strongly favor deutetrabenazine. These data have not been replicated in true head-to-head studies. Current evidence supports that deutetrabenazine is an effective therapeutic treatment option for chorea in HD and may provide a more favorable adverse effect profile than tetrabenazine. However, more data are needed, particularly in the form of head-to-head studies between deutetrabenazine and other treatment options as well as longer term clinical experience with deutetrabenazine.

Multiple-dose safety study of ibuprofen/codeine and aspirin/codeine combinations.

PubMed

Friedman, H; Seckman, C; Stubbs, C; Oster, H; Royer, G

1990-01-01

This multiple-dose, double-blind, placebo-controlled, randomized, normal volunteer study compared formulations of ibuprofen/codeine and aspirin/codeine for systemic safety. Vital signs, hematologic, biochemical and urinary parameters, side effects, mood and mental alertness, were monitored. The placebo group had less gastrointestinal side effects and more frequent stools than the active treatment groups. There was statistical evidence for greater adverse effects of aspirin/codeine on mood and mental alertness in comparison to ibuprofen/codeine and placebo. Ibuprofen/codeine had a more favorable adverse effect profile than aspirin/codeine. A mild respiratory and cardiac depressant effect attributable to codeine was evident in all active treatment groups after 7 days of frequent therapy. More work needs to be done to elucidate the factors regulating the development of tolerance to the respiratory and cardiovascular depressant effects of opiates in general, and for codeine in particular.

Does decreased access to emergency departments affect patient outcomes? Analysis of acute myocardial infarction population 1996-2005.

PubMed

Shen, Yu-Chu; Hsia, Renee Y

2012-02-01

We analyze whether decreased emergency department (ED) access results in adverse patient outcomes or changes in the patient health profile for patients with acute myocardial infarction (AMI). We merge Medicare claims, American Hospital Association annual surveys, Medicare hospital cost reports, and location information for 1995-2005. We define four ED access change categories and estimate a ZIP Code fixed-effects regression models on the following AMI outcomes: mortality rates, age, and probability of percutaneous transluminal coronary angioplasty (PTCA) on day of admission. We find a small increase in 30-day to 1-year mortality rates among patients in communities that experience a <10-minute increase in driving time. Among patients in communities with >30-minute increases, we find a substantial increase in long-term mortality rates, a shift to younger ages (suggesting that older patients die en route), and a higher probability of immediate PTCA. Most of the adverse effects disappear after the transition years. Deterioration in geographic access to ED affects a small segment of the population, and most adverse effects are transitory. Policy planners can minimize the adverse effects by providing assistance to ensure adequate capacity of remaining EDs, and facilitating the realignment of health care resources during the critical transition periods. © Health Research and Educational Trust.

Short infusion of paclitaxel imbalances plasmatic lipid metabolism and correlates with cardiac markers of acute damage in patients with breast cancer.

PubMed

Panis, C; Binato, R; Correa, S; Victorino, V J; Dias-Alves, V; Herrera, A C S A; Cecchini, R; Simão, A N C; Barbosa, D S; Pizzatti, L; Abdelhay, E

2017-09-01

Although paclitaxel-based chemotherapy is widely used for treating breast cancer, paclitaxel therapy has been associated with several adverse effects. Such adverse effects have primarily been associated with long-term regimens, but some acute effects are being increasingly reported in the literature. In this context, the present study analyzed the systemic proteomic profiles of women diagnosed with breast cancer at the first cycle of short paclitaxel infusion (n = 30). Proteomic profiles thus obtained were compared with those of breast cancer patients without chemotherapy (n = 50), as well as with those of healthy controls (n = 40). Plasma samples were evaluated by label-free LC-MS to obtain systemic proteomic profiles. Putative dysregulated pathways were identified and validated by in silico analysis of proteomic profiles. Our results identified 188 proteins that were differentially expressed in patients who received a single short paclitaxel infusion when compared to patients who did not receive the infusion. Gene ontology analysis indicated that the cholesterol pathway may be dysregulated by paclitaxel in these patients. Validation analysis showed that paclitaxel treatment significantly reduced plasma high-density lipoprotein levels and increased plasma hydroperoxide levels when compared to breast cancer patients without chemotherapy. Furthermore, augmented C-reactive protein and creatine kinase fraction MB were found to be significantly higher in paclitaxel-treated patients in comparison with healthy controls. Taken together, these data suggest that a single dose of short paclitaxel infusion is sufficient to trigger significant alterations in lipid metabolism, which puts breast cancer patients at risk for increased incidence of cardiovascular disease.

Levetiracetam-induced neutropenia following traumatic brain injury.

PubMed

Bunnell, Kristen; Pucci, Francesco

2015-01-01

Levetiracetam is being increasingly utilized for post-traumatic brain injury seizure prophylaxis, in part because of its more favourable adverse effect profile compared to other anti-epileptics. This report highlights an unusual, clinically significant adverse drug reaction attributed to levetiracetam use in a patient with blunt traumatic brain injury. This study describes a case of isolated neutropenia associated with levetiracetam in a 52-year-old man with traumatic brain injury. The patient developed neutropenia on day 3 of therapy with levetiracetam, with an absolute neutrophil count nadir of 200. There were no other medications that may have been implicated in the development of this haematological toxicity. Neutropenia rapidly resolved upon cessation of levetiracetam therapy. Clinicians should be aware of potentially serious adverse reactions associated with levetiracetam in patients with neurological injury.

Short-term open-label chamomile (Matricaria chamomilla L.) therapy of moderate to severe generalized anxiety disorder.

PubMed

Keefe, John R; Mao, Jun J; Soeller, Irene; Li, Qing S; Amsterdam, Jay D

2016-12-15

Conventional drug treatments for Generalized Anxiety Disorder (GAD) are often accompanied by substantial side effects, dependence, and/or withdrawal syndrome. A prior controlled study of oral chamomile (Matricaria chamomilla L.) extract showed significant efficacy versus placebo, and suggested that chamomile may have anxiolytic activity for individuals with GAD. We hypothesized that treatment with chamomile extract would result in a significant reduction in GAD severity ratings, and would be associated with a favorable adverse event and tolerability profile. We report on the open-label phase of a two-phase randomized controlled trial of chamomile versus placebo for relapse-prevention of recurrent GAD. Subjects with moderate to severe GAD received open-label treatment with pharmaceutical-grade chamomile extract 1500mg/day for up to 8 weeks. Primary outcomes were the frequency of clinical response and change in GAD-7 symptom scores by week 8. Secondary outcomes included the change over time on the Hamilton Rating Scale for Anxiety, the Beck Anxiety Inventory, and the Psychological General Well Being Index. Frequency of treatment-emergent adverse events and premature treatment discontinuation were also examined. Of 179 subjects, 58.1% (95% CI: 50.9% to 65.5%) met criteria for response, while 15.6% prematurely discontinued treatment. Significant improvement over time was also observed on the GAD-7 rating (β=-8.4 [95% CI=-9.1 to -7.7]). A similar proportion of subjects demonstrated statistically significant and clinically meaningful reductions in secondary outcome ratings of anxiety and well-being. Adverse events occurred in 11.7% of subjects, although no serious adverse events occurred. Chamomile extract produced a clinically meaningful reduction in GAD symptoms over 8 weeks, with a response rate comparable to those observed during conventional anxiolytic drug therapy and a favorable adverse event profile. Future comparative effectiveness trials between chamomile and conventional drugs may help determine the optimal risk/benefit of these therapies for patients suffering from GAD. Copyright © 2016 Elsevier GmbH. All rights reserved.

Proteomic analysis on the alteration of protein expression in the early-stage placental villous tissue of electromagnetic fields associated with cell phone exposure.

PubMed

Luo, Qiong; Jiang, Ying; Jin, Min; Xu, Jian; Huang, He-Feng

2013-09-01

To explore the possible adverse effects and search for cell phone electromagnetic field (EMF)-responsive proteins in human early reproduction, a proteomics approach was employed to investigate the changes in protein expression profile induced by cell phone EMF in human chorionic tissues of early pregnancy in vivo. Volunteer women about 50 days pregnant were exposed to EMF at the average absorption rate of 1.6 to 8.8 W/kg for 1 hour with the irradiation device placed 10 cm away from the umbilicus at the midline of the abdomen. The changes in protein profile were examined using 2-dimensional electrophoresis (2-DE). Up to 15 spots have yielded significant change at least 2- to 2.5-folds up or down compared to sham-exposed group. Twelve proteins were identified- procollagen-proline, eukaryotic translation elongation factor 1 delta, chain D crystal structure of human vitamin D-binding protein, thioredoxin-like 3, capping protein, isocitrate dehydrogenase 3 alpha, calumenin, Catechol-O-methyltransferase protein, proteinase inhibitor 6 (PI-6; SerpinB6) protein, 3,2-trans-enoyl-CoA isomerase protein, chain B human erythrocyte 2,3-bisphosphoglycerate mutase, and nucleoprotein. Cell phone EMF might alter the protein profile of chorionic tissue of early pregnancy, during the most sensitive stage of the embryos. The exposure to EMF may cause adverse effects on cell proliferation and development of nervous system in early embryos. Furthermore, 2-DE coupled with mass spectrometry is a promising approach to elucidate the effects and search for new biomarkers for environmental toxic effects.

Influenza vaccines: Evaluation of the safety profile

PubMed Central

Trombetta, Claudia Maria; Gianchecchi, Elena; Montomoli, Emanuele

2018-01-01

ABSTRACT The safety of vaccines is a critical factor in maintaining public trust in national vaccination programs. Vaccines are recommended for children, adults and elderly subjects and have to meet higher safety standards, since they are administered to healthy subjects, mainly healthy children. Although vaccines are strictly monitored before authorization, the possibility of adverse events and/or rare adverse events cannot be totally eliminated. Two main types of influenza vaccines are currently available: parenteral inactivated influenza vaccines and intranasal live attenuated vaccines. Both display a good safety profile in adults and children. However, they can cause adverse events and/or rare adverse events, some of which are more prevalent in children, while others with a higher prevalence in adults. The aim of this review is to provide an overview of influenza vaccine safety according to target groups, vaccine types and production methods. PMID:29297746

Potential adverse effects of oseltamivir in rats: males are more vulnerable than females.

PubMed

El-Sayed, Wael M; Al-Kahtani, Mohamed Ali

2011-09-01

Oseltamivir is the most widely used antiviral drug for the treatment and prophylaxis of influenza. However, not much is known about its adverse effects. The potential side effects were investigated in male and female rats (140-170 g). Oseltamivir was administered at 2.2 mg·kg(-1)·day(-1) for 5 days. For both genders, treatment with oseltamivir resulted in significant reductions in the hepatic activities of glutathione reductase, glutathione peroxidase, and glutathione S-transferase. Also for both genders, oseltamivir produced modest reductions in the hepatic activities of UDP-glucuronosyltransferase, quinone oxidoreductase, thioredoxin reductase, CYP1A1/2, and CYP3A, as well as hepatic glutathione content. For both genders, neither the kidney functions nor protein profile was affected by oseltamivir. Oseltamivir also caused significant elevation in serum levels of both triacylglycerols and LDL-cholesterol and in the activity of γ-glutamyl transpeptidase, in both genders. For male animals only, oseltamivir treatment elevated the serum level of total cholesterol as well as the activity of serum alanine aminotransferase, and reduced the hepatic activities of superoxide dismutase and catalase. Oseltamivir caused oxidative stress and acute toxicity in the liver, and disrupted the cholesterol and lipid metabolism but was less likely to cause serious drug interactions. There was a sexual differentiation in these adverse effects, with adverse effects being more evident in male rats.

Psychosocial risk factors for coronary heart disease in UK South Asian men and women.

PubMed

Williams, E D; Steptoe, A; Chambers, J C; Kooner, J S

2009-12-01

South Asian people in the UK and other western countries have elevated rates of coronary heart disease (CHD). Psychosocial factors contribute to CHD risk, but information about psychosocial risk profiles in UK South Asians is limited. This study aimed to examine the profile of conventional and novel psychosocial risk factors in South Asian compared with white men and women. Using a cross-sectional population study design, psychosocial profiles were assessed in 1130 South Asian and 818 white European healthy men and women aged between 35 and 75 years, who had previously participated in a cardiovascular risk assessment programme in West London. Psychosocial factors potentially contributing to CHD risk were assessed using standardised questionnaires. UK South Asians reported significantly higher psychosocial adversity compared with UK whites. South Asian men and women experienced greater chronic stress, in the form of financial strain, residential crowding, family conflict, social deprivation and discrimination, than white Europeans. They had larger social networks, but reported lower social support and greater depression and hostility. These effects were largely independent of socioeconomic status. UK South Asians experience significant psychosocial adversity compared with UK white Europeans. This is consistent with the heightened vulnerability to CHD observed in this population.

Nasal mucosa and blood cell transcriptome profiles do not reflect respiratory symptoms associated with moisture-damage.

PubMed

Ndika, Joseph; Suojalehto, Hille; Täubel, Martin; Lehto, Maili; Karvala, Kirsi; Pallasaho, Paula; Sund, Jukka; Auvinen, Petri; Järvi, Kati; Pekkanen, Juha; Kinaret, Pia; Greco, Dario; Hyvärinen, Anne; Alenius, Harri

2018-05-04

Upper and lower respiratory symptoms and asthma are adverse health effects associated with moisture-damaged buildings. Quantitative measures to detect adverse health effects related to exposure to dampness and mold are needed. Here, we investigate differences in gene expression between occupants of moisture-damaged and reference buildings. Moisture-damaged (N=11) and control (N=5) buildings were evaluated for dampness and mold by trained inspectors. The transcriptomics cohort consisted of nasal brushings and peripheral blood mononuclear cells (PBMCs) from 86 teachers, with/without self-perceived respiratory symptoms. Subject categories comprised reference (R) and damaged (D) buildings with (S) or without (NS) symptoms; i.e. R-S, R-NS, DS and D-NS. Component analyses and k-means clustering of transcriptome profiles did not distinguish building status (R/D) or presence of respiratory symptoms (S/NS). Only one nasal mucosa gene (YBX3P1) exhibited a significant change in expression between D-S and D-NS. Nine other nasal mucosa genes were differentially expressed between R-S and D-S teachers. No differentially expressed genes were identified in PBMCs. We conclude that the observed mRNA differences provide very weak biological evidence for adverse health effects associated with subject occupancy of the specified moisture-damaged buildings. This emphasizes the need to evaluate all potential factors (including those not related to toxicity) influencing perceived/self-reported ill-health in moisture-damaged buildings. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Unsteady boundary-layer injection

NASA Technical Reports Server (NTRS)

Telionis, D. P.; Jones, G. S.

1981-01-01

The boundary-layer equations for two-dimensional incompressible flow are integrated numerically for the flow over a flat plate and a Howarth body. Injection is introduced either impulsively or periodically along a narrow strip. Results indicate that injection perpendicular to the wall is transmitted instantly across the boundary layer and has little effect on the velocity profile parallel to the wall. The effect is a little more noticeable for flows with adverse pressure gradients. Injection parallel to the wall results in fuller velocity profiles. Parallel and oscillatory injection appears to influence the mean. The amplitude of oscillation decreases with distance from the injection strip but further downstream it increases again in a manner reminiscent of an unstable process.

Nurse-Led Medicines' Monitoring for Patients with Dementia in Care Homes: A Pragmatic Cohort Stepped Wedge Cluster Randomised Trial.

PubMed

Jordan, Susan; Gabe-Walters, Marie Ellenor; Watkins, Alan; Humphreys, Ioan; Newson, Louise; Snelgrove, Sherrill; Dennis, Michael S

2015-01-01

People with dementia are susceptible to adverse drug reactions (ADRs). However, they are not always closely monitored for potential problems relating to their medicines: structured nurse-led ADR Profiles have the potential to address this care gap. We aimed to assess the number and nature of clinical problems identified and addressed and changes in prescribing following introduction of nurse-led medicines' monitoring. Pragmatic cohort stepped-wedge cluster Randomised Controlled Trial (RCT) of structured nurse-led medicines' monitoring versus usual care. Five UK private sector care homes. 41 service users, taking at least one antipsychotic, antidepressant or anti-epileptic medicine. Nurses completed the West Wales ADR (WWADR) Profile for Mental Health Medicines with each participant according to trial step. Problems addressed and changes in medicines prescribed. Information was collected from participants' notes before randomisation and after each of five monthly trial steps. The impact of the Profile on problems found, actions taken and reduction in mental health medicines was explored in multivariate analyses, accounting for data collection step and site. Five of 10 sites and 43 of 49 service users approached participated. Profile administration increased the number of problems addressed from a mean of 6.02 [SD 2.92] to 9.86 [4.48], effect size 3.84, 95% CI 2.57-4.11, P <0.001. For example, pain was more likely to be treated (adjusted Odds Ratio [aOR] 3.84, 1.78-8.30), and more patients attended dentists and opticians (aOR 52.76 [11.80-235.90] and 5.12 [1.45-18.03] respectively). Profile use was associated with reduction in mental health medicines (aOR 4.45, 1.15-17.22). The WWADR Profile for Mental Health Medicines can improve the quality and safety of care, and warrants further investigation as a strategy to mitigate the known adverse effects of prescribed medicines. ISRCTN 48133332.

Refractory obstetrical antiphospholipid syndrome: Features, treatment and outcome in a European multicenter retrospective study.

PubMed

Mekinian, Arsène; Alijotas-Reig, Jaume; Carrat, Fabrice; Costedoat-Chalumeau, Nathalie; Ruffatti, Amelia; Lazzaroni, Maria Grazia; Tabacco, Sara; Maina, Aldo; Masseau, Agathe; Morel, Nathalie; Esteve-Valverde, Enrique Esteve; Ferrer-Oliveras, Raquel; Andreoli, Laura; De Carolis, Sara; Josselin-Mahr, Laurence; Abisror, Noémie; Nicaise-Roland, Pascale; Tincani, Angela; Fain, Olivier

2017-07-01

To describe the consecutive pregnancy outcome and treatment in refractory obstetrical antiphospholipid syndrome (APS). Retrospective multicenter open-labelled study from December 2015 to June 2016. We analyzed the outcome of pregnancies in patients with obstetrical APS (Sydney criteria) and previous adverse obstetrical event despite low-dose aspirin and low-molecular weight heparin LMWH (LMWH) conventional treatment who experienced at least one subsequent pregnancy. Forty nine patients with median age 27years (23-32) were included from 8 European centers. Obstetrical APS was present in 71%, while 26% had obstetrical and thrombotic APS. Lupus anticoagulant was present in 76% and triple antiphospholipid antibody (APL) positivity in 45% of patients. Pregnancy loss was noted in 71% with a median age of gestation of 11 (8-21) weeks. The presence of APS non-criteria features (35% vs 17% in pregnancies without adverse obstetrical event; p=0.09), previous intrauterine death (65% vs 38%; p=0.06), of LA (90% vs 65%; p=0.05) were more frequent in pregnancies with adverse pregnancy outcome, whereas isolated recurrent miscarriage profile was more frequent in pregnancies without any adverse pregnancy outcome (15% vs 41%; p=0.04). In univariate analysis considering all pregnancies (index and subsequent ones), an history of previous intrauterine death was associated with pregnancy loss (odds-ratio 2.51 (95% CI 1.274.96); p=0.008), whereas previous history of prematurity related to APS (odds-ratio 0.13 95%CI 0.04 0.41, P=0.006), steroids use during the pregnancy (odds-ratio 0.30 95% CI 0.11-0.82, p=0.019) and anticardiolipids isolated profile (odds-ratio 0.51 95% CI 0.26-1.03, p=0.0588) were associated with favorable outcome. In multivariate analysis, only previous history of prematurity, steroids use and anticardiolipids isolated profiles were associated with live-birth pregnancy. The main features of refractory obstetrical APS were the high rates of LA and triple APL positivity. Steroids could be effective in this APS profile, but prospective studies are necessary. Copyright © 2017 Elsevier B.V. All rights reserved.

Pharmacovigilance of herbal medicines: the potential contributions of ethnobotanical and ethnopharmacological studies.

PubMed

Rodrigues, Eliana; Barnes, Joanne

2013-01-01

Typically, ethnobotanical/ethnopharmacological (EB/EP) surveys are used to describe uses, doses/dosages, sources and methods of preparation of traditional herbal medicines; their application to date in examining the adverse effects, contraindications and other safety aspects of these preparations is limited. From a pharmacovigilance perspective, numerous challenges exist in applying its existing methods to studying the safety profile of herbal medicines, particularly where used by indigenous cultures. This paper aims to contribute to the methodological aspects of EB/EP field work, and to extend the reach of pharmacovigilance, by proposing a tool comprising a list of questions that could be applied during interview and observational studies. The questions focus on the collection of information on the safety profile of traditional herbal medicines as it is embedded in traditional knowledge, as well as on identifying personal experiences (spontaneous reports) of adverse or undesirable effects associated with the use of traditional herbal medicines. Questions on the precise composition of traditional prescriptions or 'recipes', their preparation, storage, administration and dosing are also included. Strengths and limitations of the tool are discussed. From this interweaving of EB/EP and pharmacovigilance arises a concept of ethnopharmacovigilance for traditional herbal medicines: the scope of EB/EP is extended to include exploration of the potential harmful effects of medicinal plants, and the incorporation of pharmacovigilance questions into EB/EP studies provides a new opportunity for collection of 'general' traditional knowledge on the safety of traditional herbal medicines and, importantly, a conduit for collection of spontaneous reports of suspected adverse effects. Whether the proposed tool can yield data sufficiently rich and of an appropriate quality for application of EB/EP (e.g. data verification and quantitative analysis tools) and pharmacovigilance techniques (e.g. causality assessment and data mining) requires field testing.

Polyphenols content, phenolics profile and antioxidant activity of organic red wines produced without sulfur dioxide/sulfites addition in comparison to conventional red wines.

PubMed

Garaguso, Ivana; Nardini, Mirella

2015-07-15

Wine exerts beneficial effects on human health when it is drunk with moderation. Nevertheless, wine may also contain components negatively affecting human health. Among these, sulfites may induce adverse effects after ingestion. We examined total polyphenols and flavonoids content, phenolics profile and antioxidant activity of eight organic red wines produced without sulfur dioxide/sulfites addition in comparison to those of eight conventional red wines. Polyphenols and flavonoids content were slightly higher in organic wines in respect to conventional wines, however differences did not reach statistical significance. The phenolic acids profile was quite similar in both groups of wines. Antioxidant activity was higher in organic wines compared to conventional wines, although differences were not statistically significant. Our results indicate that organic red wines produced without sulfur dioxide/sulfites addition are comparable to conventional red wines with regard to the total polyphenols and flavonoids content, the phenolics profile and the antioxidant activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Modeling U-shaped dose-response curves for manganese using categorical regression.

PubMed

Milton, Brittany; Krewski, Daniel; Mattison, Donald R; Karyakina, Nataliya A; Ramoju, Siva; Shilnikova, Natalia; Birkett, Nicholas; Farrell, Patrick J; McGough, Doreen

2017-01-01

Manganese is an essential nutrient which can cause adverse effects if ingested to excess or in insufficient amounts, leading to a U-shaped exposure-response relationship. Methods have recently been developed to describe such relationships by simultaneously modeling the exposure-response curves for excess and deficiency. These methods incorporate information from studies with diverse adverse health outcomes within the same analysis by assigning severity scores to achieve a common response metric for exposure-response modeling. We aimed to provide an estimate of the optimal dietary intake of manganese to balance adverse effects from deficient or excess intake. We undertook a systematic review of the literature from 1930 to 2013 and extracted information on adverse effects from manganese deficiency and excess to create a database on manganese toxicity following oral exposure. Although data were available for seven different species, only the data from rats was sufficiently comprehensive to support analytical modelling. The toxicological outcomes were standardized on an 18-point severity scale, allowing for a common analysis of all available toxicological data. Logistic regression modelling was used to simultaneously estimate the exposure-response profile for dietary deficiency and excess for manganese and generate a U-shaped exposure-response curve for all outcomes. Data were available on the adverse effects of 6113 rats. The nadir of the U-shaped joint response curve occurred at a manganese intake of 2.70mg/kgbw/day with a 95% confidence interval of 2.51-3.02. The extremes of both deficient and excess intake were associated with a 90% probability of some measurable adverse event. The manganese database supports estimation of optimal intake based on combining information on adverse effects from systematic review of published experiments. There is a need for more studies on humans. Translation of our results from rats to humans will require adjustment for interspecies differences in sensitivity to manganese. Copyright © 2016 Elsevier B.V. All rights reserved.

Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting.

PubMed

Grindlay, Joanne; Babl, Franz E

2009-02-01

This article reviews the evidence for the analgesic efficacy of methoxyflurane in both prehospital and ED settings, as well as the adverse event profile associated with methoxyflurane use. Although there are no published controlled trials of methoxyflurane in sub-anaesthetic doses, available data indicate that it is an efficacious analgesic. There is inadequate evidence regarding its use as an agent for procedural pain. Despite the potential for renal impairment evident when it was used in anaesthetic doses, no significant adverse effects have been reported in the literature, neither in patients nor occupationally, when the dose used is limited to that currently recommended.

[ANTHROPOMETRIC INDICATORS AND CARDIOMETABOLIC EVENTS AMONG SCHOOL-AGED CHILDREN FROM SONORA, MEXICO].

PubMed

Peralta Peña, Sandra Lidia; Reséndiz González, Eunice; Rubí Vargas, María; Terrazas Medina, Efraín Alonso; Cupul Uicab, Lea Aurora

2015-10-01

obesity in childhood is predictive of obesity in adulthood and it is associated with adverse health effect apparent since childhood; however, the joint assessment of obesity and adverse events among children in clinical settings is unusual. to assess the association of overweight and obesity, abdominal obesity, and excess body fat with systolic [SBP] and diastolic [DBP] blood pressure, lipid profile and glucose levels; and to identify the best anthropometric indicator of such events. we conducted a cross-sectional study in a sample of 412 schoolchildren. The presence of overweight and obesity, abdominal obesity and excess body fat was determined among all participants; levels of total cholesterol, triglycerides, high and low density lipoproteins, and glucose were measured in a subsample (n = 133). The associations of interest were assessed using adjusted linear and logistic regression models. 33% of the children were overweight or obese. Overall, overweight, obesity, abdominal obesity, and excess body fat were associated with elevated SBP and DBP and with a lipid profile and glucose levels that could indicate health risks among these children. Overweight and obesity were the best predictors of such events. among these school-aged children, we observed that obesity was associated with high odds of having adverse health outcomes such as high blood pressure, lipids and glucose. Such adverse events can be predicted by the presence of obesity measured by BMI, which is a noninvasive, inexpensive and easy to implement measure. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Association of cardiometabolic risk profile with prehypertension accompany hyperhomocysteinaemia.

PubMed

Chen, Huili; Sun, Yuemin; Wang, Xuechun; Si, Quan; Yao, Wei; Wan, Zheng

2015-01-01

Study suggested that elevated homocysteine showed a multiplicative effect on cardiovascular diseases in hypertensive subjects. It was reported that elevated homocysteine level was independently associated with increased arterial stiffness in prehypertensives. It remains unclear whether prehypertensives combined with elevated homocysteine have adverse cardiovascular risk factors. We aimed to compare cardiometabolic risk profile between prehypertensives with hyperhomocysteinaemia and those without either condition. Plasma total homocysteine and risk profile were determined among 874 Chinese non-hypertension individuals in Tianjin. They were subdivided into four groups: prehypertension with hyperhomocysteinaemia (≥10 μmol/L), prehypertension with normal homocysteine (<10 μmol/L), normotension with hyperhomocysteinaemia, normotension with normol homocysteine, respectively. In 874 participants, 22.5% of them were male, mean age was 56.8 years. In multiple comparisons, after adjustment for age, gender, smoking, alcohol, exercise, education prehypertensives had higher body mass index (BMI) and high sensitive C reactive protein (hs-CRP) than normotensives (p < 0.05, respectively); Only prehypertensive subjects with hyperhomocysteinaemia had higher triglyceride and serum uric acid compared to normotensive subjects, and lower HDL cholesterol than normotensives with normal homocysteine (p < 0.05, respectively). However, the significance of higher hs-CRP, uric acid and lower HDL cholesterol were abolished when further adjustment was made for BMI. The combination of prehypertension and hyperhomocusteinaemia increases the likelihood of having adverse cardiometabolic risk profile. Strict lipid management and weigh control may be needed in prehypertensives with elevated homocysteine.

Adverse effects of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine in 6- to 7-year-old children.

PubMed

Wei, Sung-Hsi; Chao, Yen-Nan; Huang, Song-En; Lee, Tsuey-Feng; Chang, Luan-Yin

2011-02-01

Although the safety profile of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines in adolescents and adults has been documented, few data have reported about their adverse events in children. Healthy 6- to 7-year-old children who were immunized with Tdap vaccine were evaluated for adverse events on Days 1, 2, 4, and 7 postimmunization. Information of sex, body mass index (BMI), and previous diphtheria-pertussis-tetanus (DPT) immunization history was obtained and evaluated for the association with the adverse events. A total of 243 6- to 7-year-old children were immunized with Tdap. Among the 243 children immunized, remarkable adverse events included redness more than or equal to 10 mm in 47 (19%) children, induration more than or equal to 10 mm in 57 (23%), tenderness in 130 (53%), and fever in 12 (5%). Redness and induration resolved in 7 days and fever resolved on Day 4. The adverse events were not associated with gender, BMI above the mean value, or the type of fourth DPT immunization. Adverse events after Tdap vaccination were mild and dissolved within 7 days in 6- to 7-year-old children. Copyright © 2011. Published by Elsevier B.V.

The turbulent boundary layer on a porous plate: An experimental study of the fluid mechanics for adverse free stream pressure gradients

NASA Technical Reports Server (NTRS)

Anderson, P. S.; Kays, W. M.; Moffat, R. J.

1972-01-01

An experimental investigation of transpired turbulent boundary layers in zero and adverse pressure gradients has been carried out. Profiles of: (1) the mean velocity, (2) the three intensities of the turbulent fluctuations, and (3) the Reynolds stress were obtained by hot-wire anemometry. The friction coefficients were measured by using an integrated form of the boundary layer equation to extrapolate the measured shear stress profiles to the wall.

Psychopathology, childhood trauma, and personality traits in patients with borderline personality disorder and their sisters.

PubMed

Laporte, Lise; Paris, Joel; Guttman, Herta; Russell, Jennifer

2011-08-01

The aim of this study was to document and compare adverse childhood experiences, and personality profiles in women with borderline personality disorder (BPD) and their sisters, and to determine how these factors impact current psychopathology. Fifty-six patients with BPD and their sisters were compared on measures assessing psychopathology, personality traits, and childhood adversities. Most sisters showed little evidence of psychopathology. Both groups reported dysfunctional parent-child relationships and a high prevalence of childhood trauma. Subjects with BPD reported experiencing more emotional abuse and intrafamilial sexual abuse, but more similarities than differences between probands and sisters were found. In multilevel analyses, personality traits of affective instability and impulsivity predicted DIB-R scores and SCL-90-R scores, above and beyond trauma. There were few relationships between childhood adversities and other measures of psychopathology. Sensitivity to adverse experiences, as reflected in the development of psychopathology, appears to be influenced by personality trait profiles.

The turbulent boundary layer on a porous plate: An experimental study of the heat transfer behavior with adverse pressure gradients

NASA Technical Reports Server (NTRS)

Blackwell, B. F.; Kays, W. M.; Moffat, R. J.

1972-01-01

An experimental investigation of the heat transfer behavior of the near equilibrium transpired turbulent boundary layer with adverse pressure gradient has been carried out. Stanton numbers were measured by an energy balance on electrically heated plates that form the bottom wall of the wind tunnel. Two adverse pressure gradients were studied. Two types of transpiration boundary conditions were investigated. The concept of an equilibrium thermal boundary layer was introduced. It was found that Stanton number as a function of enthalpy thickness Reynolds number is essentially unaffected by adverse pressure gradient with no transpiration. Shear stress, heat flux, and turbulent Prandtl number profiles were computed from mean temperature and velocity profiles. It was concluded that the turbulent Prandtl number is greater than unity in near the wall and decreases continuously to approximately 0.5 at the free stream.

Ibrutinib in CLL: a focus on adverse events, resistance, and novel approaches beyond ibrutinib.

PubMed

Kaur, Varinder; Swami, Arjun

2017-07-01

Bruton's tyrosine kinase (BTK), a mediator in B cell receptor signaling has been successfully exploited as a therapeutic target in treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a BTK inhibitor that has shown excellent efficacy in treatment-naïve, heavily pre-treated, and high-risk CLL/SLL. With remarkable efficacy, good oral bioavailability, and modest adverse events profile, ibrutinib use is likely to continue to increase. As data with ibrutinib use in CLL matures, concerns regarding adverse events and drug resistance have emerged. New insights into mechanisms of ibrutinib resistance in CLL have uncovered potential therapeutic targets. Several promising novel agents are currently in early phases of development for overcoming ibrutinib resistance in CLL/SLL. We provide a comprehensive analysis of emerging adverse events profile of ibrutinib, summarize our current understanding of ibrutinib resistance in CLL, and review promising novel therapeutic tools to overcome this challenge.

A randomized, controlled trial comparing acetaminophen plus ibuprofen versus acetaminophen plus codeine plus caffeine (Tylenol 3) after outpatient breast surgery.

PubMed

Mitchell, Alex; McCrea, Patrick; Inglis, Karen; Porter, Geoffrey

2012-11-01

The combination of acetaminophen, codeine, and caffeine (Tylenol 3, T3) is a standard postoperative analgesia after breast surgery despite the adverse effects and variable efficacy of narcotics. This study compared the efficacy of a nonnarcotic approach (acetaminophen and ibuprofen; AcIBU) to T3 after outpatient breast surgery. This double-blind randomized equivalence trial involved patients undergoing outpatient breast surgery. Patients were randomized (stratified by procedure type) to receive AcIBU or T3 four times daily for 7 days, or until free of pain. Pain intensity, measured four times daily by the visual analog scale, was the primary outcome; secondary outcomes were pain relief with analgesic, days until freedom from pain, adverse effects, discontinuation of drug as a result of adverse effects, and patient satisfaction. There were 71 patients randomized to AcIBU and 70 patients to T3. Repeated measures analysis showed no significant difference in average pain intensity over 7 days (AcIBU 19.9 mm vs. T3 20.6 mm; P = 0.78). Similarly, there was no significant difference in pain relief with analgesic (P = 0.46). Although no difference in the incidence of adverse effects was observed (P = 0.94), discontinuation of the study drug as a result of adverse effects was more common with T3 (19 % vs. 6 %; P = 0.018). No significant differences were identified in days until freedom from pain or patient satisfaction; 92 % of AcIBU and 89 % of T3 patients were satisfied with their pain control (P = 0.55). AcIBU is a safe, effective method of pain control after outpatient breast surgery. Compared to T3, it provides at least equivalent analgesia and has a more tolerable adverse effect profile.

Exploration of the Anti-Inflammatory Drug Space Through Network Pharmacology: Applications for Drug Repurposing

PubMed Central

de Anda-Jáuregui, Guillermo; Guo, Kai; McGregor, Brett A.; Hur, Junguk

2018-01-01

The quintessential biological response to disease is inflammation. It is a driver and an important element in a wide range of pathological states. Pharmacological management of inflammation is therefore central in the clinical setting. Anti-inflammatory drugs modulate specific molecules involved in the inflammatory response; these drugs are traditionally classified as steroidal and non-steroidal drugs. However, the effects of these drugs are rarely limited to their canonical targets, affecting other molecules and altering biological functions with system-wide effects that can lead to the emergence of secondary therapeutic applications or adverse drug reactions (ADRs). In this study, relationships among anti-inflammatory drugs, functional pathways, and ADRs were explored through network models. We integrated structural drug information, experimental anti-inflammatory drug perturbation gene expression profiles obtained from the Connectivity Map and Library of Integrated Network-Based Cellular Signatures, functional pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases, as well as adverse reaction information from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The network models comprise nodes representing anti-inflammatory drugs, functional pathways, and adverse effects. We identified structural and gene perturbation similarities linking anti-inflammatory drugs. Functional pathways were connected to drugs by implementing Gene Set Enrichment Analysis (GSEA). Drugs and adverse effects were connected based on the proportional reporting ratio (PRR) of an adverse effect in response to a given drug. Through these network models, relationships among anti-inflammatory drugs, their functional effects at the pathway level, and their adverse effects were explored. These networks comprise 70 different anti-inflammatory drugs, 462 functional pathways, and 1,175 ADRs. Network-based properties, such as degree, clustering coefficient, and node strength, were used to identify new therapeutic applications within and beyond the anti-inflammatory context, as well as ADR risk for these drugs, helping to select better repurposing candidates. Based on these parameters, we identified naproxen, meloxicam, etodolac, tenoxicam, flufenamic acid, fenoprofen, and nabumetone as candidates for drug repurposing with lower ADR risk. This network-based analysis pipeline provides a novel way to explore the effects of drugs in a therapeutic space. PMID:29545755

Exploration of the Anti-Inflammatory Drug Space Through Network Pharmacology: Applications for Drug Repurposing.

PubMed

de Anda-Jáuregui, Guillermo; Guo, Kai; McGregor, Brett A; Hur, Junguk

2018-01-01

The quintessential biological response to disease is inflammation. It is a driver and an important element in a wide range of pathological states. Pharmacological management of inflammation is therefore central in the clinical setting. Anti-inflammatory drugs modulate specific molecules involved in the inflammatory response; these drugs are traditionally classified as steroidal and non-steroidal drugs. However, the effects of these drugs are rarely limited to their canonical targets, affecting other molecules and altering biological functions with system-wide effects that can lead to the emergence of secondary therapeutic applications or adverse drug reactions (ADRs). In this study, relationships among anti-inflammatory drugs, functional pathways, and ADRs were explored through network models. We integrated structural drug information, experimental anti-inflammatory drug perturbation gene expression profiles obtained from the Connectivity Map and Library of Integrated Network-Based Cellular Signatures, functional pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases, as well as adverse reaction information from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The network models comprise nodes representing anti-inflammatory drugs, functional pathways, and adverse effects. We identified structural and gene perturbation similarities linking anti-inflammatory drugs. Functional pathways were connected to drugs by implementing Gene Set Enrichment Analysis (GSEA). Drugs and adverse effects were connected based on the proportional reporting ratio (PRR) of an adverse effect in response to a given drug. Through these network models, relationships among anti-inflammatory drugs, their functional effects at the pathway level, and their adverse effects were explored. These networks comprise 70 different anti-inflammatory drugs, 462 functional pathways, and 1,175 ADRs. Network-based properties, such as degree, clustering coefficient, and node strength, were used to identify new therapeutic applications within and beyond the anti-inflammatory context, as well as ADR risk for these drugs, helping to select better repurposing candidates. Based on these parameters, we identified naproxen, meloxicam, etodolac, tenoxicam, flufenamic acid, fenoprofen, and nabumetone as candidates for drug repurposing with lower ADR risk. This network-based analysis pipeline provides a novel way to explore the effects of drugs in a therapeutic space.

Noise Whitening in Airborne Wind Profiling With a Pulsed 2-Micron Coherent Doppler Lidar at NASA Langley Research Center

NASA Technical Reports Server (NTRS)

Beyon, Jeffrey Y.; Arthur, Grant E.; Koch, Grady J.; Kavaya, Michael J.

2012-01-01

Two different noise whitening methods in airborne wind profiling with a pulsed 2-micron coherent Doppler lidar system at NASA Langley Research Center in Virginia are presented. In order to provide accurate wind parameter estimates from the airborne lidar data acquired during the NASA Genesis and Rapid Intensification Processes (GRIP) campaign in 2010, the adverse effects of background instrument noise must be compensated properly in the early stage of data processing. The results of the two methods are presented using selected GRIP data and compared with the dropsonde data for verification purposes.

Peroxide as a Novel Treatment for Ecchymoses

PubMed Central

Sroa, Novie; Campbell, Shannon M.; Bechtel, Mark A.; Mitch Opremcak, E.

2010-01-01

Ecchymoses, commonly known as bruises, frequently occur after injury to the skin causes extravasation of red blood cells into interstitial tissue. This extravasation can lead to an inflammatory cascade. The case report presented details one patient who displayed rapid improvement in the pain and appearance of a partially treated bruise on her thigh after an eight-hour application of hydrogen peroxide 15% carbamide gel under occlusion. Hydrogen peroxide 15% carbamide gel may represent a novel treatment for ecchymoses. This potential new treatment for bruises needs to be studied further to detail its adverse effects, safety profile, and efficacy profile. PMID:21103315

Effect of Ibuprofen Dose on Platelet Aggregation and Coagulation in Blood Samples From Pigs

DTIC Science & Technology

2015-03-01

is not known and would be more of an issue with chronic misuse of the drug. Aspirin is another widely used NSAID. Despite similar anti-inflammatory...analgesic, and antipyretic effects, different profiles of actions have been observed in Aspirin and ibupro- fen. At equivalent effective doses of...ibuprofen (2,400 mg/day, equivalent to 3 + in this study) and aspirin (3,900 mg/day), liver function and platelet aggregation are more adversely affected by

Subjective reactions to cocaine and marijuana are associated with abuse and dependence.

PubMed

Grant, Julia D; Scherrer, Jeffrey F; Lyons, Michael J; Tsuang, Ming; True, William R; Bucholz, Kathleen K

2005-09-01

Subjective effects of marijuana and cocaine use are associated with amount of drug use and potentially with risk of abuse and dependence. We used Latent Class Analyses (LCA) to examine subjective responses to two categories of drugs and link these to abuse and dependence. In 1992, subjective responses were queried of 2506 marijuana and 661 cocaine lifetime users who were members of the Vietnam Era Twin Registry. LCA was used to identify classes of subjective effects. Multinomial logistic regression models were computed to test for an association between classes and marijuana and cocaine abuse or dependence. The best LCA solution for marijuana identified 6 distinct classes characterized as positive, relaxed, reactive, adverse, low and very reactive. The best LCA solution for cocaine identified 5 distinct classes characterized as positive, alert, adverse, low and very reactive. Marijuana abuse and dependence were significantly associated with each latent class. Cocaine abuse was associated with the reactive class (OR=3.9; 95% CI: 1.6-9.5). Cocaine dependence was associated with reactive (OR=15.3; 95% CI: 7.1-32.6), adverse (OR=9.7; 95% CI: 4.5-21.0) and very reactive (OR=18.7; 95% CI: 5.6-62.6) classes. We found evidence for both qualitative and quantitative subjective effect profiles. Subjective effects, both positive and adverse are associated with lifetime risk for marijuana and cocaine dependence.

Does Decreased Access to Emergency Departments Affect Patient Outcomes? Analysis of Acute Myocardial Infarction Population 1996–2005

PubMed Central

Shen, Yu-Chu; Hsia, Renee Y

2012-01-01

Objective We analyze whether decreased emergency department (ED) access results in adverse patient outcomes or changes in the patient health profile for patients with acute myocardial infarction (AMI). Data We merge Medicare claims, American Hospital Association annual surveys, Medicare hospital cost reports, and location information for 1995–2005. Study Design We define four ED access change categories and estimate a ZIP Code fixed-effects regression models on the following AMI outcomes: mortality rates, age, and probability of percutaneous transluminal coronary angioplasty (PTCA) on day of admission. Principal Findings We find a small increase in 30-day to 1-year mortality rates among patients in communities that experience a <10-minute increase in driving time. Among patients in communities with >30-minute increases, we find a substantial increase in long-term mortality rates, a shift to younger ages (suggesting that older patients die en route), and a higher probability of immediate PTCA. Most of the adverse effects disappear after the transition years. Conclusions Deterioration in geographic access to ED affects a small segment of the population, and most adverse effects are transitory. Policy planners can minimize the adverse effects by providing assistance to ensure adequate capacity of remaining EDs, and facilitating the realignment of health care resources during the critical transition periods. PMID:22091922

Safety profiles of old and new antimicrobials for the treatment of MRSA infections.

PubMed

Bassetti, Matteo; Righi, Elda

2016-01-01

Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of severe nosocomial and community-acquired infections. Various adverse effects have been associated with compounds that are commonly used in the treatment of MRSA. Prolonged use of high-dose vancomycin has been linked with nephrotoxicity. Linezolid use has been associated with lactic acidosis in regimens longer than 14 days and occurrence of thrombocytopenia in patients with renal impairment. Daptomycin use correlates with reversible and often asymptomatic myopathy. Among new compounds, telavancin has shown increased toxicity compared to vancomycin, especially in patients with severe renal impairment, while a low rate of adverse effects was reported others glycolipopeptides such as dalbavancin and oritavancin and for new cephalosporins. Recently studied oxazolidinones (tedizolid and radezolid) also showed mild adverse effects in Phase 2 and 3 clinical trials. Due to the constant increase in antimicrobial resistance, the use of higher doses and prolonged regimens of antibiotics employed in the treatment of Gram-positive infections has become more common and linked to increased toxicity. Furthermore, new compounds with MRSA activity have been recently approved and will be regularly employed in clinical practice. The knowledge of the adverse effects and risk factors for the development of toxicity associated with anti-MRSA antimicrobials is paramount for the correct use of old and new compounds, especially in the treatment of severe infections.

Earnings Profiles of Department Heads: Comparing Cross-Sectional and Panel Models.

ERIC Educational Resources Information Center

Ragan, James F., Jr.; Rehman, Qazi Najeeb

1996-01-01

A cross-sectional study of 842 faculty who served as department heads between 1965-92 was compared with 170 in a panel study for whom earnings were estimated using a personal effects model. The average chair received a 12% wage premium for administrative service. Skill depreciation was most severe and wage growth most adversely affected in the…

The lowest-dose, extended-cycle combined oral contraceptive pill with continuous ethinyl estradiol in the United States: a review of the literature on ethinyl estradiol 20 μg/levonorgestrel 100 μg + ethinyl estradiol 10 μg.

PubMed

Krishnan, Sheila; Kiley, Jessica

2010-08-10

Extended-cycle oral contraceptives (OCs) are increasing in popularity in the United States. A new extended-cycle OC that contains the lowest doses of ethinyl estradiol (EE) and levonorgestrel (LNG) + continuous EE throughout the cycle is now available. It provides 84 days of a low-dose, combined active pill containing levonorgestrel 100 μg and ethinyl estradiol 20 μg. Instead of 7 days of placebo following the active pills, the regimen delivers 7 days of ethinyl estradiol 10 μg. Existing studies reveal a similar efficacy and adverse effect profile compared with other extended-regimen OCs. Specifically, the unscheduled bleeding profile is similar to other extended-cycle OCs and improves with the increase in the duration of use. Although lower daily doses of hormonal exposure have potential benefit, to our knowledge, there are no published studies indicating that this specific regimen offers a lower incidence of hormone-related side effects or adverse events. In summary, this new extended-cycle OC provides patients a low-dose, extended-regimen OC option without sacrificing efficacy or tolerability.

Isobolographic characterization of the anticonvulsant interaction profiles of levetiracetam in combination with clonazepam, ethosuximide, phenobarbital and valproate in the mouse pentylenetetrazole-induced seizure model.

PubMed

Dudra-Jastrzebska, Monika; Andres-Mach, Marta M; Ratnaraj, Neville; Patsalos, Philip N; Czuczwar, Stanislaw J; Luszczki, Jarogniew J

2009-11-01

This study was designed so as to characterize the interactions between levetiracetam (LEV) and the conventional antiepileptic drugs (AEDs) clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced clonic seizures in mice by use of type II isobolographic analysis. Adverse-effect profiles of the drugs in combination were determined and brain AED concentrations were measured. The combinations of VPA and ETS with LEV at the fixed-ratio of 1:2, CZP with LEV (1:20,000), and PB with LEV (1:20) were supra-additive (synergistic) in suppressing seizures. In contrast, VPA and ETS with LEV (1:1, 2:1, and 4:1), CZP with LEV (1:1000, 1:5000, and 1:10,000), and PB with LEV (1:1, 1:5, and 1:10) were additive. No adverse effects were observed. ETS significantly reduced brain LEV concentrations but no other pharmacokinetic changes were observed. The combinations of CZP with LEV (1:20,000); VPA and ETS with LEV (1:2); and PB with LEV (1:20) appear to be favorable combinations exerting supra-additive interactions in suppressing PTZ-induced seizures.

Patient compliance with drug therapy in schizophrenia. Economic and clinical issues.

PubMed

Lindström, E; Bingefors, K

2000-08-01

The effectiveness of drug treatment in clinical practice is considerably lower than the efficacy shown in controlled studies. The lower effectiveness in practice presumably leads to lower cost effectiveness of drug treatment in real-life situations compared with that demonstrated by studies based on results from controlled trials. Improved cost effectiveness in routine clinical practice would be a significant advantage in the treatment of schizophrenia, one of the most costly diseases in society. The aetiology of schizophrenia is unknown, and there is no cure. The main aims of therapy with antipsychotic medication include the effective relief of symptoms without the introduction of adverse effects or serious adverse events, improved quality of life, cost effectiveness and a positive long term outcome. The older classical antipsychotic drugs do not always meet these requirements because of their well-known limitations, such as a lack of response in a subgroup of individuals with schizophrenia and intolerable adverse effects. There has long been a need for new antipsychotics that can ameliorate more symptoms and have no or few adverse effects. Some of the recently introduced antipsychotics have been shown to be more effective in certain clinical situations and to have a more favourable adverse effect profile than the classical antipsychotics. A major factor contributing to the lower effectiveness of drug treatment is noncompliance, which may be very high in schizophrenia. There are several factors influencing compliance, including drug type and formulation, patient, disease status, physician, health care system, community care and family. There have been very few studies of compliance improvement strategies in schizophrenia or, indeed, in medicine in general. Current methods are relatively complex and there are differing opinions on their effectiveness. There are several ways to increase compliance in schizophrenia--the evidence is strongest for psychoeducative methods, changing to a new drug or using a depot formulation. However, considerably more research is needed in the field of compliance strategies.

Udenafil for the treatment of erectile dysfunction

PubMed Central

Cho, Min Chul; Paick, Jae-Seung

2014-01-01

Erectile dysfunction (ED) is often perceived by both patients and sexual partners as a serious problem that can jeopardize quality of life, psychosocial or emotional well-being, and the partnership in the long term. Since their introduction, oral phosphodiesterase type 5 inhibitors (PDE5Is) have been found to be highly effective and well tolerated, and are available as the first-line therapy for the treatment of ED. Udenafil is one of the selective PDE5Is made available in recent years for the treatment of ED. Udenafil has clinical properties of both relatively rapid onset and long duration of action due to its pharmacokinetic profile, thereby providing an additional treatment option for ED men to better suit individual needs. There is positive evidence that udenafil is effective and well tolerated in the treatment of ED of a broad spectrum of etiologies or severity. Udenafil is as effective in the treatment of diabetes mellitus-associated ED as other PDE5Is. Due to the clinical property of relatively long duration of action, udenafil may be another option in daily dosing treatment for ED, as suggested by its favorable efficacy and safety profile. Most adverse effects reported from clinical trials are mild or moderate in severity, without any serious adverse event, with headache and flushing being the most common. Also, the concomitant use of anti-hypertensive drugs or alpha-1-blockers does not significantly affect the efficacy and safety profile of udenafil. However, additional studies with larger cohorts including prospective, multicenter, comparative studies with patients of different ethnicities are needed to further validate the favorable findings of udenafil in the treatment of ED. PMID:24868160

Pharmacotherapy of Essential Tremor

PubMed Central

Hedera, Peter; Cibulčík, František; Davis, Thomas L.

2013-01-01

Essential tremor (ET) is a common movement disorder but its pathogenesis remains poorly understood. This has limited the development of effective pharmacotherapy. The current therapeutic armamentaria for ET represent the product of careful clinical observation rather than targeted molecular modeling. Here we review their pharmacokinetics, metabolism, dosing, and adverse effect profiles and propose a treatment algorithm. We also discuss the concept of medically refractory tremor, as therapeutic trials should be limited unless invasive therapy is contraindicated or not desired by patients. PMID:24385718

Cobedding of twin premature infants: calming effects on pain responses.

PubMed

Badiee, Zohreh; Nassiri, Zohreh; Armanian, Amirmohammad

2014-08-01

The purpose of this trial was to determine whether cobedding of preterm twins has analgesic effects during heel lancing or not. One hundred premature twins (50 sets) born between 26 weeks' and 34 weeks' gestation undergoing heel blood sampling were randomly assigned into two groups: the cobedding group (receiving care in the same incubator) and the standard care group (receiving care in separate incubators). Pain was assessed using the premature infant pain profile score. Duration of crying was measured after heel blood sampling, and salivary cortisol was measured prior to and after heel blood sampling. Infants in the standard care group cried for a longer time during heel lancing than those in the cobedding group (42.6 ± 19.8 seconds vs. 36.4 ± 21.7 seconds, p = 0.03). The mean premature infant pain profile score after heel lancing was significantly higher in the standard care group (9.8 ± 2.6 vs. 8.06 ± 2.8, p = 0.002). The mean salivary cortisol after heel lancing was also significantly higher in the standard care group (24.3 ± 7.4 nmol/L vs. 20.8 ± 7.4 nmol/L, p = 0.02). No significant adverse effects were seen with cobedding. Cobedding is a comforting measure for twin premature infants during heel lancing, which can be performed without any significant adverse effects. Copyright © 2014. Published by Elsevier B.V.

Propofol for ECT anesthesia a review of the literature.

PubMed

Rasmussen, Keith G

2014-09-01

Propofol is a commonly used anesthetic drug for electroconvulsive therapy (ECT), as evidenced by the frequency with which its use is reported in ECT literature. Concerns have been raised over its propensity to be associated with shortened seizure duration vis-à-vis other anesthetic drugs, thus limiting its use in some settings. However, in the surgical anesthesia literature, propofol has shown distinct advantages such as improved hemodynamics and postanesthesia recovery. Given the capricious availability of standard barbiturate anesthetics in some countries, propofol use has probably increased. Thus, a review of its profile for a number of outcome measures in ECT is appropriate. Herein, the author reviews the extensive literature for propofol in ECT, focusing on 5 outcome measures: seizure duration, hemodynamics, postanesthesia recovery, cognitive adverse effects, and therapeutic efficacy. Results indicate that propofol is indeed robustly associated with shorter seizures than other anesthetics but that antidepressant efficacy does not seem to be compromised. Heart rate and blood pressure changes are not as high with propofol, and postanesthesia recovery may be quicker with propofol as well. Not enough data are available regarding cognitive adverse effects to make definitive conclusions, but so far, there does not seem to be a worsened cognitive profile when it is used in ECT. Propofol seems to be an acceptable anesthetic for ECT with advantages for some situations. Using the lowest effective anesthetic dosage minimizes its effect on seizure elicitation and duration.

Alcohol, metabolic risk and elevated serum gamma-glutamyl transferase (GGT) in Indigenous Australians.

PubMed

Haren, Matthew T; Li, Ming; Petkov, John; McDermott, Robyn A

2010-08-03

The interaction between overweight/obesity and alcohol intake on liver enzyme concentrations have been demonstrated. No studies have yet examined the interaction between metabolic syndrome or multiple metabolic risk factors and alcohol intake on liver enzymes. The aim of this study was to examine if alcohol consumption modifies the effect of metabolic risk on elevated serum GGT in Indigenous Australians. Data were from N = 2609 Indigenous Australians who participated in a health screening program in rural far north Queensland in 1999-2000 (44.5% response rate). The individual and interactive effects of metabolic risk and alcohol drinking on elevated serum GGT concentrations (>or=50 U/L) were analyzed using logistic regression. Overall, 26% of the population had GGT>or=50 U/L. Elevated GGT was associated with alcohol drinking (moderate drinking: OR 2.3 [95%CI 1.6 - 3.2]; risky drinking: OR 6.0 [4.4 - 8.2]), and with abdominal obesity (OR 3.7 [2.5 - 5.6]), adverse metabolic risk cluster profile (OR 3.4 [2.6 - 4.3]) and metabolic syndrome (OR 2.7 [2.1 - 3.5]) after adjustment for age, sex, ethnicity, smoking, physical activity and BMI. The associations of obesity and metabolic syndrome with elevated GGT were similar across alcohol drinking strata, but the association of an adverse metabolic risk cluster profile with elevated GGT was larger in risky drinkers (OR 4.9 [3.7 - 6.7]) than in moderate drinkers (OR 2.8 [1.6 - 4.9]) and abstainers (OR 1.6 [0.9 - 2.8]). In this Indigenous population, an adverse metabolic profile conferred three times the risk of elevated GGT in risky drinkers compared with abstainers, independent of sex and ethnicity. Community interventions need to target both determinants of the population's metabolic status and alcohol consumption to reduce the risk of elevated GGT.

Alcohol, metabolic risk and elevated serum gamma-glutamyl transferase (GGT) in Indigenous Australians

PubMed Central

2010-01-01

Background The interaction between overweight/obesity and alcohol intake on liver enzyme concentrations have been demonstrated. No studies have yet examined the interaction between metabolic syndrome or multiple metabolic risk factors and alcohol intake on liver enzymes. The aim of this study was to examine if alcohol consumption modifies the effect of metabolic risk on elevated serum GGT in Indigenous Australians. Methods Data were from N = 2609 Indigenous Australians who participated in a health screening program in rural far north Queensland in 1999-2000 (44.5% response rate). The individual and interactive effects of metabolic risk and alcohol drinking on elevated serum GGT concentrations (≥50 U/L) were analyzed using logistic regression. Results Overall, 26% of the population had GGT≥50 U/L. Elevated GGT was associated with alcohol drinking (moderate drinking: OR 2.3 [95%CI 1.6 - 3.2]; risky drinking: OR 6.0 [4.4 - 8.2]), and with abdominal obesity (OR 3.7 [2.5 - 5.6]), adverse metabolic risk cluster profile (OR 3.4 [2.6 - 4.3]) and metabolic syndrome (OR 2.7 [2.1 - 3.5]) after adjustment for age, sex, ethnicity, smoking, physical activity and BMI. The associations of obesity and metabolic syndrome with elevated GGT were similar across alcohol drinking strata, but the association of an adverse metabolic risk cluster profile with elevated GGT was larger in risky drinkers (OR 4.9 [3.7 - 6.7]) than in moderate drinkers (OR 2.8 [1.6 - 4.9]) and abstainers (OR 1.6 [0.9 - 2.8]). Conclusions In this Indigenous population, an adverse metabolic profile conferred three times the risk of elevated GGT in risky drinkers compared with abstainers, independent of sex and ethnicity. Community interventions need to target both determinants of the population's metabolic status and alcohol consumption to reduce the risk of elevated GGT. PMID:20682033

Energy drink exposures reported to Texas poison centers: Analysis of adverse incidents in relation to total sales, 2010-2014.

PubMed

Borron, Stephen W; Watts, Susan H; Herrera, Jessica; Larson, Joshua; Baeza, Salvador; Kingston, Richard L

2018-05-21

The ill-defined term "energy drink" includes a disparate group of products (beverages, shots, concentrates, and workout powders) having large differences in caffeine content and concentration and intended use. Hence, inaccurate conclusions may be drawn when describing adverse events associated with "energy drinks". The FDA is considering new regulation of these products but product specificity is needed to evaluate safety. To help address this, we queried Texas Poison Center Network data for single substance exposures to "energy drinks" from 2010 to 2014, then analyzed adverse events by product type. We specifically compared energy beverage exposures with sales data for the same time period to evaluate the safety profile of this category of energy drinks. Among 855 documented "energy drink" exposures, poison center-determined outcome severity revealed 291 with no/minimal effects, 417 judged nontoxic or minor/not followed, 64 moderate and 4 major effects, and no deaths. Serious complications included 2 seizures and 1 episode of ventricular tachycardia. Outcome severity by category for beverages: 11 moderate/1 major effects (none in children <17 years); shots: 19 moderate/2 major; non-liquids: 16 moderate/1 major; concentrates: 7 moderate; unknown: 10 moderate. Call incidence to poison centers for beverage type exposures was 0.58 (for moderate effects) and 0.053 (for major) per hundred million units sold. Small volume and concentrated products were associated with a greater number of adverse effects than beverage versions of "energy drinks". Copyright © 2018 Elsevier Inc. All rights reserved.

Adverse effects reported in the use of gastroesophageal reflux disease treatments in children: a 10 years literature review

PubMed Central

Cohen, Shlomi; Bueno de Mesquita, Mirjam; Mimouni, Francis B

2015-01-01

Gastroesophageal reflux (GER) is commonly observed in children, particularly during the first year of life. Pharmacological therapy is mostly reserved for symptomatic infants diagnosed with GER disease (GERD), usually as defined in a recent consensus statement. The purpose of the present article was to review the reported adverse effects of pharmacological agents used in the treatment of paediatric GERD. We conducted this review using the electronic journal database Pubmed and Cochrane database systematic reviews using the latest 10-year period (1 January 2003 to 31 December 2012). Our search strategy included the following keywords: omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, rantidine, cimetidine, famotidine, nizatidine, domperidone, metoclopramide, betanechol, erythromycin, baclofen, alginate. We used Pubmed’s own filter of: ’child: birth–18 years’. All full articles were reviewed and we only included randomized controlled trials retrieved from our search. We addressed a summary of our search on a drug-by-drug basis with regard to its mechanism of action and clinical applications, and reviewed all of the adverse effects reported and the safety profile of each drug. Adverse effects have been reported in at least 23% of patients treated with histamine H2 receptor antagonists (H2RAs) and 34% of those treated with proton pump inhibitors (PPIs), and mostly include headaches, diarrhoea, nausea (H2RAs and PPIs) and constipation (PPIs). Acid suppression may place immune-deficient infants and children, or those with indwelling catheters, at risk for the development of lower respiratory tract infections and nosocomial sepsis. Prokinetic agents have many adverse effects, without major benefits to support their routine use. PMID:25752807

Efficacy and Safety of Remifentanil as an Alternative Labor Analgesic

PubMed Central

Devabhakthuni, Sandeep

2013-01-01

The objective of this review was to evaluate the clinical efficacy and safety of remifentanil in the management of labor pain. Although neuraxial analgesia is the best option during labor, alternative analgesic options are needed for patients with contraindications. Using a systematic literature search, clinical outcomes of remifentanil for labor pain have been summarized. Also, comparisons of remifentanil to other options including meperidine, epidural analgesia, fentanyl, and nitrous oxide are provided. Based on the literature review, remifentanil is associated with high overall maternal satisfaction and favorable side-effect profile. However, due to the low reporting of adverse events, large, randomized controlled trials are needed to evaluate maternal and neonatal safety adequately and determine the optimal dosing needed to provide effective analgesia. While remifentanil is a feasible alternative for patients who cannot or do not want to receive epidural analgesia, administration should be monitored closely for potential adverse effects. PMID:24665213

Calcium and zinc DTPA administration for internal contamination with plutonium-238 and americium-241.

PubMed

Kazzi, Ziad N; Heyl, Alexander; Ruprecht, Johann

2012-08-01

The accidental or intentional release of plutonium or americium can cause acute and long term adverse health effects if they enter the human body by ingestion, inhalation, or injection. These effects can be prevented by rapid removal of these radionuclides by chelators such as calcium or zinc diethylenetriaminepentaacetate (calcium or zinc DTPA). These compounds have been shown to be efficacious in enhancing the elimination of members of the actinide family particularly plutonium and americium when administered intravenously or by nebulizer. The efficacy and adverse effects profile depend on several factors that include the route of internalization of the actinide, the type, and route time of administration of the chelator, and whether the calcium or zinc salt of DTPA is used. Current and future research efforts should be directed at overcoming limitations associated with the use of these complex drugs by using innovative methods that can enhance their structural and therapeutic properties.

Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study.

PubMed

Blau, Jenny E; Bauman, Viviana; Conway, Ellen M; Piaggi, Paolo; Walter, Mary F; Wright, Elizabeth C; Bernstein, Shanna; Courville, Amber B; Collins, Michael T; Rother, Kristina I; Taylor, Simeon I

2018-04-19

Sodium glucose cotransporter-2 (SGLT2) inhibitors are the most recently approved class of drugs for type 2 diabetes and provide both glycemic efficacy and cardiovascular risk reduction. A number of safety issues have been identified, including treatment-emergent bone fractures. To understand the overall clinical profile, these safety issues must be balanced against an attractive efficacy profile. Our study was designed to investigate pathophysiological mechanisms mediating treatment-emergent adverse effects on bone health. We conducted a single-blind randomized crossover study in hospitalized healthy adults (n = 25) receiving either canagliflozin (300 mg/d) or placebo for 5 days. The primary end-point was the drug-induced change in AUC for plasma intact fibroblast growth factor 23 (FGF23) immunoactivity between 24 and 72 hours. Canagliflozin administration increased placebo-subtracted mean levels of serum phosphorus (+16%), plasma FGF23 (+20%), and plasma parathyroid hormone (PTH) (+25%), while decreasing the level of 1,25-dihydroxyvitamin D (-10%). There was substantial interindividual variation in the magnitude of each of these pharmacodynamic responses. The increase in plasma FGF23 was correlated with the increase in serum phosphorus, and the decrease in plasma 1,25-dihydroxyvitamin D was correlated with the increase in plasma FGF23. Canagliflozin induced a prompt increase in serum phosphorus, which triggers downstream changes in FGF23, 1,25-dihydroxyvitamin D, and PTH, with potential to exert adverse effects on bone health. These pharmacodynamic data provide a foundation for future research to elucidate pathophysiological mechanisms of adverse effects on bone health, with the objective of devising therapeutic strategies to mitigate the drug-associated fracture risk. ClinicalTrial.gov (NCT02404870). Supported by the Intramural Program of NIDDK.

Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study

PubMed Central

Blau, Jenny E.; Bauman, Viviana; Conway, Ellen M.; Walter, Mary F.; Wright, Elizabeth C.; Bernstein, Shanna; Courville, Amber B.; Collins, Michael T.; Rother, Kristina I.

2018-01-01

BACKGROUND. Sodium glucose cotransporter-2 (SGLT2) inhibitors are the most recently approved class of drugs for type 2 diabetes and provide both glycemic efficacy and cardiovascular risk reduction. A number of safety issues have been identified, including treatment-emergent bone fractures. To understand the overall clinical profile, these safety issues must be balanced against an attractive efficacy profile. Our study was designed to investigate pathophysiological mechanisms mediating treatment-emergent adverse effects on bone health. METHODS. We conducted a single-blind randomized crossover study in hospitalized healthy adults (n = 25) receiving either canagliflozin (300 mg/d) or placebo for 5 days. The primary end-point was the drug-induced change in AUC for plasma intact fibroblast growth factor 23 (FGF23) immunoactivity between 24 and 72 hours. RESULTS. Canagliflozin administration increased placebo-subtracted mean levels of serum phosphorus (+16%), plasma FGF23 (+20%), and plasma parathyroid hormone (PTH) (+25%), while decreasing the level of 1,25-dihydroxyvitamin D (–10%). There was substantial interindividual variation in the magnitude of each of these pharmacodynamic responses. The increase in plasma FGF23 was correlated with the increase in serum phosphorus, and the decrease in plasma 1,25-dihydroxyvitamin D was correlated with the increase in plasma FGF23. CONCLUSIONS. Canagliflozin induced a prompt increase in serum phosphorus, which triggers downstream changes in FGF23, 1,25-dihydroxyvitamin D, and PTH, with potential to exert adverse effects on bone health. These pharmacodynamic data provide a foundation for future research to elucidate pathophysiological mechanisms of adverse effects on bone health, with the objective of devising therapeutic strategies to mitigate the drug-associated fracture risk. TRIAL REGISTRATION. ClinicalTrial.gov (NCT02404870). FUNDING. Supported by the Intramural Program of NIDDK. PMID:29669938

Prospective, randomized, and controlled trial on ketamine infusion during bilateral axillo-breast approach (BABA) robotic or endoscopic thyroidectomy: Effects on postoperative pain and recovery profiles

PubMed Central

Kim, Dong-Ho; Choi, June Young; Kim, Byoung-Gook; Hwang, Jin-Young; Park, Seong-Joo; Oh, Ah-Young; Jeon, Young-Tae; Ryu, Jung-Hee

2016-01-01

Abstract Background: Robotic or endoscopic thyroidectomy using bilateral axillo-breast approach (BABA) is frequently performed for excellent cosmesis. However, postoperative pain is remained as concerns due to the extent tissue dissection and tension during the operation. Ketamine is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that reduces acute postoperative pain. We evaluated the effects of intraoperative ketamine infusion on postoperative pain control and recovery profiles following BABA robotic or endoscopic thyroidectomy. Methods: Fifty-eight adult patients scheduled for BABA robotic or endoscopic thyroidectomy were randomized into a control group (n = 29) and ketamine group (n = 29). Following induction of anesthesia, patients in each group were infused with the same volume of saline or ketamine solution (1 mg/kg bolus, 60 μg/kg/h continuous infusion). Total intravenous anesthesia with propofol and remifentanil was used to induce and maintain anesthesia. Pain scores (101-point numerical rating scale, 0 = no pain, 100 = the worst imaginable pain), the consumption of rescue analgesics, and other postoperative adverse effects were assessed at 1, 6, 24, and 48 hours postoperatively. Results: Patients in the ketamine group reported lower pain scores than those in the control group at 6 hours (30 [30] vs 50 [30]; P = 0.017), 24 hours (20 [10] vs 30 [20]; P < 0.001), and 48 hours (10 [10] vs 20 [15]; P < 0.001) in neck area. No statistically significant differences were found between the 2 groups in terms of the requirements for rescue analgesics or the occurrence of adverse events. Conclusion: Intravenous ketamine infusion during anesthesia resulted in lower postoperative pain scores following BABA robotic or endoscopic thyroidectomy, with no increase in adverse events. PMID:27930531

Prospective, randomized, and controlled trial on ketamine infusion during bilateral axillo-breast approach (BABA) robotic or endoscopic thyroidectomy: Effects on postoperative pain and recovery profiles: A consort compliant article.

PubMed

Kim, Dong-Ho; Choi, June Young; Kim, Byoung-Gook; Hwang, Jin-Young; Park, Seong-Joo; Oh, Ah-Young; Jeon, Young-Tae; Ryu, Jung-Hee

2016-12-01

Robotic or endoscopic thyroidectomy using bilateral axillo-breast approach (BABA) is frequently performed for excellent cosmesis. However, postoperative pain is remained as concerns due to the extent tissue dissection and tension during the operation. Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that reduces acute postoperative pain. We evaluated the effects of intraoperative ketamine infusion on postoperative pain control and recovery profiles following BABA robotic or endoscopic thyroidectomy. Fifty-eight adult patients scheduled for BABA robotic or endoscopic thyroidectomy were randomized into a control group (n = 29) and ketamine group (n = 29). Following induction of anesthesia, patients in each group were infused with the same volume of saline or ketamine solution (1 mg/kg bolus, 60 μg/kg/h continuous infusion). Total intravenous anesthesia with propofol and remifentanil was used to induce and maintain anesthesia. Pain scores (101-point numerical rating scale, 0 = no pain, 100 = the worst imaginable pain), the consumption of rescue analgesics, and other postoperative adverse effects were assessed at 1, 6, 24, and 48 hours postoperatively. Patients in the ketamine group reported lower pain scores than those in the control group at 6 hours (30 [30] vs 50 [30]; P = 0.017), 24 hours (20 [10] vs 30 [20]; P < 0.001), and 48 hours (10 [10] vs 20 [15]; P < 0.001) in neck area. No statistically significant differences were found between the 2 groups in terms of the requirements for rescue analgesics or the occurrence of adverse events. Intravenous ketamine infusion during anesthesia resulted in lower postoperative pain scores following BABA robotic or endoscopic thyroidectomy, with no increase in adverse events.

Evolution of pharmacological obesity treatments: focus on adverse side-effect profiles.

PubMed

Krentz, A J; Fujioka, K; Hompesch, M

2016-06-01

Pharmacotherapy directed toward reducing body weight may provide benefits for both curbing obesity and lowering the risk of obesity-associated comorbidities; however, many weight loss medications have been withdrawn from the market because of serious adverse effects. Examples include pulmonary hypertension (aminorex), cardiovascular toxicity, e.g. flenfluramine-induced valvopathy, stroke [phenylpropanolamine (PPA)], excess non-fatal cardiovascular events (sibutramine), and neuro-psychiatric issues (rimonabant; approved in Europe, but not in the USA). This negative experience has helped mould the current drug development and approval process for new anti-obesity drugs. Differences between the US Food and Drug Administration (FDA) and the European Medicines Agency, however, in perceptions of risk-benefit considerations for individual drugs have resulted in discrepancies in approval and/or withdrawal of weight-reducing medications. Thus, two drugs recently approved by the FDA, i.e. lorcaserin and phentermine + topiramate extended release, are not available in Europe. In contrast, naltrexone sustained release (SR)/bupropion SR received FDA approval, and liraglutide 3.0 mg was recently approved in both the USA and Europe. Regulatory strategies adopted by the FDA to manage the potential for uncommon but potentially serious post-marketing toxicity include: (i) risk evaluation and mitigation strategy programmes; (ii) stipulating post-marketing safety trials; (iii) considering responder rates and limiting cumulative exposure by discontinuation if weight loss is not attained within a reasonable timeframe; and (iv) requiring large cardiovascular outcome trials before or after approval. We chronicle the adverse effects of anti-obesity pharmacotherapy and consider how the history of high-profile toxicity issues has shaped the current regulatory landscape for new and future weight-reducing drugs. © 2016 John Wiley & Sons Ltd.

Adverse Effects of GLP-1 Receptor Agonists

PubMed Central

Filippatos, Theodosios D.; Panagiotopoulou, Thalia V.; Elisaf, Moses S.

2014-01-01

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1 receptor agonists are described. The review also provides the reader with structured data that compare the rates of the most common adverse effects for each of the various GLP-1 receptor agonists. PMID:26177483

Safety profile and protocol prevention of adverse reactions to uroangiographic contrast media in diagnostic imaging.

PubMed

Rossi, C; Reginelli, A; D'Amora, M; Di Grezia, G; Mandato, Y; D'Andrea, A; Brunese, L; Grassi, R; Rotondi, A

2014-01-01

The purpose of the study is to examine the incidence of adverse reactions caused by non-ionic contrast media in selected patients after desensitization treatment and to evaluate the safety profile of organ iodine contrast media (i.c.m.) in a multistep prevention protocol. In a population of 2000 patients that had received a CT scan, 100 patients with moderate/high risk for adverse reactions against iodinated contrast agents followed a premedication protocol and all adverse reactions are reported and classified as mild, moderate or severe. 1.7 percent of the pre-treated patients reported a mild, immediate type reaction to iodine contrast; of these five patients with allergy 0.71 percent had received iomeprol, 0.35 percent received ioversol and 0.71 percent received iopromide. The incidence of adverse reactions was reported to be higher (4 out of 5 patients) among those that referred a history of hypersensitivity against iodinated i.c.m. Although intravenous contrast materials have greatly improved, especially in terms of their safety profile, they should not be administered if there isn't a clear or justified indication. In conclusion, even if we know that the majority of these reactions are idiosyncratic and unpredictable we propose, with the aim of improving our knowledge on this subject, a multicenter study, based on skin allergy tests (prick test, patch test, intradermal reaction) in selected patients that have had previous experiences of hypersensitivity against parenteral organ iodine contrast media.

Clopidogrel-Induced Neutropenia after Coronary Stenting: Is Cilostazol a Good Alternative?

PubMed Central

Montalto, Massimo; Porto, Italo; Gallo, Antonella; Camaioni, Claudia; Della Bona, Roberta; Grieco, Antonio; Crea, Filippo; Landolfi, Raffaele

2011-01-01

Dual antiplatelet therapy with aspirin plus thienopyridines has become the standard treatment of patients undergoing coronary stenting. Clopidogrel has mostly replaced the use of ticlopidine due to its more favourable adverse event profile. However, also the use of clopidogrel is not without side effects. Clopidogrel major adverse events are represented by marrow suppression, manifesting with aplastic anaemia, thrombocytopenia and neutropenia. When clopidogrel toxicity occurs, there are few and unsubstantiated alternative treatments and thus, in these cases, medical decisions may be very difficult. We report a case of clopidogrel-induced bone marrow toxicity manifesting with severe neutropenia in a patient treated with multiple coronary stents and provide suggestions for an alternative treatment. PMID:21860799

Effects of Bazedoxifene Alone and with Conjugated Equine Estrogens on Coronary and Peripheral Artery Atherosclerosis of Postmenopausal Monkeys

PubMed Central

Clarkson, Thomas B.; Ethun, Kelly F.; Chen, Haiying; Golden, Debbie; Floyd, Edison; Appt, Susan E.

2012-01-01

Objective The objective was to evaluate the effects of bazedoxifene acetate (BZA), a new selective estrogen receptor modulator, on coronary and peripheral artery atherosclerosis and to determine if it would antagonize the atheroprotective effects of conjugated equine estrogens (CEE) in a monkey model. Methods Ninety-eight surgically postmenopausal monkeys (Macaca fascicularis) were fed a moderately atherogenic diet and then randomized to receive no treatment, or women’s equivalent doses of BZA (20 mg/day), CEE (0.45 mg/day) or BZA+CEE. The experiment period was for 20 months (approximately equivalent to 5 years of patient experience) during which interim measures were made of cardiovascular risk factors. At the end of the experimental period, the extent and severity of coronary and iliac artery atherosclerosis was quantified. Results Body weight, adiposity, fasting glucose concentrations and plasma lipid profiles were not different among treatment conditions. BZA had no adverse effects on coronary artery nor common iliac artery atherosclerosis extent or severity when compared to no-treatment. CEE, administered soon after inducing menopause, had a robust atheroprotective effect on both iliac and coronary artery extent and severity. The addition of BZA to the CEE treatment antagonized the atheroprotective effect of the CEE. Conclusions In this nonhuman primate trial, treatment with BZA alone, CEE alone and BZA and CEE in combination did not have significant effects on plasma lipid profiles. CEE markedly inhibited the progression and complication of both coronary and iliac artery atherosclerosis. BZA had no adverse effects on atherosclerosis but attenuated the atheroprotective effects of CEE. PMID:23435024

Comparison of the adverse event profiles of levofloxacin 500 mg and 750 mg in clinical trials for the treatment of respiratory infections.

PubMed

Khashab, Mohammed M; Xiang, Jim; Kahn, James B

2006-10-01

To compare safety data with levofloxacin 500 mg and 750 mg from clinical trials for the treatment of respiratory infections. We compared adverse event data for levofloxacin 500 mg and 750 mg from clinical trials in acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia. Adverse events occurring after the initiation of therapy were classified as treatment-emergent adverse events (TEAE); drug-related adverse events (DRAE) were TEAE assessed by the clinical investigator as definitely/very likely or probably related to levofloxacin therapy. Overall, the safety profile of the two doses was similar but not identical. TEAE occurred in 49.0% (1601/3268) of those treated with 500 mg and in 45.5% (519/1141) of those treated with 750 mg (p = 0.042); the corresponding rates of DRAE were 7.6% (248/3268) and 8.0% (91/1141) (p = 0.699). There was no statistically significant difference in terms of overall TEAE and DRAE rates within each of the three infectious conditions, but there were in specific events, all of which are expected with levofloxacin therapy. The limitations of this analysis include that it utilized a subset of available safety data, that it includes data only from clinical trials, and that we report primarily on events occurring in > or = 2% of patients. Given similar adverse event profiles and the advantages of higher dose therapy, including shorter courses of therapy and potential impact on preventing resistance, clinicians should consider utilizing the 750 mg dose of levofloxacin when choosing between dosage strengths for treatment of indicated infections.

The Role of Agonistic Striving in the Association Between Cortisol and High Blood Pressure.

PubMed

Ewart, Craig K; Elder, Gavin J; Jorgensen, Randall S; Fitzgerald, Sheila T

2017-05-01

A social action theory of chronic stress proposes that agonistic striving (seeking to influence or control others) impairs cardiovascular health by magnifying the impact of high adversity-induced cortisol levels on blood pressure. We tested three predictions of social action theory: (1) the social action theory taxonomy of regulatory strivings characterizes young adults from high-adversity neighborhoods; (2) high cortisol levels predict high blood pressure more reliably in the subgroup with the agonistic striving profile than in subgroups with other profiles; (3) the association of higher cortisol and higher blood pressure with agonistic striving is not explained by negative affect (depressive symptoms/dysphoria, anger, hostility). Participants were young adults (N = 198, mean [SD] age = 32 [3.4] years); 71% female; 65% black) from disadvantaged urban neighborhoods. Motive profiles (including agonistic strivings) were assessed using the Social Competence Interview. Cortisol levels were derived from saliva samples; blood pressure level was obtained during two days of ambulatory monitoring. Psychological measures of negative affect were assessed using questionnaires. The predicted taxonomy of regulatory strivings was replicated in this sample; the interaction between cortisol and motive profile was significant (F(2, 91) = 6.72, p = .002); analyses of simple effects disclosed that higher cortisol levels predicted higher ambulatory blood pressure only in individuals who exhibited agonistic striving. Depressive symptoms/dysphoria, trait anger, and hostility were not correlated with agonistic striving, cortisol, or blood pressure. Agonistic striving may represent a distinctive (and novel) social-cognitive mechanism of toxic stress and cardiovascular risk.

American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer

PubMed Central

Burstein, Harold J.; Prestrud, Ann Alexis; Seidenfeld, Jerome; Anderson, Holly; Buchholz, Thomas A.; Davidson, Nancy E.; Gelmon, Karen E.; Giordano, Sharon H.; Hudis, Clifford A.; Malin, Jennifer; Mamounas, Eleftherios P.; Rowden, Diana; Solky, Alexander J.; Sowers, MaryFran R.; Stearns, Vered; Winer, Eric P.; Somerfield, Mark R.; Griggs, Jennifer J.

2010-01-01

Purpose To develop evidence-based guidelines, based on a systematic review, for endocrine therapy for postmenopausal women with hormone receptor–positive breast cancer. Methods A literature search identified relevant randomized trials. Databases searched included MEDLINE, PREMEDLINE, the Cochrane Collaboration Library, and those for the Annual Meetings of the American Society of Clinical Oncology (ASCO) and the San Antonio Breast Cancer Symposium (SABCS). The primary outcomes of interest were disease-free survival, overall survival, and time to contralateral breast cancer. Secondary outcomes included adverse events and quality of life. An expert panel reviewed the literature, especially 12 major trials, and developed updated recommendations. Results An adjuvant treatment strategy incorporating an aromatase inhibitor (AI) as primary (initial endocrine therapy), sequential (using both tamoxifen and an AI in either order), or extended (AI after 5 years of tamoxifen) therapy reduces the risk of breast cancer recurrence compared with 5 years of tamoxifen alone. Data suggest that including an AI as primary monotherapy or as sequential treatment after 2 to 3 years of tamoxifen yields similar outcomes. Tamoxifen and AIs differ in their adverse effect profiles, and these differences may inform treatment preferences. Conclusion The Update Committee recommends that postmenopausal women with hormone receptor–positive breast cancer consider incorporating AI therapy at some point during adjuvant treatment, either as up-front therapy or as sequential treatment after tamoxifen. The optimal timing and duration of endocrine treatment remain unresolved. The Update Committee supports careful consideration of adverse effect profiles and patient preferences in deciding whether and when to incorporate AI therapy. PMID:20625130

Budesonide Foam Has a Favorable Safety Profile for Inducing Remission in Mild-to-Moderate Ulcerative Proctitis or Proctosigmoiditis.

PubMed

Rubin, David T; Sandborn, William J; Bosworth, Brian; Zakko, Salam; Gordon, Glenn L; Sale, Mark E; Rolleri, Robert L; Golden, Pamela L; Barrett, Andrew C; Bortey, Enoch; Forbes, William P

2015-11-01

Budesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis. The aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam. Data from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam. A similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0%, respectively). Adverse events occurred in 41.4 and 36.3% of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic-pituitary-adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration. This integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis.

Association between Pesticide Profiles Used on Agricultural Fields near Maternal Residences during Pregnancy and IQ at Age 7 Years.

PubMed

Coker, Eric; Gunier, Robert; Bradman, Asa; Harley, Kim; Kogut, Katherine; Molitor, John; Eskenazi, Brenda

2017-05-09

We previously showed that potential prenatal exposure to agricultural pesticides was associated with adverse neurodevelopmental outcomes in children, yet the effects of joint exposure to multiple pesticides is poorly understood. In this paper, we investigate associations between the joint distribution of agricultural use patterns of multiple pesticides (denoted as "pesticide profiles") applied near maternal residences during pregnancy and Full-Scale Intelligence Quotient (FSIQ) at 7 years of age. Among a cohort of children residing in California's Salinas Valley, we used Pesticide Use Report (PUR) data to characterize potential exposure from use within 1 km of maternal residences during pregnancy for 15 potentially neurotoxic pesticides from five different chemical classes. We used Bayesian profile regression (BPR) to examine associations between clustered pesticide profiles and deficits in childhood FSIQ. BPR identified eight distinct clusters of prenatal pesticide profiles. Two of the pesticide profile clusters exhibited some of the highest cumulative pesticide use levels and were associated with deficits in adjusted FSIQ of -6.9 (95% credible interval: -11.3, -2.2) and -6.4 (95% credible interval: -13.1, 0.49), respectively, when compared with the pesticide profile cluster that showed the lowest level of pesticides use. Although maternal residence during pregnancy near high agricultural use of multiple neurotoxic pesticides was associated with FSIQ deficit, the magnitude of the associations showed potential for sub-additive effects. Epidemiologic analysis of pesticides and their potential health effects can benefit from a multi-pollutant approach to analysis.

Minimal adverse effects profile following implantation of periauricular percutaneous electrical nerve field stimulators: a retrospective cohort study

PubMed Central

Roberts, Arthur; Sithole, Alec; Sedghi, Marcos; Walker, Charles A; Quinn, Theresa M

2016-01-01

The periauricular percutaneous implantation of the Neuro-Stim System™ family of devices EAD, MFS, and BRIDGE is a procedure involving the use of a non-opiate, neuromodulation analgesic for relieving acute and chronic pain. It has been approved as a minimal-risk procedure by multiple governmental and institutional facilities. This retrospective report of findings will help quantify the incidence of clinically observed bleeding, localized dermatitis, and infections at the implantation sites of the electrode/needle arrays, dermatitis at the site of the generator, and patient syncope. A total of 1,207 devices, each producing up to 16 percutaneous punctures, for a total of 19,312 punctures were monitored for adverse effects, based on retrospective chart audits conducted at six clinical facilities over a 1-year period. PMID:27843360

Safety of treatment options for spondyloarthritis: a narrative review.

PubMed

D'Angelo, Salvatore; Carriero, Antonio; Gilio, Michele; Ursini, Francesco; Leccese, Pietro; Palazzi, Carlo

2018-05-01

Spondyloarthritis (SpA) are chronic inflammatory diseases with overlapping pathogenic mechanisms and clinical features. Treatment armamentarium against SpA includes non-steroidal anti-inflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs (DMARDs, including sulfasalazine, methotrexate, leflunomide, cyclosporine), targeted synthetic DMARDs (apremilast) and biological DMARDs (TNF inhibitors, anti-IL 12/23 and anti-IL-17 agents). Areas covered: A narrative review of published literature on safety profile of available SpA treatment options was performed. Readers will be provided with a comprehensive overview on frequent and rare adverse events associated with each drug listed in current SpA treatment recommendations. Expert opinion: The overall safety profile of such molecules is good and serious adverse events are rare but need to be promptly recognized and treated. However, the monitoring of adverse events is a major challenge for clinicians because it is not adequately addressed by current treatment recommendations. A tailored treatment is crucial and rheumatologists must accurately select patients in order to identify those more susceptible to develop adverse events.

Effect of eslicarbazepine acetate and oxcarbazepine on cognition and psychomotor function in healthy volunteers.

PubMed

Milovan, Denise; Almeida, Luis; Romach, Myroslava K; Nunes, Teresa; Rocha, José Francisco; Sokowloska, Marta; Sellers, Edward M; Soares-da-Silva, Patrício

2010-08-01

The results of two single-blind studies conducted to evaluate the cognitive and psychomotor effects of eslicarbazepine acetate and oxcarbazepine following single and repeated administration in healthy volunteers are reported. The cognitive and psychomotor evaluation consisted of several computerized and paper-and-pencil measures. Eslicarbazepine acetate and oxcarbazepine had similar overall cognitive profiles and did not cause clinically relevant cognitive impairment. The incidence of adverse events was lower with eslicarbazepine acetate than with oxcarbazepine. Copyright 2010. Published by Elsevier Inc.

Preliminary Experience with Transdermal Oxybutynin Patches for Hyperhidrosis.

PubMed

Bergón-Sendín, M; Pulido-Pérez, A; Sáez-Martín, L C; Suárez-Fernández, R

2016-12-01

Hyperhidrosis is very common and has a considerable impact on patients' quality of life. While oral oxybutynin is associated with good response rates, adverse effects are common and frequently cause patients to stop treatment. Following the recent launch of oxybutynin in a transdermal patch formulation in Spain, we undertook a preliminary study to assess treatment response and adverse effects in patients with hyperhidrosis. This prospective study of 25 patients treated twice weekly with transdermal oxybutynin patches over 10 weeks assessed treatment response on 2 subjective scales: the Hyperhidrosis Disease Severity Scale (HDSS) and a visual analog scale (VAS) for sweating. Sixty percent of patients showed an improvement in HDSS scores. VAS scores improved in all cases, and 68% of patients achieved a reduction of 3 points or more. Just 2 patients (8%) experienced treatment-related adverse effects (irritant dermatitis at the patch application site in both cases). Although our results are based on a small sample, they suggest that transdermal oxybutynin could be a useful option for the treatment of hyperhidrosis and that it has an excellent safety and tolerability profile. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Management of normal tissue toxicity associated with chemoradiation (primary skin, esophagus, and lung).

PubMed

Yazbeck, Victor Y; Villaruz, Liza; Haley, Marsha; Socinski, Mark A

2013-01-01

Nearly one quarter of patients with lung cancer present with locally advanced disease where concurrent chemoradiotherapy is the current standard of care for patients with good performance status. Cisplatin-based concurrent chemoradiotherapy consistently showed an improvement in survival compared with sequential chemoradiotherapy, at the expense of an increase in the toxicity profile. Over the past decades, several encouraging biomarkers such as transforming growth factor-beta and radioprotective agents such as amifostine were studied but without reaching approval for patient care. We reviewed the prevalence and risk factors for different adverse effects associated with the combined chemoradiotherapy modality, especially dermatitis, mucositis, esophagitis, and pneumonitis. These adverse effects can further be divided into acute, subacute, and chronic. Dermatitis is usually rare and responds well to topical steroids and usual skin care. Acute esophagitis occurs in 30% of patients and is treated with proton pump inhibitors, promotility agents, local anesthetic, and dietary changes. Radiation pneumonitis is a subacute complication seen in 15% of patients and is usually managed with steroids. Chronic adverse effects such as radiation fibrosis and esophageal stricture occur approximately 6 months after completion of radiation therapy and are usually permanent. In this review, complications of chemoradiotherapy for patients with locally advanced lung cancer are delineated, and approaches to their management are described. Given that treatment interruption is associated with a worse outcome, patients are aggressively treated with a curative intent. Therefore, planning for treatment adverse effects improves patient tolerance, compliance, and outcome.

Safety and Efficacy Profile of Echinacea purpurea to Prevent Common Cold Episodes: A Randomized, Double-Blind, Placebo-Controlled Trial

PubMed Central

Jawad, M.; Schoop, R.; Suter, A.; Klein, P.; Eccles, R.

2012-01-01

Objective. To investigate the safety (risk) and efficacy (benefit) of Echinacea purpurea extract in the prevention of common cold episodes in a large population over a 4-month period. Methods. 755 healthy subjects were allocated to receive either an alcohol extract from freshly harvested E. purpurea (95% herba and 5% root) or placebo. Participants were required to record adverse events and to rate cold-related issues in a diary throughout the investigation period. Nasal secretions were sampled at acute colds and screened for viruses. Results. A total of 293 adverse events occurred with Echinacea and 306 with placebo treatment. Nine and 10% of participants experienced adverse events, which were at least possibly related to the study drug (adverse drug reactions). Thus, the safety of Echinacea was noninferior to placebo. Echinacea reduced the total number of cold episodes, cumulated episode days within the group, and pain-killer medicated episodes. Echinacea inhibited virally confirmed colds and especially prevented enveloped virus infections (P < 0.05). Echinacea showed maximal effects on recurrent infections, and preventive effects increased with therapy compliance and adherence to the protocol. Conclusions. Compliant prophylactic intake of E. purpurea over a 4-month period appeared to provide a positive risk to benefit ratio. PMID:23024696

Probable topiramate-induced diarrhea in a 2-month-old breast-fed child - A case report.

PubMed

Westergren, Tone; Hjelmeland, Knut; Kristoffersen, Bjørg; Johannessen, Svein Ivar; Kalikstad, Betty

2014-01-01

An infant developed a severe condition of recurrent and persistent watery diarrhea at 40 days of age. The child had been partially breast-fed, and the mother used topiramate for epilepsy. Hospital examination excluded a viral or bacterial infection and failed to identify any other potential cause. After two weeks, topiramate exposure was suspected to be the cause, and breast-feeding was suspended. The diarrhea ceased within 2 days. Analysis of the breast milk showed a topiramate concentration of 15.7 μmol/L (5.3 μg/mL). There is little information on the use of topiramate in breast-feeding women. The potential effects on the children are not known. Topiramate passes into breast milk, and the concentration may equal the therapeutic plasma concentration. In this case, the infant may have ingested up to 40% of the mother's weight-adjusted dose. Diarrhea is a well-known adverse reaction to topiramate and has the potential to cause serious electrolyte disturbances in neonates and infants. The condition improved rapidly after suspension of breast-feeding. Topiramate in breast milk may reach levels that cause adverse effects in infants. Based on the adverse reaction profile of topiramate and the milk concentration, the diarrhea was assessed as a probable adverse drug reaction in the infant.

Mass spectrometry profiling of oxylipins, endocannabinoids, and N-acylethanolamines in human lung lavage fluids reveals responsiveness of prostaglandin E2 and associated lipid metabolites to biodiesel exhaust exposure.

PubMed

Gouveia-Figueira, Sandra; Karimpour, Masoumeh; Bosson, Jenny A; Blomberg, Anders; Unosson, Jon; Pourazar, Jamshid; Sandström, Thomas; Behndig, Annelie F; Nording, Malin L

2017-04-01

The adverse effects of petrodiesel exhaust exposure on the cardiovascular and respiratory systems are well recognized. While biofuels such as rapeseed methyl ester (RME) biodiesel may have ecological advantages, the exhaust generated may cause adverse health effects. In the current study, we investigated the responses of bioactive lipid mediators in human airways after biodiesel exhaust exposure using lipidomic profiling methods. Lipid mediator levels in lung lavage were assessed following 1-h biodiesel exhaust (average particulate matter concentration, 159 μg/m 3 ) or filtered air exposure in 15 healthy individuals in a double-blinded, randomized, controlled, crossover study design. Bronchoscopy was performed 6 h post exposure and lung lavage fluids, i.e., bronchial wash (BW) and bronchoalveolar lavage (BAL), were sequentially collected. Mass spectrometry methods were used to detect a wide array of oxylipins (including eicosanoids), endocannabinoids, N-acylethanolamines, and related lipid metabolites in the collected BW and BAL samples. Six lipids in the human lung lavage samples were altered following biodiesel exhaust exposure, three from BAL samples and three from BW samples. Of these, elevated levels of PGE 2 , 12,13-DiHOME, and 13-HODE, all of which were found in BAL samples, reached Bonferroni-corrected significance. This is the first study in humans reporting responses of bioactive lipids following biodiesel exhaust exposure and the most pronounced responses were seen in the more peripheral and alveolar lung compartments, reflected by BAL collection. Since the responsiveness and diagnostic value of a subset of the studied lipid metabolites were established in lavage fluids, we conclude that our mass spectrometry profiling method is useful to assess effects of human exposure to vehicle exhaust.

Editor's Highlight: Transcriptome Profiling Reveals Bisphenol A Alternatives Activate Estrogen Receptor Alpha in Human Breast Cancer Cells.

PubMed

Mesnage, Robin; Phedonos, Alexia; Arno, Matthew; Balu, Sucharitha; Corton, J Christopher; Antoniou, Michael N

2017-08-01

Plasticizers with estrogenic activity, such as bisphenol A (BPA), have potential adverse health effects in humans. Due to mounting evidence of these health effects, BPA is being phased out and replaced by other bisphenol variants in "BPA-free" products. We have compared estrogenic activity of BPA with 6 bisphenol analogues [bisphenol S (BPS); bisphenol F (BPF); bisphenol AP (BPAP); bisphenol AF (BPAF); bisphenol Z (BPZ); bisphenol B (BPB)] in 3 human breast cancer cell lines. Estrogenicity was assessed (10-11-10-4 M) by cell growth in an estrogen receptor (ER)-mediated cell proliferation assay, and by the induction of estrogen response element-mediated transcription in a luciferase assay. BPAF was the most potent bisphenol, followed by BPB > BPZ ∼ BPA > BPF ∼ BPAP > BPS. The addition of ICI 182,780 antagonized the activation of ERs. Data mining of ToxCast high-throughput screening assays confirm our results but also show divergence in the sensitivities of the assays. Gene expression profiles were determined in MCF-7 cells by microarray analysis. The comparison of transcriptome profile alterations resulting from BPA alternatives with an ERα gene expression biomarker further indicates that all BPA alternatives act as ERα agonists in MCF-7 cells. These results were confirmed by Illumina-based RNA sequencing. In conclusion, BPA alternatives are not necessarily less estrogenic than BPA in human breast cancer cells. BPAF, BPB, and BPZ were more estrogenic than BPA. These findings point to the importance of better understanding the risk of adverse effects from exposure to BPA alternatives, including hormone-dependent breast cancer. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

EPA Science Inventory

Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male...

TOXICOLOGY OF MALE REPRODUCTIVE DEVELOPMENT: PROFILING 774 CHEMICALS FOR MOLECULAR TARGETS AND ADVERSE OUTCOMES (SOT)

EPA Science Inventory

Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male...

Can profiles of poly- and Perfluoroalkyl substances (PFASs) in human serum provide information on major exposure sources?

PubMed

Hu, Xindi C; Dassuncao, Clifton; Zhang, Xianming; Grandjean, Philippe; Weihe, Pál; Webster, Glenys M; Nielsen, Flemming; Sunderland, Elsie M

2018-02-01

Humans are exposed to poly- and perfluoroalkyl substances (PFASs) from diverse sources and this has been associated with negative health impacts. Advances in analytical methods have enabled routine detection of more than 15 PFASs in human sera, allowing better profiling of PFAS exposures. The composition of PFASs in human sera reflects the complexity of exposure sources but source identification can be confounded by differences in toxicokinetics affecting uptake, distribution, and elimination. Common PFASs, such as perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) and their precursors are ubiquitous in multiple exposure sources. However, their composition varies among sources, which may impact associated adverse health effects. We use available PFAS concentrations from several demographic groups in a North Atlantic seafood consuming population (Faroe Islands) to explore whether chemical fingerprints in human sera provide insights into predominant exposure sources. We compare serum PFAS profiles from Faroese individuals to other North American populations to investigate commonalities in potential exposure sources. We compare individuals with similar demographic and physiological characteristics and samples from the same years to reduce confounding by toxicokinetic differences and changing environmental releases. Using principal components analysis (PCA) confirmed by hierarchical clustering, we assess variability in serum PFAS concentrations across three Faroese groups. The first principal component (PC)/cluster consists of C9-C12 perfluoroalkyl carboxylates (PFCAs) and is consistent with measured PFAS profiles in consumed seafood. The second PC/cluster includes perfluorohexanesulfonic acid (PFHxS) and the PFOS precursor N-ethyl perfluorooctane sulfonamidoacetate (N-EtFOSAA), which are directly used or metabolized from fluorochemicals in consumer products such as carpet and food packaging. We find that the same compounds are associated with the same exposure sources in two North American populations, suggesting generalizability of results from the Faroese population. We conclude that PFAS homologue profiles in serum provide valuable information on major exposure sources. It is essential to compare samples collected at similar time periods and to correct for demographic groups that are highly affected by differences in physiological processes (e.g., pregnancy). Information on PFAS homologue profiles is crucial for attributing adverse health effects to the proper mixtures or individual PFASs.

Nurse-Led Medicines' Monitoring for Patients with Dementia in Care Homes: A Pragmatic Cohort Stepped Wedge Cluster Randomised Trial

PubMed Central

Jordan, Susan; Gabe-Walters, Marie Ellenor; Watkins, Alan; Humphreys, Ioan; Newson, Louise; Snelgrove, Sherrill; Dennis, Michael S

2015-01-01

Background People with dementia are susceptible to adverse drug reactions (ADRs). However, they are not always closely monitored for potential problems relating to their medicines: structured nurse-led ADR Profiles have the potential to address this care gap. We aimed to assess the number and nature of clinical problems identified and addressed and changes in prescribing following introduction of nurse-led medicines’ monitoring. Design Pragmatic cohort stepped-wedge cluster Randomised Controlled Trial (RCT) of structured nurse-led medicines’ monitoring versus usual care. Setting Five UK private sector care homes Participants 41 service users, taking at least one antipsychotic, antidepressant or anti-epileptic medicine. Intervention Nurses completed the West Wales ADR (WWADR) Profile for Mental Health Medicines with each participant according to trial step. Outcomes Problems addressed and changes in medicines prescribed. Data Collection and Analysis Information was collected from participants’ notes before randomisation and after each of five monthly trial steps. The impact of the Profile on problems found, actions taken and reduction in mental health medicines was explored in multivariate analyses, accounting for data collection step and site. Results Five of 10 sites and 43 of 49 service users approached participated. Profile administration increased the number of problems addressed from a mean of 6.02 [SD 2.92] to 9.86 [4.48], effect size 3.84, 95% CI 2.57–4.11, P <0.001. For example, pain was more likely to be treated (adjusted Odds Ratio [aOR] 3.84, 1.78–8.30), and more patients attended dentists and opticians (aOR 52.76 [11.80–235.90] and 5.12 [1.45–18.03] respectively). Profile use was associated with reduction in mental health medicines (aOR 4.45, 1.15–17.22). Conclusion The WWADR Profile for Mental Health Medicines can improve the quality and safety of care, and warrants further investigation as a strategy to mitigate the known adverse effects of prescribed medicines. Trial Registration ISRCTN 48133332 PMID:26461064

Regulation of low-density lipoprotein subfractions by carbohydrates.

PubMed

Gerber, Philipp A; Berneis, Kaspar

2012-07-01

This article aims at reviewing the recent findings that have been made concerning the crosstalk of carbohydrate metabolism with the generation of small, dense low-density lipoprotein (LDL) particles, which are known to be associated with an adverse cardiovascular risk profile. Studies conducted during the past few years have quite unanimously shown that the quantity of carbohydrates ingested is associated with a decrease of LDL particle size and an increase in its density. Conversely, diets that aim at a reduction of carbohydrate intake are able to improve LDL quality. Furthermore, a reduction of the glycaemic index without changing the amount of carbohydrates ingested has similar effects. Diseases with altered carbohydrate metabolism, for example, type 2 diabetes, are associated with small, dense LDL particles. Finally, even the kind of monosaccharide the carbohydrate intake consists of is important concerning LDL particle size: fructose has been shown to alter the LDL particle subclass profile more adversely than glucose in many recent studies. LDL particle quality, rather than its quantity, is affected by carbohydrate metabolism, which is of clinical importance, in particular, in the light of increased carbohydrate consumption in today's world.

[Safety profile of zolpidem: two studies of 3805 patients by Swiss practitioners].

PubMed

Ganzoni, E; Gugger, M

1999-06-24

Evaluation and treatment of insomnia are frequent procedures in the physician's everyday practice, since many patients seek medical treatment for this condition. Knowledge of pharmacological therapeutical alternatives is therefore decisive, in order to identify the most efficaceous and safe therapy for the patient among the available hypnotics. The short-acting hypnotic zolpidem has been investigated in Switzerland in two multicenter safety studies in ambulatory practice. In the first study 8.9% (n = 125 of 1,972 treated patients), and in the second 7.2% of the patients (n = 175 of 1,833 treated patients) reported an adverse event. The most frequent events were related to the central nervous system (CNS) (somnolence, headache, confusion, vertigo); gastrointestinal and cutaneous symptoms were the most frequent non CNS-dependent effects. New, unknown or serious adverse events were not found and no specific risk factor or population at risk was identified. The safety profile of zolpidem is consistent with its known pharmacological properties, the results of previous clinical trials and the international experience obtained in large patients groups.

Naloxegol: A Novel Therapy in the Management of Opioid-Induced Constipation.

PubMed

Jones, Rachel; Prommer, Eric; Backstedt, David

2016-11-01

Opioid-related bowel dysfunction is a common and potentially severe adverse effect from treatment with opioid analgesics. Its development is not dose related, nor do patients develop tolerance. Opioid-induced constipation (OIC) can lead to fecal impaction, bowel obstruction, and bowel perforation as well as noncompliance with opioid analgesics and poor quality of life. Routine administration of laxatives is necessary to maintain bowel function, and, in refractory cases, other modalities must be pursued. Available options are limited but include peripherally acting μ-opioid receptor antagonists (PAMORAs), including methylnaltrexone. Naloxegol is a newly developed PAMORA that is available through the oral route. At the therapeutic dose of 25 mg daily, naloxegol is effective and safe, with a limited side effect profile and is associated with preservation of centrally mediated analgesia. In this article, we discuss the pharmacokinetics, pharmacodynamics, adverse effects, clinical trials, and cost considerations of naloxegol. Finally, we discuss its potential role as a novel key treatment for OIC in palliative medicine patients. © The Author(s) 2015.

Subjective and physiological effects after controlled Sativex and oral THC administration.

PubMed

Karschner, E L; Darwin, W D; McMahon, R P; Liu, F; Wright, S; Goodwin, R S; Huestis, M A

2011-03-01

Sativex is a cannabis-plant extract delivering nearly 1:1 Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4 mg THC, 5.0 mg CBD) and high (16.2 mg THC, 15.0 mg CBD) doses of Sativex. At therapeutic doses, no substantial CBD-induced modulation of THC's effects was evident. Oral THC and Sativex produced similar, clinically insignificant increases in heart rate, anxiety, and "good drug effects" with no serious adverse events. Oral and oromucosal THC have slower absorption, lower rate of THC delivery to the brain, and fewer associated adverse events as compared with smoked cannabis. These results indicate that Sativex has a pharmacodynamic safety profile comparable to that of oral THC at low, therapeutic doses.

[Therapeutic effects of venlafaxine extended release for patients with depressive and anxiety disorders in the German outpatient setting - results of 2 observational studies including 8500 patients].

PubMed

Anghelescu, I-G; Dierkes, W; Volz, H-P; Loeschmann, P-A; Schmitt, A B

2009-11-01

The therapeutic effects of venlafaxine extended release have been investigated by two prospective observational studies including 8506 patients in the outpatient setting of office based general practitioners and specialists. The efficacy has been documented by the Clinical Global Impression (CGI) scale and by the Hamilton depression (HAMD-21) scale. The tolerability has been assessed by the documentation of adverse events. About (2/3) of the patients were treated because of depression and about (1/3) mainly because of anxiety disorder. The patients of specialists did receive higher dosages and were more severely affected. The response rate on the CGI scale was 87.4 for the patients of general practitioners and 74.2 % for the patients of specialists. The results of the HAMD-21 scale, which has been used by specialists, showed a response rate of 71.8 and a remission rate of 56.3 %. These positive effects could be demonstrated even for the more severely and chronically affected patients. The incidence of adverse events was low in both studies and comparable to the tolerability profile of randomized studies. Importantly, the good tolerability profile was similar even for patients with concomitant cardiovascular disease. In conclusion, these results confirm the efficacy and good tolerability of venlafaxine extended release in the outpatient setting in Germany. Georg Thieme Verlag KG Stuttgart, New York.

Depression, anxiety, and the cardiovascular system: the psychiatrist's perspective.

PubMed

Roose, S P

2001-01-01

It is becoming clear that the comorbidity of depression and cardiovascular disease does not occur by chance but rather is an inevitable consequence of the relationship between the conditions. Depression in patients with cardiovascular disease is a significant risk factor for developing symptomatic and fatal ischemic heart disease. Moreover, depressed patients have a higher than expected rate of sudden cardiovascular death. Therefore, appropriate treatment of patients with depression and cardiovascular disease cannot be restricted to considerations of either depression or cardiovascular disease in isolation. The tricyclic antidepressants (TCAs) have various effects on the cardiovascular system, including Type IA antiarrhythmic activity that has been associated with an increased risk of mortality in post-myocardial infarction patients. The selective serotonin reuptake inhibitors (SSRIs) are not associated with adverse cardiac effects. The SSRI paroxetine was compared with a therapeutic level of the TCA nortriptyline in a randomized, controlled study and demonstrated a benign cardiovascular profile, while the TCA induced a significantly higher rate of serious adverse cardiovascular events. On the basis of this favorable cardiovascular profile, the SSRIs should therefore be the preferred choice for the treatment of most patients with comorbid depression and cardiovascular disease. Investigation of putative pathophysiologic mechanisms linking depression and cardiovascular mortality, such as the role of platelet activation, will form the basis for further investigation of antidepressant treatments in order to establish if the antidepressants have a beneficial effect on the prognosis of cardiovascular diseases.

The topical 5% lidocaine medicated plaster in localized neuropathic pain: a reappraisal of the clinical evidence

PubMed Central

de León-Casasola, Oscar A; Mayoral, Victor

2016-01-01

Topical 5% lidocaine medicated plasters represent a well-established first-line option for the treatment of peripheral localized neuropathic pain (LNP). This review provides an updated overview of the clinical evidence (randomized, controlled, and open-label clinical studies, real-life daily clinical practice, and case series). The 5% lidocaine medicated plaster effectively provides pain relief in postherpetic neuralgia, and data from a large open-label controlled study indicate that the 5% lidocaine medicated plaster is as effective as systemic pregabalin in postherpetic neuralgia and painful diabetic polyneuropathy but with an improved tolerability profile. Additionally, improved analgesia and fewer side effects were experienced by patients treated synchronously with the 5% lidocaine medicated plaster, further demonstrating the value of multimodal analgesia in LNP. The 5% lidocaine medicated plaster provides continued benefit after long-term (≤7 years) use and is also effective in various other LNP conditions. Minor application-site reactions are the most common adverse events associated with the 5% lidocaine medicated plaster; there is minimal risk of systemic adverse events and drug–drug interactions. Although further well-controlled studies are warranted, the 5% lidocaine medicated plaster is efficacious and safe in LNP and may have particular clinical benefit in elderly and/or medically compromised patients because of the low incidence of adverse events. PMID:26929664

Bilastine and the central nervous system.

PubMed

Montoro, J; Mullol, J; Dávila, I; Ferrer, M; Sastre, J; Bartra, J; Jáuregui, I; del Cuvillo, A; Valero, A

2011-01-01

Antihistamines have been classifed as first or second generation drugs, according to their pharmacokinetic properties, chemical structure and adverse effects. The adverse effects of antihistamines upon the central nervous system (CNS) depend upon their capacity to cross the blood-brain barrier (BBB) and bind to the central H1 receptors (RH1). This in turn depends on the lipophilicity of the drug molecule, its molecular weight (MW), and affinity for P-glycoprotein (P-gp) (CNS xenobiotic substances extractor protein). First generation antihistamines show scant affinity for P-gp, unlike the second generation molecules which are regarded as P-gp substrates. Histamine in the brain is implicated in many functions (waking-sleep cycle, attention, memory and learning, and the regulation of appetite), with numerous and complex interactions with different types of receptors in different brain areas. Bilastine is a new H1 antihistamine that proves to be effective in treating allergic rhinoconjunctivitis (seasonal and perennial) and urticaria. The imaging studies made, as well as the objective psychomotor tests and subjective assessment of drowsiness, indicate the absence of bilastine action upon the CNS. This fact, and the lack of interaction with benzodiazepines and alcohol, define bilastine as a clinically promising drug with a good safety profile as regards adverse effects upon the CNS.

Comparative transcriptional profiling of Gracilariopsis lemaneiformis in response to salicylic acid- and methyl jasmonate-mediated heat resistance

PubMed Central

Wang, Chongbin; Zou, Tonglei; Xu, Nianjun; Sun, Xue

2017-01-01

Culturing the economically important macroalga Gracilariopsis lemaneiformis (Rhodophyta) is limited due to the high temperatures in the summertime on the southern Chinese coast. Previous studies have demonstrated that two phytohormones, salicylic acid (SA) and methyl jasmonate (MJ), can alleviate the adverse effects of high-temperature stress on Gp. lemaneiformis. To elucidate the molecular mechanisms underlying SA- and MJ-mediated heat tolerance, we performed comprehensive analyses of transcriptome-wide gene expression profiles using RNA sequencing (RNA-seq) technology. A total of 14,644 unigenes were assembled, and 10,501 unigenes (71.71%) were annotated to the reference databases. In the SA, MJ and SA/MJ treatment groups, 519, 830, and 974 differentially expressed unigenes were detected, respectively. Unigenes related to photosynthesis and glycometabolism were enriched by SA, while unigenes associated with glycometabolism, protein synthesis, heat shock and signal transduction were increased by MJ. A crosstalk analysis revealed that 216 genes were synergistically regulated, while 18 genes were antagonistically regulated by SA and MJ. The results indicated that the two phytohormones could mitigate the adverse effects of heat on multiple pathways, and they predominantly acted synergistically to resist heat stress. These results will provide new insights into how SA and MJ modulate the molecular mechanisms that counteract heat stress in algae. PMID:28464018

Safety and tolerability of prescription omega-3 fatty acids: A systematic review and meta-analysis of randomized controlled trials.

PubMed

Chang, Cheng-Ho; Tseng, Ping-Tao; Chen, Nai-Yu; Lin, Pei-Chin; Lin, Pao-Yen; Chang, Jane Pei-Chen; Kuo, Feng-Yu; Lin, Jenshinn; Wu, Ming-Chang; Su, Kuan-Pin

2018-02-01

Omega-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] are widely recommended for health promotion. Over the last decade, prescription omega-3 fatty acid products (RxOME3FAs) have been approved for medical indications. Nonetheless, there is no comprehensive analysis of safety and tolerability of RxOME3FAs so far. A systematic review of randomized controlled trials (RCTs) was carried out based on searches in six electronic databases. The studies involving marketed RxOME3FA products were included, and adverse-effect data were extracted for meta-analysis. Subgroup analysis and meta-regression were conducted to explore the sources of potential heterogeneity. Among the 21 included RCTs (total 24,460 participants; 12,750 from RxOME3FA treatment cohort and 11,710 from control cohort), there was no definite evidence of any RxOME3FA-emerging serious adverse event. Compared with the control group, RxOME3FAs were associated with more treatment-related dysgeusia (fishy taste; p = 0.011) and skin abnormalities (eruption, itching, exanthema, or eczema; p < 0.001). Besides, RxOME3FAs had mild adverse effects upon some non-lipid laboratory measurements [elevated fasting blood sugar (p = 0.005); elevated alanine transaminase (p = 0.022); elevated blood urea nitrogen (p = 0.047); decreased hemoglobin (p = 0.002); decreased hematocrit (p = 0.009)]. Subgroup analysis revealed that EPA/DHA combination products were associated with more treatment-related gastrointestinal adverse events [eructation (belching; p = 0.010); nausea (p = 0.044)] and low-density lipoprotein cholesterol elevation (p = 0.009; difference in means = 4.106mg/dL). RxOME3FAs are generally safe and well tolerated but not free of adverse effects. Post-marketing surveillance and observational studies are still necessary to identify long-term adverse effects and to confirm the safety and tolerability profiles of RxOME3FAs. Copyright © 2018 Elsevier Ltd. All rights reserved.

Use of 2D chemical structure and bioactivity profiles to generate chemical categories within an Adverse Outcome Pathway network

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework has emerged to capitalise on the vast quantity of mechanistic data generated by alternative techniques, as well as advances in systems biology, cheminformatics, and bioinformatics. AOPs provide a scaffold onto which mechanistic data can...

6'-Guanidinonaltrindole (6'-GNTI) is a G protein-biased κ-opioid receptor agonist that inhibits arrestin recruitment.

PubMed

Rives, Marie-Laure; Rossillo, Mary; Liu-Chen, Lee-Yuan; Javitch, Jonathan A

2012-08-03

κ-Opioid receptor (KOR) agonists do not activate the reward pathway stimulated by morphine-like μ-opioid receptor (MOR) agonists and thus have been considered to be promising nonaddictive analgesics. However, KOR agonists produce other adverse effects, including dysphoria, diuresis, and constipation. The therapeutic promise of KOR agonists has nonetheless recently been revived by studies showing that their dysphoric effects require arrestin recruitment, whereas their analgesic effects do not. Moreover, KOR agonist-induced antinociceptive tolerance observed in vivo has also been proposed to be correlated to the ability to induce arrestin-dependent phosphorylation, desensitization, and internalization of the receptor. The discovery of functionally selective drugs that are therapeutically effective without the adverse effects triggered by the arrestin pathway is thus an important goal. We have identified such an extreme G protein-biased KOR compound, 6'-guanidinonaltrindole (6'-GNTI), a potent partial agonist at the KOR receptor for the G protein activation pathway that does not recruit arrestin. Indeed, 6'-GNTI functions as an antagonist to block the arrestin recruitment and KOR internalization induced by other nonbiased agonists. As an extremely G protein-biased KOR agonist, 6'-GNTI represents a promising lead compound in the search for nonaddictive opioid analgesic as its signaling profile suggests that it will be without the dysphoria and other adverse effects promoted by arrestin recruitment and its downstream signaling.

Pharmacokinetics of the injectable formulation of methadone hydrochloride administered orally in horses.

PubMed

Linardi, R L; Stokes, A M; Barker, S A; Short, C; Hosgood, G; Natalini, C C

2009-10-01

Methadone hydrochloride is a synthetic mu-opioid receptor agonist with potent analgesic properties. Oral methadone has been successfully used in human medicine and may overcome some limitations of other analgesics in equine species for producing analgesia with minimal adverse effects. However, there are no studies describing the pharmacokinetics (PK) of oral opioids in horses. The aim of this study was to describe the PK of orally administered methadone (0.1, 0.2 and 0.4 mg/kg) and physical effects in 12 healthy adult horses. Serum methadone concentrations were measured by gas chromatography/mass spectrometry at predetermined time points for 24 h, and PK parameters were estimated using a noncompartmental model. Physical effects were observed and recorded by experienced clinicians. No drug toxicity, behavioural or adverse effects were observed in the horses. The disposition of methadone followed first order elimination and a biphasic serum profile with rapid absorption and elimination phases. The PK profile of methadone was characterized by high clearance (Cl/F), small volume of distribution (V(d)/F) and short elimination half-life (t(1/2)). The mean of the estimated t(1/2) (SD) for each dose (0.1, 0.2 and 0.4 mg/kg) was 2.2 (35.6), 1.3 (46.1) and 1.5 (40.8), and the mean for the estimated C(max) (SD) was 33.9 (6.7), 127.9 (36.0) and 193.5 (65.8) respectively.

Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans.

PubMed

Lennerz, Belinda S; Vafai, Scott B; Delaney, Nigel F; Clish, Clary B; Deik, Amy A; Pierce, Kerry A; Ludwig, David S; Mootha, Vamsi K

2015-01-01

Sodium benzoate is a widely used preservative found in many foods and soft drinks. It is metabolized within mitochondria to produce hippurate, which is then cleared by the kidneys. We previously reported that ingestion of sodium benzoate at the generally regarded as safe (GRAS) dose leads to a robust excursion in the plasma hippurate level [1]. Since previous reports demonstrated adverse effects of benzoate and hippurate on glucose homeostasis in cells and in animal models, we hypothesized that benzoate might represent a widespread and underappreciated diabetogenic dietary exposure in humans. Here, we evaluated whether acute exposure to GRAS levels of sodium benzoate alters insulin and glucose homeostasis through a randomized, controlled, cross-over study of 14 overweight subjects. Serial blood samples were collected following an oral glucose challenge, in the presence or absence of sodium benzoate. Outcome measurements included glucose, insulin, glucagon, as well as temporal mass spectrometry-based metabolic profiles. We did not find a statistically significant effect of an acute oral exposure to sodium benzoate on glucose homeostasis. Of the 146 metabolites targeted, four changed significantly in response to benzoate, including the expected rise in benzoate and hippurate. In addition, anthranilic acid, a tryptophan metabolite, exhibited a robust rise, while acetylglycine dropped. Although our study shows that GRAS doses of benzoate do not have an acute, adverse effect on glucose homeostasis, future studies will be necessary to explore the metabolic impact of chronic benzoate exposure. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans

PubMed Central

Lennerz, Belinda; Vafai, Scott B.; Delaney, Nigel F.; Clish, Clary B.; Deik, Amy A.; Pierce, Kerry A.; Ludwig, David S.; Mootha, Vamsi K.

2014-01-01

Sodium benzoate is a widely used preservative found in many foods and soft drinks. It is metabolized within mitochondria to produce hippurate, which is then cleared by the kidneys. We previously reported that ingestion of sodium benzoate at the generally regarded as safe (GRAS) dose leads to a robust excursion in the plasma hippurate level [1]. Since previous reports demonstrated adverse effects of benzoate and hippurate on glucose homeostasis in cells and in animal models, we hypothesized that benzoate might represent a widespread and underappreciated diabetogenic dietary exposure in humans. Here, we evaluated whether acute exposure to GRAS levels of sodium benzoate alters insulin and glucose homeostasis through a randomized, controlled, cross-over study of 14 overweight subjects. Serial blood samples were collected following an oral glucose challenge, in the presence or absence of sodium benzoate. Outcome measurements included glucose, insulin, glucagon, as well as temporal mass spectrometry-based metabolic profiles. We did not find a statistically significant effect of an acute oral exposure to sodium benzoate on glucose homeostasis. Of the 146 metabolites targeted, four changed significantly in response to benzoate, including the expected rise in benzoate and hippurate. In addition, anthranilic acid, a tryptophan metabolite, exhibited a robust rise, while acetylglycine dropped. Although our study shows that GRAS doses of benzoate do not have an acute, adverse effect on glucose homeostasis, future studies will be necessary to explore the metabolic impact of chronic benzoate exposure. PMID:25497115

Effectiveness and security of chronic hepatitis C treatment in coinfected patients in real-world.

PubMed

Uriarte-Pinto, Moisés; Navarro-Aznarez, Herminia; De La Llama-Celis, Natalia; Arazo-Garcés, Piedad; Martínez-Sapiña, Ana María; Abad-Sazatornil, María Reyes

2018-06-01

Background HIV-HCV coinfection produces high morbi-mortality. Direct-acting antivirals (DAAs) have shown high efficacy, although special attention should be paid to the risk of drug interactions. However, due to the lack of representativeness of coinfected patients in clinical trials, it is important to know real-world results. Objective To evaluate DAA treatment effectiveness in coinfected patients. We also analyse safety profile of DAA treatment and drug interactions between HCV and HIV therapy. Setting Descriptive study carried in a tertiary hospital of Spain Method HIV-HCV coinfected patients treated with DAAs between November 2014 and June 2016 were included. Main outcome measure Efficacy was measured in terms of sustained virologic response at week 12 after the end of therapy. Adverse events that led to treatment discontinuation were registered to evaluate the safety profile, and also drug interactions between DAAs and antiretroviral treatment were evaluated. Results Main HCV genotypes were 1a (34.9%) and 4 (24.5%). 51.9% were HCV previously treated, 54.7% had grade 4 liver fibrosis. SVR12 was reported in 90.6%. HCV treatment was well tolerated and there were no discontinuations because of adverse events. 30.2% of HIV treatments had to be modified before DAA treatment was started due to interactions, HIV suppression was not compromised. Conclusion DAA treatment in coinfected patients seems to be highly effective and secure. Evaluation of drug interactions must be a priority in order to maximize effectiveness and avoid toxicity.

Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists.

PubMed

Janero, David R

2012-03-01

Addiction to chemical substances with abuse potential presents medical needs largely unsolved by extant therapeutic strategies. Signal transmission through the cannabinoid-1 receptor (CB1R) in the central nervous system (CNS) modulates neurotransmitters/neuronal pathways contributing to the rewarding properties and hedonic effects of certain nondrug stimuli (e.g., food) and many prototypical addictive drugs, promoting excessive intake and its pathological consequences. Typical CB1R antagonists/inverse agonists reduce the rewarding effects and normalize behavioral phenotypes associated with food and abused drugs, but carry an unacceptable adverse-event profile that may reflect, at least partly, their intrinsic ability to alter basal homeostatic CB1R signaling in the CNS and elicit a negative efficacy response. Alternatively, peripherally biased CB1R inverse agonists with limited CNS permeability and putative CB1R neutral antagonists expressing modest (if any) inverse-agonist efficacy are garnering attention for treating obesity and related cardiometabolic complications with a potentially enhanced benefit-to-risk profile. This mini-review calls attention to the proposition that CB1R neutral antagonists offer attractive opportunities for pharmacotherapeutic exploitation in the substance abuse/drug addiction space, whereas the restricted CNS accessibility of peripherally biased CB1R inverse agonists circumscribes their therapeutic utility for this indication. The unique preclinical pharmacology, efficacy profiles, and reduced adverse-event risk of CB1R neutral antagonists make them worthy of translational study for their potential therapeutic application beyond obesity/cardiometabolic disease to include substance-abuse/drug-addiction disorders.

Circadian rhythm, sleep pattern, and metabolic consequences: an overview on cardiovascular risk factors.

PubMed

Machado, Roberta Marcondes; Koike, Marcia Kiyomi

2014-04-01

Sleep duration is a risk factor for cardiovascular disease. Alteration in sleep pattern can induce the loss of circadian rhythmicity. Chronically, this desynchronization between endogenous rhythm and behavioral cycles can lead to an adverse metabolic profile, a proinflammatory condition and can increase the risk of cardiovascular disease. The circadian cycle can vary due to environmental cues. The circadian pacemaker is located in the suprachiasmatic nuclei; this central clock coordinates the circadian rhythm in the central nervous system and peripheral tissues. The mechanisms involved in sleep disturbance, circadian misalignment and adverse metabolic effects have yet to be fully elucidated. This review looks over the association among sleep alteration, circadian rhythm and the development of risk factors implicated in cardiovascular disease.

Effectiveness and safety of generic version of abacavir/lamivudine and efavirenz in treatment naïve HIV-infected patients: a nonrandomized, open-label, phase IV study in Cali-Colombia, 2011-2012.

PubMed

Galindo, Jaime; Amariles, Pedro; Mueses-Marín, Héctor F; Hincapié, Jaime A; González-Avendaño, Sebastián; Galindo-Orrego, Ximena

2016-10-03

Generic drug policies are often associated with concerns about the quality and effectiveness of these products. Phase IV clinical trials may be a suitable design to assess the effectiveness and safety of generic drugs. The objective of this study was to describe the effectiveness and the safety of the generic abacavir/lamivudine and efavirenz in treatment-naïve HIV-infected patients. A monocentric, nonrandomized, open-label, phase IV study in treatment naïve HIV-infected patients 18 years or older with indication to receive abacavir/lamivudine and efavirenz were recruited from a program that provides comprehensive outpatient consultation and continuing care. The primary end-point was to achieve viral load <40 copies/mL at 12 months after baseline to assess effectiveness. Secondary end-point of the study were 1) to asses increasing in T-CD4 lymphocytes levels as accompaniment to asses effectiveness, and 2) to assess both gastrointestinal, skin, and central nervous system symptoms, and lipid profile, cardiovascular risk, renal, and hepatic function as safety profile. Data were determined at baseline, 3, 6, and 12 months. Close clinical monitoring and pharmaceutical care were used for data collection. Wilcoxon matched-pairs signed-rank test was used to compare proportions or medians. Sixty patients were invited to participate in the study; 42 were enrolled and 33 completed the follow-up. Of the nine patients excluded from the study, only one was withdrawn due to adverse events. At 12 months, 31 of 42 patients (73.8 % in intention-to-treat analysis) achieved a viral load of HIV1 RNA <40 copies/mL. There was a significant increase (172 cells/mm 3 ) in the median for CD4 T lymphocyte count. The adverse events were mild and met the safety profile for this antiretroviral regimen, mainly of central nervous system symptoms, skin rash, lipid abnormalities, and an increase of 2 % in the median of the percentage of cardiovascular risk. The clinical outcomes of generic version of abacavir/lamivudine and efavirenz in HIV treatment naïve patients showed the expected safety and effectiveness profile of proprietary ARV drugs. Registro Público Cubano de Ensayos Clínicos (RPCEC) ID: RPCEC00000202 . Registered 19 November 2015.

[Research Progress on Forensic Toxicology of Z-drugs].

PubMed

Zhang, Yong-zhi; He, Hong-yuan; She, Cai-meng; Lian, Jie

2015-08-01

The Z-drugs (zolpidem, zopiclone, and zaleplon), as the innovative hypnotics, have an improvement over the traditional benzodiazepines in the management of insomnia. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. As benzodiazepines, Z-drugs exert their effects through increasing the transmission of γ-aminobutyric acid. Z-drugs overdose are less likely to be fatal, more likely would result in poisoning. Z-drugs can be detected in blood, urine, saliva, and other postmortem specimens through liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Z-drugs have improved pharmacokinetic profiles, but incidence of neuropsychiatric sequelae, poisoning, and death may prove to be similar to the other hypnotics. This review focuses on the pharmacology and toxicology of Z-drugs with respect to their adverse effect profile and toxicity and toxicology data in the field of forensic medicine.

Benefit-risk assessment of levetiracetam in the treatment of partial seizures.

PubMed

Abou-Khalil, Bassel

2005-01-01

Levetiracetam is a novel antiepileptic drug that has been demonstrated as being effective in the management of partial seizures. It is rapidly and completely absorbed after oral administration and it is predominantly eliminated as unchanged drug in the urine. Its metabolism is independent of the cytochrome P450 enzyme system, nor does it induce cytochrome P450 enzymes. As a result of its pharmacokinetic features, levetiracetam has not been demonstrated to interact with other drugs in either direction. In double-blind, placebo-controlled trials, all the levetiracetam dosages tested were effective, including 1000 mg/day, 2000 mg/day and 3000 mg/day. The ineffective dose is not known. Efficacy seemed to be maintained in long-term studies, with no evidence of tolerance. In major double-blind, placebo-controlled trials discontinuation rates because of adverse events were 6.9-10.9% for levetiracetam-treated patients (all doses) compared with 5.3-8.6% for placebo-treated patients. The most common adverse events that differed between treatment groups and placebo control groups were somnolence, asthenia, dizziness and, in the US study, infection. Since levetiracetam was marketed, behavioural effects have been reported, namely irritability, agitation, anger and aggressive behaviour. These adverse effects are more likely in learning disabled individuals, those with prior psychiatric history and those with symptomatic generalised epilepsy. Overall, the risk has been estimated at 12-15%. Laboratory parameters overall seem to be not significantly affected by levetiracetam, although slight trends to lower white and red blood cell counts were detected in the studies. No organ toxicity has been described so far, with patient exposures exceeding 500,000. In summary, levetiracetam exhibits a very favourable safety profile in patients with partial onset seizures. Whereas somnolence, asthenia and dizziness were the most prominent adverse effects in clinical trials, behavioural adverse effects have generally been the most common reason for drug discontinuation in clinical practice.

Safety and bleeding profile of continuous levonorgestrel 90 mcg/ethinyl estradiol 20 mcg based on 2 years of clinical trial data in Canada.

PubMed

Reid, Robert L; Fortier, Michel P; Smith, Lynne; Mirkin, Sebastian; Grubb, Gary S; Constantine, Ginger D

2010-12-01

The study was conducted to evaluate bleeding profile and safety of continuous oral contraceptive (OC) containing levonorgestrel (LNG) 90 mcg/ethinyl estradiol (EE) 20 mcg. Healthy women who participated at seven Canadian sites in 1-year open-label study of LNG 90 mcg/EE 20 mcg daily were eligible for this second-year extension study. Primary end points included bleeding profile and adverse events. Seventy-nine women enrolled without interrupting pill taking; 62 (78.5%) completed. Adverse events were comparable to cyclic OC regimens, except unscheduled vaginal bleeding. Amenorrhea and absence of bleeding increased to about 80% and 90%, respectively, by Pill Pack 18. Mean (median) number of bleeding days for the last two 90-day intervals was 1.1 (0) and 0.7 (0) days, respectively. Continuous LNG 90 mcg/EE 20 mcg had a safety profile similar to low-dose cyclic OCs. Short-term safety profile remained excellent, with increasing rates of amenorrhea and decreasing incidence of unscheduled bleeding and/or spotting. Copyright © 2010 Elsevier Inc. All rights reserved.

A safety assessment of Coriolus versicolor biomass as a food supplement.

PubMed

Barros, Ana B; Ferrão, Jorge; Fernandes, Tito

2016-01-01

Coriolus versicolor (CV) is a common mushroom with antitumor, anti-inflammatory, antioxidant, antiviral, antibacterial, and immunomodulatory properties. The existence of these properties has been extensively proven mainly using CV extract; research on the biomass form is scarce. The aim of this study was to investigate the safety of the CV biomass form, as it is commonly used as a food supplement. CV biomass powder was dissolved in distilled water and administered daily (2.5, 5.0, and 7.5 g/kg live weight) in single doses by gavage to both female and male Charles River albino rats. No adverse or lethal effects were observed as a consequence of the daily administration of CV biomass. In addition, compared with the control group, no abnormal findings were observed at necropsy and histopathological examination. A safe profile of CV biomass for human consumption can be inferred from the absence of any remarkable adverse effects in rats.

Oral medications regarding their safety and efficacy in the management of patent ductus arteriosus

PubMed Central

Oncel, Mehmet Yekta; Erdeve, Omer

2016-01-01

Patent ductus arteriosus (PDA) is a common clinical condition in preterm infants which is inversely related to birth weight and gestational age. Cyclooxygenase inhibitors such as indomethacin and ibuprofen which block the prostaglandin conversion from arachidonic acid are the most commonly used drugs for ductal closure. This review focuses on the safety and efficacy oral medications in the management of PDA in preterm infants. Ibuprofen seems to be the first choice due to its higher safety profile, as it is associated with fewer gastrointestinal and renal side effects when compared to indomethacin. PDA closure rates are better with oral than with intravenous ibuprofen probably due to the pharmacokinetic of the drug. However, these medications were reported to be associated with several adverse including transient renal failure, gastrointestinal bleeding and perforation, hyperbilirubinemia and platelet dysfunction. Paracetamol seems be an alternative to PDA therapy with lower adverse events and side effects. PMID:26862505

Global Aesthetics Consensus: Avoidance and Management of Complications from Hyaluronic Acid Fillers—Evidence- and Opinion-Based Review and Consensus Recommendations

PubMed Central

Liew, Steven; Sundaram, Hema; De Boulle, Koenraad L.; Goodman, Greg J.; Monheit, Gary; Wu, Yan; Trindade de Almeida, Ada R.; Swift, Arthur; Vieira Braz, André

2016-01-01

Background: Although the safety profile of hyaluronic acid fillers is favorable, adverse reactions can occur. Clinicians and patients can benefit from ongoing guidance on adverse reactions to hyaluronic acid fillers and their management. Methods: A multinational, multidisciplinary group of experts in cosmetic medicine convened the Global Aesthetics Consensus Group to review the properties and clinical uses of Hylacross and Vycross hyaluronic acid products and develop updated consensus recommendations for early and late complications associated with hyaluronic acid fillers. Results: The consensus panel provided specific recommendations focusing on early and late complications of hyaluronic acid fillers and their management. The impact of patient-, product-, and technique-related factors on such reactions was described. Most of these were noted to be mild and transient. Serious adverse events are rare. Early adverse reactions to hyaluronic acid fillers include vascular infarction and compromise; inflammatory reactions; injection-related events; and inappropriate placement of filler material. Among late reactions are nodules, granulomas, and skin discoloration. Most adverse events can be avoided with proper planning and technique. Detailed understanding of facial anatomy, proper patient and product selection, and appropriate technique can further reduce the risks. Should adverse reactions occur, the clinician must be prepared and have tools available for effective treatment. Conclusions: Adverse reactions with hyaluronic acid fillers are uncommon. Clinicians should take steps to further reduce the risk and be prepared to treat any complications that arise. PMID:27219265

Smallpox vaccines for biodefense: need and feasibility.

PubMed

Artenstein, Andrew W; Grabenstein, John D

2008-10-01

Smallpox, eradicated as a cause of natural disease through an intensive global effort in the later part of the 20th Century, has resurfaced as a possible agent of bioterrorism. For this reason, there is renewed interest in smallpox vaccines. Live vaccinia virus, an orthopoxvirus related to smallpox, has a long and successful clinical track record as an effective smallpox vaccine; however, its use is associated with uncommon yet serious adverse events. This has led to a surge of recent research into newer-generation smallpox vaccines with improved safety profiles and retained efficacy. This article will review the history of smallpox vaccines, assess the status of newer-generation vaccines and examine the overall risk-versus-benefit profile of smallpox vaccination.

Association of Long-term Proton Pump Inhibitor Therapy with Bone Fractures and effects on Absorption of Calcium, Vitamin B12, Iron, and Magnesium

PubMed Central

Ito, Tetsuhide; Jensen, Robert T.

2010-01-01

Proton pump inhibitors (PPI) are now one of the most widely used classes of drugs. PPIs have proven to have a very favorable safety profile and it is unusual for a patient to stop these drugs because of side effects. However, increasing numbers of patients are chronically taking PPIs for gastroesophageal reflux disease and a number of other common persistent conditions, therefore the long-term potential adverse effects are receiving increasing attention. One area that is receiving much attention and generally has been poorly studied, is the long-term effects of chronic acid suppression on the absorption of vitamins and nutrients. This area has received increased attention because of the reported potential adverse effect of chronic PPI treatment leading to an increased occurrence of bone fractures. This has led to an increased examination of the effects of PPIs on calcium absorption/metabolism as well as numerous cohort, case control and prospective studies of their ability to affect bone density and cause bone fractures. In this article these studies are systematically examined, as well as the studies of the effects of chronic PPI usage on VB12, iron and magnesium absorption. In general the studies in each of thee areas have led to differing conclusions, but when examined systematically, a number of the studies are showing consistent results that support the conclusion that long-term adverse effects on these processes can have important clinical implications. PMID:20882439

Overnight switching from oxcarbazepine to eslicarbazepine acetate: an observational study.

PubMed

Schmid, E; Kuchukhidze, G; Kirschner, M; Leitinger, M; Höfler, J; Rohracher, A; Kalss, G; Wendling, A-S; Steinhoff, B J; Trinka, E

2017-04-01

There are clinical situations where it might be appropriate to switch patients from immediate-release oxcarbazepine (OXC) to eslicarbazepine acetate (ESL). We investigated the effects of transitioning patients overnight from OXC to ESL. A retrospective, single-center study was conducted in which patients with drug-resistant focal epilepsy on a stable dose of immediate-release OXC for at least 4 weeks were switched overnight to ESL. Patients were switched because they experienced persistent seizures with OXC but were unable to tolerate increased OXC dosing due to adverse events. Tolerability was assessed using the Adverse Events Profile (AEP), quality of life was assessed using the Quality of Life in Epilepsy Inventory 10 (QOLIE-10), and alertness was assessed as reaction time using a subtest of the Test Battery for Attention Performance version 2.3. Assessments were performed immediately prior to and 5 days after switching from OXC to ESL (days 0 and 5, respectively). The analysis included 21 patients (12 women, 9 men; mean age 36 years). After switching from OXC to ESL, there were significant improvements in mean scores for AEP (P<.001), QOLIE-10 (P=.001), and alertness (P<.05). Adverse Events Profile total scores improved for 21/21 (100.0%) patients, QOLIE-10 total scores improved for 17/21 (81.0%) patients, and alertness scores improved for 16/21 (76.2%) patients. In this short-term, single-center study, an overnight switch from twice-daily OXC to once-daily ESL in patients with drug-resistant focal epilepsies resulted in improvements in side effects, quality of life, and alertness. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

An assessment of predictive value of the biophysical profile in women with preeclampsia using data from the fullPIERS database.

PubMed

Payne, Beth A; Kyle, Phillipa M; Lim, Kenneth; Lisonkova, Sarka; Magee, Laura A; Pullar, Barbra; Qu, Ziguang; von Dadelszen, Peter

2013-07-01

Pre-eclampsia is associated with increased risk to both the mother and fetus. Effective monitoring of the fetal condition is essential to the management of women with pre-eclampsia. The biophysical profile (BPP) is one monitoring tool available to clinicians. To compare the BPP test with cardiotocography/non-stress test (CTG/NST) alone for their ability to predict fetal acidemia at birth or a composite adverse perinatal outcome among women with preeclampsia and to estimate the effect of BPP assessment on mode of delivery and birth outcome. Secondary analysis of a prospective cohort of women with preeclampsia. The predictive ability of the tests was assessed based on sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-). Women assessed with the BPP were compared with matched controls not assessed with the BPP to determine the odds of Cesarean delivery or adverse perinatal outcomes after adjustment for potential confounders. Five out of 89 women (5.6%) had an abnormal BPP; 18 out of 89 (20.2%) had an abnormal CTG/NST. Fetal acidemia was diagnosed in 13 fetuses (14.6%); composite adverse perinatal outcome in 68 fetuses/infants (76.4%). Both tests had relatively poor predictive performance for both outcomes (LR+ between 2.50 and 3.90 and LR- between 0.64 and 0.93). Assessment with the BPP was positively associated with fetal acidemia (adjusted OR 4.84; 95% CI 1.33-17.66). The BPP and CTG/NST alone were poor predictors of perinatal outcome in this cohort; multiple tests should be considered when assessing fetal risk in women with preeclampsia. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Gastrointestinal adverse effects of cyclin-dependent kinase 4 and 6 inhibitors in breast cancer patients: a systematic review and meta-analysis

PubMed Central

Shohdy, Kyrillus S.; Lasheen, Shaimaa; Kassem, Loay; Abdel-Rahman, Omar

2017-01-01

Background: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors show promising results in metastatic breast cancer. However, an increased incidence of adverse events is remarkable. Among others, gastrointestinal (GI) involvement is of momentous impact on patients and their quality of life. Methods: Our search included PubMed, ASCO, ESMO and SABCS databases. Randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors were identified and considered relevant based on providing a sufficient safety profile on the incidence of adverse GI effects. Results: Of the 999 records initially screened for relevance, 33 articles were found relevant and 4 studies were finally eligible for meta-analysis with a total of 2007 patients. The relative risk (RR) for all-grade nausea was 1.48 [95% confidence interval (CI): 1.12–1.93, p = 0.005], vomiting was 1.74 (95% CI: 1.09–2.76, p = 0.02), decreased appetite was 1.42 (95% CI: 1.07–1.88, p = 0.02), and for diarrhea it was 1.44 (95% CI: 1.19–1.74, p = 0.0002). Meanwhile, the RR for high-grade nausea was 1.10 (95% CI: 0.29–4.13, p = 0.89), vomiting was 1.38 (95% CI: 0.25–7.75, p = 0.72), decreased appetite was 4.00 (95% CI: 0.87–18.37, p = 0.07), and high-grade diarrhea was 1.19 (95% CI: 0.44–3.21, p = 0.73). Conclusion: Selective CDK4/6 inhibitors were not associated with higher-grade GI toxicities reflecting a well-tolerated safety profile. Regarding the increase in all-grade GI toxicities, it needs further caution with addition of cytotoxic chemotherapy. PMID:29090083

Gastrointestinal adverse effects of cyclin-dependent kinase 4 and 6 inhibitors in breast cancer patients: a systematic review and meta-analysis.

PubMed

Shohdy, Kyrillus S; Lasheen, Shaimaa; Kassem, Loay; Abdel-Rahman, Omar

2017-11-01

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors show promising results in metastatic breast cancer. However, an increased incidence of adverse events is remarkable. Among others, gastrointestinal (GI) involvement is of momentous impact on patients and their quality of life. Our search included PubMed, ASCO, ESMO and SABCS databases. Randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors were identified and considered relevant based on providing a sufficient safety profile on the incidence of adverse GI effects. Of the 999 records initially screened for relevance, 33 articles were found relevant and 4 studies were finally eligible for meta-analysis with a total of 2007 patients. The relative risk (RR) for all-grade nausea was 1.48 [95% confidence interval (CI): 1.12-1.93, p = 0.005], vomiting was 1.74 (95% CI: 1.09-2.76, p = 0.02), decreased appetite was 1.42 (95% CI: 1.07-1.88, p = 0.02), and for diarrhea it was 1.44 (95% CI: 1.19-1.74, p = 0.0002). Meanwhile, the RR for high-grade nausea was 1.10 (95% CI: 0.29-4.13, p = 0.89), vomiting was 1.38 (95% CI: 0.25-7.75, p = 0.72), decreased appetite was 4.00 (95% CI: 0.87-18.37, p = 0.07), and high-grade diarrhea was 1.19 (95% CI: 0.44-3.21, p = 0.73). Selective CDK4/6 inhibitors were not associated with higher-grade GI toxicities reflecting a well-tolerated safety profile. Regarding the increase in all-grade GI toxicities, it needs further caution with addition of cytotoxic chemotherapy.

Long-Term Seizure, Quality of Life, Depression, and Verbal Memory Outcomes in a Controlled Mesial Temporal Lobe Epilepsy Surgical Series Using Portuguese-Validated Instruments.

PubMed

Dias, Luis Augusto; Angelis, Geisa de; Teixeira, Wagner Afonso; Casulari, Luiz Augusto

2017-08-01

We aimed to evaluate long-term surgical outcomes in patients treated for mesial temporal lobe epilepsy compared with a similar group of patients who underwent a preoperative evaluation. Patient interviews were conducted by an independent neuropsychologist and included a sociodemographic questionnaire and validated versions of the Beck Depression Inventory-II, Adverse Events Profile, Quality of Life in Epilepsy-31, and Rey Auditory Verbal Learning Test. Seventy-one patients who underwent surgery and 20 who underwent mesial temporal lobe epilepsy preoperative evaluations were interviewed. After an 81-month mean postoperative follow-up, 44% of the surgical patients achieved complete seizure relief according to the Engel classification and 68% according to the International League Against Epilepsy classification. The surgical group had a significantly lower prevalence of depression (P = 0.002) and drug-related adverse effects (P = 0.002). Improvement on unemployment (P = 0.02) was achieved but not on driving or education. Delayed verbal memory recall was impaired in 76% of the surgical and 65% of the control cases (P = 0.32). Regarding the Quality of Life in Epilepsy-31, the operated patients scored higher in their total score (mean, 75.44 vs. mean, 60.08; P < 0.001) and in all but the cognitive functioning domain irrespective of the follow-up length. Seizure control, Beck Depression Score, and Adverse Events Profile severity explained 73% of the variance in the surgical group quality of life. Our study found that, although surgical treatment was effective, its impact on social indicators was modest. Moreover, the self-reported quality of life relied not only on seizure control but also on depressive symptoms and antiepileptic drug burden. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

21 CFR 601.35 - Evaluation of safety.

Code of Federal Regulations, 2010 CFR

2010-04-01

... established, low-risk profile). Upon reviewing the relevant product characteristics and safety information..., carrier, or ligand; (3) The risks of an incorrect diagnostic determination; (4) The adverse reaction profile of the drug; (5) Results of human experience with the radiopharmaceutical for other uses; and (6...

78 FR 71620 - Agency Information Collection Activities; Proposed Collection; Comment Request; Adverse Event...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-29

... devices in clinical use. This system is called the Medical Product Safety Network (MedSun). FDA is seeking... the user facilities participating in MedSun, to obtain a demographic profile of the facilities, and... collecting data on the electronic adverse event report form, MedSun collects additional information from...

Severe Affective and Behavioural Dysregulation Is Associated with Significant Psychosocial Adversity and Impairment

ERIC Educational Resources Information Center

Jucksch, Viola; Salbach-Andrae, Harriet; Lenz, Klaus; Goth, Kirstin; Dopfner, Manfred; Poustka, Fritz; Freitag, Christine M.; Lehmkuhl, Gerd; Lehmkuhl, Ulrike; Holtmann, Martin

2011-01-01

Background: Recently, a highly heritable behavioral phenotype of simultaneous deviance on the Anxious/Depressed, Attention Problems, and Aggressive Behavior syndrome scales has been identified on the Child Behavior Checklist (CBCL-Dysregulation Profile, CBCL-DP). This study aims to investigate psychosocial adversity and impairment of the CBCL-DP.…

Seizures as a Potential Complication of Treatment With Simeprevir and Sofosbuvir.

PubMed

Syal, Gaurav; Heldenbrand, Seth D; Duarte-Rojo, Andres

2016-01-01

Newer direct-acting antiviral agents have revolutionized the medical management of chronic hepatitis C. In addition to being extremely efficacious, they report very mild adverse drug reactions from experience in clinical trials. However, because they are relatively new on the horizon, postmarketing surveillance studies refining the safety profile are not yet available. We present a case of seizures as a potential side effect of antiviral therapy with sofosbuvir and simeprevir.

Subjective and Physiological Effects After Controlled Sativex and Oral THC Administration

PubMed Central

Karschner, EL; Darwin, WD; McMahon, RP; Liu, F; Wright, S; Goodwin, RS; Huestis, MA

2013-01-01

Sativex is a cannabis-plant extract delivering nearly 1:1 Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4 mg THC, 5.0 mg CBD) and high (16.2 mg THC, 15.0 mg CBD) doses of Sativex. At therapeutic doses, no substantial CBD-induced modulation of THC's effects was evident. Oral THC and Sativex produced similar, clinically insignificant increases in heart rate, anxiety, and “good drug effects” with no serious adverse events. Oral and oromucosal THC have slower absorption, lower rate of THC delivery to the brain, and fewer associated adverse events as compared with smoked cannabis. These results indicate that Sativex has a pharmacodynamic safety profile comparable to that of oral THC at low, therapeutic doses. PMID:21289620

Evidence-based clinical update: Which local anesthetic drug for pediatric caudal block provides optimal efficacy with the fewest side effects?

PubMed

Dobereiner, Elisabeth F A; Cox, Robin G; Ewen, Alastair; Lardner, David R

2010-12-01

The purpose of this evidence-based clinical update is to identify the best evidence when selecting a long-acting local anesthetic agent for single-shot pediatric caudal anesthesia in children. A structured literature search was conducted using PubMed and Medline (OVID) using the terms "caudal" and combinations of at least two of "bupivacaine", "ropivacaine", and "levobupivacaine". The search limits included "randomized controlled trials" (RCTs), "meta-analysis", "evidence-based reviews" or "reviews", "human", and "all child: 0-18 yr". Seventeen RCTs were identified that concerned single-shot pediatric caudal anesthesia with at least two of the three drugs in question. Data were extracted for the areas of clinical efficacy and side effects. Study findings were assigned levels of evidence, and grades of recommendation were made according to Centre for Evidence-Based Medicine criteria. The three drugs investigated were found to be equivalent in terms of efficacy. Evidence showed bupivacaine with the highest incidence of motor block and ropivacaine with the lowest. Adverse effects were rare and unrelated to the choice of drug. There were no serious adverse events. None of the three agents was shown to be superior in terms of efficacy. Bupivacaine is preferred if motor block is desired, ropivacaine is preferred if motor block is to be minimized. Adverse effects in human studies are rare, mild, and unrelated to the choice of drug. Despite encountering the absence of serious adverse events in each of the studies reviewed, it is noted that animal studies suggest a safer profile with ropivacaine or levobupivacaine than with bupivacaine.

One-year prospective follow-up of pharmacological treatment in children with attention-deficit/hyperactivity disorder.

PubMed

Didoni, Anna; Sequi, Marco; Panei, Pietro; Bonati, Maurizio

2011-10-01

To delineate the safety and tolerability profile of methylphenidate and atomoxetine in children and adolescents with attention deficit hyperactivity disorder (ADHD) monitored for more than 1 year. A cohort study analyzing data from the national ADHD register on patients from the Lombardy Region treated with MPH or atomoxetine. A total of 229 children (median age 11 years, range 6-17), enrolled in 15 regional centers between June 2007 and May 2010. The prevalence rate of pharmacological treatment for ADHD was 0.23%, whereas the estimated ADHD prevalence in the population was 0.95%. In total, 73.8% of patients had been treated with atomoxetine (10-90 mg daily) or MPH (10-75 mg daily); 22% of patients also received an additional psychotropic drug. Of the treated children, 26.9% discontinued the drug prior to 1 year of treatment, mostly because of adverse effects (28.6%). No new or unexpected adverse events (rate 39.2%) were encountered. Decreased appetite, headache, and unstable mood were the leading events. The most severe events occurred in two boys: one experienced absence seizures for the first time with MPH, the other experienced hallucinations with atomoxetine. Therapy was discontinued in ten male patients (7.7%) because of adverse events. All patients with adverse effects recovered well. A very low rate of ADHD prevalence was estimated in Italian children compared to that reported in other countries. Although the medications for ADHD are generally well tolerated, with only mild or minor adverse effects in most cases, their rational use can only be guaranteed by disseminating and monitoring evidence-based practices and by monitoring the safety and efficacy of treatments in both the short and long terms with appropriate tools and approaches.

Metabolic signatures of adiposity in young adults: Mendelian randomization analysis and effects of weight change.

PubMed

Würtz, Peter; Wang, Qin; Kangas, Antti J; Richmond, Rebecca C; Skarp, Joni; Tiainen, Mika; Tynkkynen, Tuulia; Soininen, Pasi; Havulinna, Aki S; Kaakinen, Marika; Viikari, Jorma S; Savolainen, Markku J; Kähönen, Mika; Lehtimäki, Terho; Männistö, Satu; Blankenberg, Stefan; Zeller, Tanja; Laitinen, Jaana; Pouta, Anneli; Mäntyselkä, Pekka; Vanhala, Mauno; Elliott, Paul; Pietiläinen, Kirsi H; Ripatti, Samuli; Salomaa, Veikko; Raitakari, Olli T; Järvelin, Marjo-Riitta; Smith, George Davey; Ala-Korpela, Mika

2014-12-01

Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood. We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24 ± 4 kg/m(2)). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%-183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87% ± 3%; R(2)= 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160% ± 2%; R(2) = 0.92). Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood. Please see later in the article for the Editors' Summary.

The Tendril Plot-a novel visual summary of the incidence, significance and temporal aspects of adverse events in clinical trials.

PubMed

Karpefors, Martin; Weatherall, James

2018-03-21

In contrast to efficacy, safety hypotheses of clinical trials are not always pre-specified, and therefore, the safety interpretation work of a trial tends to be more exploratory, often reactive, and the analysis more statistically and graphically challenging. We introduce a new means of visualizing the adverse event data across an entire clinical trial. The approach overcomes some of the current limitations of adverse event analysis and streamlines the way safety data can be explored, interpreted and analyzed. Using a phase II study, we describe and exemplify how the tendril plot effectively summarizes the time-resolved safety profile of two treatment arms in a single plot and how that can provide scientists with a trial safety overview that can support medical decision making. To our knowledge, the tendril plot is the only way to graphically show important treatment differences with preserved temporal information, across an entire clinical trial, in a single view.

Frequency of sexual dysfunction and other reproductive side-effects in patients with schizophrenia treated with risperidone, olanzapine, quetiapine, or haloperidol: the results of the EIRE study.

PubMed

Bobes, J; Garc A-Portilla, M P; Rejas, J; Hern Ndez, G; Garcia-Garcia, M; Rico-Villademoros, F; Porras, A

2003-01-01

Atypical antipsychotics seem to differ mainly in their tolerability profile. The aim of this cross-sectional study, the Estudio de Investigaci n de Resultados en Esquizofrenia (Outcomes Research Study in Schizophrenia; EIRE study), was to assess in a clinical setting the frequency of several side-effects related to haloperidol, risperidone, olanzapine, and quetiapine. This article addresses sexual dysfunction and other reproductive side-effects (gynecomastia, menorrhage, amenorrhea, and galactorrhea). We recruited outpatients diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994) criteria and who had received a single antipsychotic (risperidone, olanzapine, quetiapine, or haloperidol) for at least 4 weeks. During a single visit, we collected data, including demographic and clinical characteristics, current antipsychotic and concomitant treatment, and adverse effects listed in a modified version of the UKU Scale. We used a Chi-squared test to determine pairs comparisons of the frequency of adverse reactions between treatments. To estimate risk of a given adverse reaction with a given treatment, we used a logistic regression method. We assessed 636 evaluable patients out of 669 recruited. Frequency of sexual dysfunction was high with haloperidol (38.1%) and also with olanzapine (35.3%), quetiapine (18.2%), and risperidone (43.2%). We found the frequency of other reproductive side-effects to be relatively low with all four drugs: haloperidol (6.9%), olanzapine (6.4%), quetiapine (2.7%), and risperidone (11.7%). Sexual dysfunction appeared to be dose-related with haloperidol, risperidone, and olanzapine. Risperidone and olanzapine showed a higher risk of sexual dysfunction and other reproductive sideeffects than haloperidol. Quetiapine showed a lower risk of sexual dysfunction during short-term treatment (< 12 weeks). However, data on longer-term treatment (> 12 weeks) are lacking. Our results suggest that none of the atypical antipsychotics that we studied significantly improved sexual dysfunction and other reproductive side-effects of the conventional antipsychotic, haloperidol, in stabilized patients during long-term treatment. Quetiapine appears to improve this profile during short-term treatment; however, longterm data, with larger samples, are required with this latter drug.

Suicidality and profiles of childhood adversities, conflict related trauma and psychopathology in the Northern Ireland population.

PubMed

McLafferty, Margaret; Armour, Cherie; O'Neill, Siobhan; Murphy, Sam; Ferry, Finola; Bunting, Brendan

2016-08-01

Over 30 years of conflict in Northern Ireland (NI) has impacted on the population's mental health. However, childhood adversities may add to the psychological impact of conflict. The aims of the study were to assess co-occurrence across childhood adversities, conflict related traumas, and psychological health, then explore demographic variations between identified classes, and examine the impact of class membership on suicidal ideation and behaviour. Data was obtained from the Northern Ireland Study of Health and Stress, a representative epidemiological study which used the CIDI to assess psychopathology and related risk factors in the NI population (N=4340, part 2 n=1986; response rate 64%). Latent Class Analysis uncovered 4 discrete profiles; a conflict class (n=191; 9.6%), a multi-risk class endorsing elevated levels of childhood adversities, conflict related traumas and psychopathology (n=85; 4.3%), a psychopathology class (n=290; 14.6%), and a low risk class (n=1420; 71.5%). Multinomial logistic regression analysis revealed that individuals who grew up during the worst years of the Troubles were more likely to have experienced multiple traumas and psychopathology. Individuals in the multi-risk class were more than fifteen times more likely to endorse suicidal ideation and behaviour. The main limitations are that the study may not be fully representative of the NI population due to the exclusion criteria applied and also the possible misclassification of conflict related events. The findings indicate that treatment providers should be cognisant that those with wide ranging adversity profiles are those also likely to be reporting psychological distress and suicidality. Copyright © 2016 Elsevier B.V. All rights reserved.

Strategic camouflage treatment of skeletal Class III malocclusion (mandibular prognathism) using bone-borne rapid maxillary expansion and mandibular anterior subapical osteotomy.

PubMed

Seo, Yu-Jin; Lin, Lu; Kim, Seong-Hun; Chung, Kyu-Rhim; Nelson, Gerald

2016-01-01

This case report presents the camouflage treatment that successfully improved the facial profile of a patient with a skeletal Class III malocclusion using bone-borne rapid maxillary expansion and mandibular anterior subapical osteotomy. The patient was an 18-year-old woman with chief complaints of crooked teeth and a protruded jaw. Camouflage treatment was chosen because she rejected orthognathic surgery under general anesthesia. A hybrid type of bone-borne rapid maxillary expander with palatal mini-implants was used to correct the transverse discrepancy, and a mandibular anterior subapical osteotomy was conducted to achieve proper overjet with normal incisal inclination and to improve her lip and chin profile. As a result, a Class I occlusion with a favorable inclination of the anterior teeth and a good esthetic profile was achieved with no adverse effects. Therefore, the hybrid type of bone-borne rapid maxillary expander and a mandibular anterior subapical osteotomy can be considered effective camouflage treatment of a skeletal Class III malocclusion, providing improved inclination of the dentition and lip profile. Copyright © 2016 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

Mode of Action Profiles for Pesticide Compounds with Rodent Liver Tumor Outcomes

EPA Science Inventory

Mode of action (MOA) provides a central framework for assessing human relevance of adverse health outcomes observed in nonclinical safety studies. The goal of this study was to characterize MOA profiles for known rodent liver tumorigens identified from a database of pesticides as...

Side effect profile similarities shared between antidepressants and immune-modulators reveal potential novel targets for treating major depressive disorders.

PubMed

Sun, Yu; Narayan, Vaibhav A; Wittenberg, Gayle M

2016-10-21

Side effects, or the adverse effects of drugs, contain important clinical phenotypic information that may be useful in predicting novel or unknown targets of a drug. It has been suggested that drugs with similar side-effect profiles may share common targets. The diagnostic class, Major Depressive Disorder, is increasingly viewed as being comprised of multiple depression subtypes with different biological root causes. One 'type' of depression generating substantial interest today focuses on patients with high levels of inflammatory burden, indicated by elevated levels of C-reactive proteins (CRP) and pro-inflammatory cytokines such as interleukin 6 (IL-6). It has been suggested that drugs targeting the immune system may have beneficial effect on this subtype of depressed patients, and several studies are underway to test this hypothesis directly. However, patients have been treated with both anti-inflammatory and antidepressant compounds for decades. It may be possible to exploit similarities in clinical readouts to better understand the antidepressant effects of immune-related drugs. Here we explore the space of approved drugs by comparing the drug side effect profiles of known antidepressants and drugs targeting the immune system, and further examine the findings by comparing the human cell line expression profiles induced by them with those induced by antidepressants. We found 7 immune-modulators and 14 anti-inflammatory drugs sharing significant side effect profile similarities with antidepressants. Five of the 7 immune modulators share most similar side effect profiles with antidepressants that modulate dopamine release and/or uptake. In addition, the immunosuppressant rapamycin and the glucocorticoid alclometasone induces transcriptional changes similar to multiple antidepressants. These findings suggest that some antidepressants and some immune-related drugs may affect common molecular pathways. Our findings support the idea that certain medications aimed at the immune system may be helpful in relieving depressive symptoms, and suggest that it may be of value to test immune-modulators for antidepressant-like activity in future proof-of-concept studies.

Evaluation of the anaesthetic properties and tolerance of 1:100,000 articaine versus 1:100,000 lidocaine. A comparative study in surgery of the lower third molar

PubMed Central

Barona-Dorado, Cristina; Martín-Arés, María; Cortés-Bretón-Brinkman, Jorge; Martínez-González, José M.

2012-01-01

Objectives: To evaluate the anaesthetic properties and tolerance of articaine versus lidocaine at equal vasoconstrictor concentration. Study Design: A total of 96 male and female patients who underwent surgical treatment of the lower third molar participated. Patients were randomly assigned to articaine hydrochloride with epinephrine 1:100,000 and lidocaine hydrochloride with epinephrine 1:100,000. The variables analysed were latency period, duration of anaesthetic effect, tolerance and adverse reactions. Results: Both the latency period and the duration of anaesthetic effect were greater for articaine, although the differences were not statistically significant. Latency: mean difference of 2.70 ± 2.12 minutes (95%CI of -1.51 minutes - 6.92 minutes). Duration: mean difference of -33 minutes 5 seconds ± 31 minutes (95% CI -1 hour 35 minutes - 29 minutes). There were 4 adverse events that did not require the patients to be withdrawn from the study. Conclusions: The anaesthetics in this study have very similar properties for use in surgery and have demonstrated a good safety and tolerability profile Key words: Articaine, lidocaine, vasoconstrictor, adverse reactions. PMID:22143691

Observational Studies on Evaluating the Safety and Adverse Effects of Traditional Chinese Medicine

PubMed Central

Tang, Jin-Ling; Wang, Jung-Der

2013-01-01

Background. This study aims to share our experiences when carrying out observational studies of traditional Chinese medicine (TCM). Methods. We have proactively monitored the safety profiles of Duhuo Jisheng Tang (DJT), Suan Zao Ren Tang (SZRT), and TMN-1. A list of adverse events (AEs), complete blood counts, and liver and kidney function tests were obtained from the participants during their scheduled hospital visits. Retrospective observational studies were conducted based on the reimbursement database of the National Health Insurance system, Taiwan, to explore the relationship between the use of TCM that have been adulterated by aristolochic acid and the risk from both nephrotoxins and carcinogens. Results. A total of 221, 287, and 203 AEs were detected after SZRT, DJT, and TMN-1 had been taken, respectively. Dizziness, headache, stomach ache, and diarrhea were judged to be probably related to SZRT treatment. Retrospective observational studies found an association between the consumption of aristolochic acid-containing Chinese formulae such as Mu Tong and an increased risk of CKD, ESRD, and urinary tract cancer. Conclusion. Prospective and retrospective observational studies seem to have specific advantages when investigating the safety and adverse effects of TCM therapies, as well as possibly other alternative/complementary therapies. PMID:24159351

Evaluation of the adverse event profile and pharmacodynamics of toceranib phosphate administered to dogs with solid tumors at doses below the maximum tolerated dose

PubMed Central

2013-01-01

Background The receptor kinase inhibitor toceranib phosphate (Palladia) was approved for use in dogs in 2009 using a dose of 3.25 mg/kg administered every other day. Preliminary data suggests that lower doses of toeceranib may be associated with a reduced adverse event profile while maintaining sufficient drug exposure to provide biologic activity. The purpose of this study was to determine the Cmax of toceranib in dogs with solid tumors receiving 2.5-2.75 mg/kg every other day and to document the adverse events associated with this dose rate. Secondary objectives included determination of plasma VEGF concentrations in treated dogs and response to therapy. Results Dogs with solid tumors were administered toceranib at an intended target dose ranging from 2.5-2.75 mg/kg every other day and plasma samples were obtained for analysis of toceranib and VEGF plasma concentrations on days 0, 7, 14 and 30 of the study at 6 and 8 hours post drug administration. Additionally, plasma samples were obtained at 0, 1, 2, 6, 8, and 12 hours from dogs on day 30 for confirmation of Cmax. Response to therapy was assessed using standard RECIST criteria and adverse events were characterized using the VCOG-CTCAE. Toceranib administered at doses between 2.4-2.9 mg/kg every other day resulted in an average 6–8 hr plasma concentration ranging from 100–120 ng/ml, well above the 40 ng/ml concentration associated with target inhibition. Plasma VEGF concentrations increased significantly over the 30 day treatment period indicating that VEGFR2 inhibition was likely achieved in the majority of dogs. The lower doses of toceranib used in this study were associated with a substantially reduced adverse event profile compared to the established label dose of 3.25 mg/kg EOD. Conclusions Doses of toceranib ranging from 2.4-2.9 mg/kg every other day provide drug exposure considered sufficient for target inhibition while resulting in an adverse event profile substantially reduced from that associated with the label dose of toceranib. This lower dose range of toceranib should be considered for future use in dogs with cancer. PMID:24079884

Potential Toxicity and Underlying Mechanisms Associated with Pulmonary Exposure to Iron Oxide Nanoparticles: Conflicting Literature and Unclear Risk

PubMed Central

Kornberg, Tiffany G.; Antonini, James M.; Rojanasakul, Yon; Castranova, Vincent; Rojanasakul, Liying W.

2017-01-01

Fine/micron-sized iron oxide particulates are incidentally released from a number of industrial processes, including iron ore mining, steel processing, welding, and pyrite production. Some research suggests that occupational exposure to these particulates is linked to an increased risk of adverse respiratory outcomes, whereas other studies suggest that iron oxide is biologically benign. Iron oxide nanoparticles (IONPs), which are less than 100 nm in diameter, have recently surged in use as components of novel drug delivery systems, unique imaging protocols, as environmental catalysts, and for incorporation into thermoplastics. However, the adverse outcomes associated with occupational exposure to IONPs remain relatively unknown. Relevant in vivo studies suggest that pulmonary exposure to IONPs may induce inflammation, pulmonary fibrosis, genotoxicity, and extra-pulmonary effects. This correlates well with in vitro studies that utilize relevant dose, cell type(s), and meaningful end points. A majority of these adverse outcomes are attributed to increased oxidative stress, most likely caused by particle internalization, dissolution, release of free iron ions, and disruption of iron homeostasis. However, because the overall toxicity profile of IONPs is not well understood, it is difficult to set safe exposure limit recommendations that would be adequate for the protection of at-risk workers. This review article will focus on known risks following IONPs exposure supported by human, animal, and cell culture-based studies, the potential challenges intrinsic to IONPs toxicity assessment, and how these may contribute to the poorly characterized IONPs toxicity profile. PMID:28984829

Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate.

PubMed

Kamp, Kimberly; Gumz, Brenda; Feelders, Richard A; Kwekkeboom, Dik J; Kaltsas, Gregory; Costa, Frederico P; de Herder, Wouter W

2013-12-01

Although (177)Lu-octreotate is an effective treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), some patients will fail or develop disease progression necessitating further treatment. We examined whether the safety and efficacy of everolimus after prior treatment with (177)Lu-octreotate is different from the published safety profile of everolimus in GEP-NETs. In this multicenter study, 24 GEP-NET patients were included. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Tumor response was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Major clinical adverse events (grade 3 or 4) during treatment with everolimus were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine transaminase levels (8.3%). By radiological review, there were four partial responses (16.7%), five patients (62.5%) with stable disease, and three patients (12.5%) with progressive disease. For two patients (8.3%), no data on tumor response were available. Median progression-free survival (PFS) was 13.1 months (95% CI, 11.5-21.2). Median PFS of the current study was longer when compared with the RADIANT-3 trial (13.1 vs 11.4 months) and shorter when compared with the RADIANT-1 trial (13.1 vs 16.7 months). In conclusion, the safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy.

Short term safety assessment of cilazapril.

PubMed

Coulter, D M

1993-11-24

To undertake an event monitoring study of cilazapril in general practice during the early marketing period, to provide some comparisons with other angiotensin converting enzyme inhibitors and to assess the monitoring method. The monitoring was undertaken in the Intensive Medicines Monitoring Programme. Cilazapril was prescribed for mild to moderate hypertension in 996 patients at a recommended dose of 2.5-5.0 mg daily. The monitoring period was six months and practitioners were asked to report all adverse events. A reaction profile was prepared and compared with profiles for lisinopril, enalapril and captopril. The chi-square test was applied to differences in proportions. There were 84 (8.4%) reports describing 133 adverse events; 124 (93%) were assessed as reactions. Withdrawals totalled 53 (5.3%). The most common reactions were cough (2.9%), nausea and vomiting (1.3%) and lethargy (1.1%). Cilazapril had a higher proportion of neurological reactions (p < 0.001) (mainly headache) but a lower proportion of skin reactions (p = 0.001) than the other ACE inhibitors. It also had relatively less diarrhoea and there were differences in the patterns of psychiatric reactions. Cilazapril has a similar reaction profile to other ACE inhibitors but this paper shows differences, some not previously reported, that may assist selection when prescribing. Although there was a high rate of reporting of known adverse reactions, other events were reported at a very low rate and spontaneous reporting is thus confirmed as an unreliable method of monitoring for unexpected adverse reactions.

A Novel, Aqueous Surface Treatment To Thermally Stabilize High Resolution Positive Photoresist Images*

NASA Astrophysics Data System (ADS)

Grunwald, John J.; Spencer, Allen C.

1986-07-01

The paper describes a new approach to thermally stabilize the already imaged profile of high resolution positive photoresists such as ULTRAMAC" PR-914. ***XD-4000, an aqueous emulsion of a blend of fluorine-bearing compounds is spun on top of the developed, positive photoresist-imaged wafer, and baked. This allows the photoresist to withstand temperatures up to at least 175 deg. C. while essentially maintaining vertical edge profiles. Also, adverse effects of "outgassing" in harsh environments, ie., plasma and ion implant are greatly minimized by allowing the high resolution imaged photoresist to be post-baked at "elevated" temperatures. Another type of product that accomplishes the same effect is ***XD-4005, an aqueous emulsion of a high temperature-resistant polymer. While the exact mechanism is yet to be identified, it is postulated that absorption of the "polymeric" species into the "skin" of the imaged resist forms a temperature resistant "envelope", thereby allowing high resolution photoresists to also serve in a "high temperature" mode, without reticulation, or other adverse effects due to thermal degradation. SEM's are presented showing imaged ULTRAMAC" PR-914 and ULTRAMAC" **EPA-914 geometries coated with XD-4000 or XD-4005 and followed by plasma etched oxide,polysilicon and aluminum. Selectivity ratios are compared with and without the novel treatment and are shown to be significantly better with the treatment. The surface-treated photoresist for thermal resistance remains easily strippable in solvent-based or plasma media, unlike photoresists that have undergone "PRIST" or other gaseous thermal stabilization methods.

Switching of biologics in psoriasis: Reasons and results.

PubMed

Honda, Hiromi; Umezawa, Yoshinori; Kikuchi, Sota; Yanaba, Koichi; Fukuchi, Osamu; Ito, Toshihiro; Nobeyama, Yoshimasa; Asahina, Akihiko; Nakagawa, Hidemi

2017-09-01

Efficacy and safety profiles of biologics have been established for moderate to severe psoriasis. However, inefficacy or adverse events sometimes require changing the treatment to other biologics. Here, we examine the effectiveness of this strategy. We retrospectively investigated cases requiring switching biologics. We enrolled 275 psoriatic patients treated with biologics between January 2010 and December 2014 in our hospital. Of these, 51 required a switch to another biologic. First-line therapies were infliximab (IFX, n = 26), adalimumab (ADA, n = 18) and ustekinumab (UST, n = 7), and second-line therapies were IFX (n = 5), ADA (n = 21) and UST (n = 25). Reasons for switching were inefficacy (n = 38), adverse events (n = 11) and others (n = 2). The details were primary failure (n = 15), secondary failure (n = 23) and infusion reactions (n = 8). In 49 patients who switched biologics due to inefficacy and adverse events, the mean Psoriasis Area and Severity Index (PASI) score at week 16 was 4.3 for first-line therapies and 2.9 for second-line therapies (P < 0.05). Switching to a second biologic therapy to address the first's inefficacy or adverse events often results in significant improvement in moderate to severe psoriasis. © 2017 Japanese Dermatological Association.

Clinical differences among nonsteroidal antiinflammatory drugs: implications for therapeutic substitution in ambulatory patients.

PubMed

Levy, R A; Smith, D L

1989-01-01

The practice of therapeutic substitution, i.e., replacing one drug with another chemically different drug from the same therapeutic class, represents an important therapeutic modification with potential clinical significance far beyond that of generic substitution. Adverse consequences following therapeutic substitution of nonsteroidal antiinflammatory drugs (NSAID) is of special concern because of substantial differences among these agents in pharmacokinetic, pharmacological, and clinical properties. Therapeutic substitution of NSAID for ambulatory patients may result in compromised clinical outcome because (1) patient response is unpredictable and selection of the optimal agent must be tailored for each patient; (2) substantial differences exist in adverse reaction profiles; (3) drug interaction studies are lacking; and (4) selection of an agent must be individualized to ensure compliance with the dosing regimen. Cost savings achieved through therapeutic substitution of NSAID may be lost by additional overall treatment costs due to adverse reactions or suboptimal therapy. The occurrence of adverse or suboptimal effects in ambulatory patients is more likely if NSAID are substituted without full knowledge of the patient's medical history and clinical status. Communication between the pharmacy and prescribing physician regarding a patient's specific needs is essential for rational substitution among NSAID.

Comparison of Efficacy of Epidural Ropivacaine versus Bupivacaine for Postoperative Pain Relief in Total Knee Replacement Surgeries.

PubMed

Bhasin, Sidharth; Dhar, Mridul; Sreevastava, Deepak Kumar; Nair, Rajiv; Chandrakar, Saurabh

2018-01-01

Epidural analgesia has become the standard of care for knee replacement surgeries worldwide. Bupivacaine has been used successfully for many years. Epidural ropivacaine is now being used increasingly and seems to have benefits other than just pain relief, in terms of a better safety profile. To compare the efficacy of bupivacaine 0.125% (Group B) versus two concentrations of ropivacaine 0.1% (Group R1) and 0.2% (Group R2), in terms of pain scores, requirement of rescue analgesia, related adverse effects, and duration of postoperative (PO) hospital stay. A retrospective study was conducted from the acute pain service data of patients who underwent joint replacement surgeries in one or both limbs, over a span of 6 months. Patients were allocated to and analyzed under one of the three groups based on the drug concentration used postoperatively by epidural infusion. Data retrieved were demographic data, daily average visual analog scale (VAS) pain scores, rescue analgesia given, adverse effects, and PO hospital stay days for all three groups. Demographic data were comparable between the three groups. Daily average VAS pain scores on days 1 and 2 were significantly higher in Group R1. Groups B and R2 were comparable. There was significantly more requirement of rescue analgesia in Group R1 on day 1. Day 2 showed no significant difference in rescue analgesic requirement in all three groups. Days of PO hospital stay were significantly higher in Group R1. Adverse effects such as hypotension and delayed motor block were higher in Group B. Ropivacaine 0.2% and bupivacaine 0.125% were equally efficacious in terms of VAS pain scores, rescue analgesic requirement, and duration of PO hospital stay, but ropivacaine had a better safety profile in terms of less hypotension and lesser motor block.

Comparison of Efficacy of Epidural Ropivacaine versus Bupivacaine for Postoperative Pain Relief in Total Knee Replacement Surgeries

PubMed Central

Bhasin, Sidharth; Dhar, Mridul; Sreevastava, Deepak Kumar; Nair, Rajiv; Chandrakar, Saurabh

2018-01-01

Background: Epidural analgesia has become the standard of care for knee replacement surgeries worldwide. Bupivacaine has been used successfully for many years. Epidural ropivacaine is now being used increasingly and seems to have benefits other than just pain relief, in terms of a better safety profile. Aim: To compare the efficacy of bupivacaine 0.125% (Group B) versus two concentrations of ropivacaine 0.1% (Group R1) and 0.2% (Group R2), in terms of pain scores, requirement of rescue analgesia, related adverse effects, and duration of postoperative (PO) hospital stay. Materials and Methods: A retrospective study was conducted from the acute pain service data of patients who underwent joint replacement surgeries in one or both limbs, over a span of 6 months. Patients were allocated to and analyzed under one of the three groups based on the drug concentration used postoperatively by epidural infusion. Data retrieved were demographic data, daily average visual analog scale (VAS) pain scores, rescue analgesia given, adverse effects, and PO hospital stay days for all three groups. Results: Demographic data were comparable between the three groups. Daily average VAS pain scores on days 1 and 2 were significantly higher in Group R1. Groups B and R2 were comparable. There was significantly more requirement of rescue analgesia in Group R1 on day 1. Day 2 showed no significant difference in rescue analgesic requirement in all three groups. Days of PO hospital stay were significantly higher in Group R1. Adverse effects such as hypotension and delayed motor block were higher in Group B. Conclusion: Ropivacaine 0.2% and bupivacaine 0.125% were equally efficacious in terms of VAS pain scores, rescue analgesic requirement, and duration of PO hospital stay, but ropivacaine had a better safety profile in terms of less hypotension and lesser motor block. PMID:29628549

Proton pump inhibitors and the risk of severe adverse events - a cardiovascular bomb?

PubMed

Cunha, Nelson; Machado, António Pedro

2018-05-24

Proton pump inhibitors are currently one of the most prescribed pharmacological classes in developed countries, given their effectiveness and safety profile previously considered favourable. However, over the last few years, several papers have been published that associate prolonged use of these drugs with a wide range of adverse effects, posing doubts about their safety. Among the adverse effects described, one should emphasize the increased risk of cardiovascular events. This relationship was first described in subjects after acute coronary syndrome by the interference of proton pump inhibitors in cytochrome P450 2C19 and the conversion of clopidogrel to active metabolite. However, more recent studies describe this relationship also with the use of antiplatelet agents that do not depend on cytochrome P450 2C19 activation. The proposed mechanism is by inhibiting dimethylarginine dimethylaminohydrolase, a physiological inhibitor of asymmetric dimethylarginine, thus increasing the plasma concentrations of the latter enzyme and in turn translating into lower levels of nitric oxide. The authors reviewing in this article the relationship between the use of proton pump inhibitors and the increased risk of cardio and cerebrovascular events, are intended to alert the scientific community to the potentially harmful effects of these drugs and recommend the setting of a moratorium on their prolonged use. Copyright © 2018 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Differential effect of subcutaneous abdominal and visceral adipose tissue on cardiometabolic risk.

PubMed

Sam, Susan

2018-03-09

Metabolic and cardiovascular diseases are increasing worldwide due to the rise in the obesity epidemic. The metabolic consequences of obesity vary by distribution of adipose tissue. Visceral and ectopic adipose accumulation are associated with adverse cardiometabolic consequences, while gluteal-femoral adipose accumulation are negatively associated with these adverse complications and subcutaneous abdominal adipose accumulation is more neutral in its associations. Gender, race and ethnic differences in adipose tissue distribution have been described and could account for the observed differences in risk for cardiometabolic disease. The mechanisms behind the differential impact of adipose tissue on cardiometabolic risk have started to be unraveled and include differences in adipocyte biology, inflammatory profile, connection to systemic circulation and most importantly the inability of the subcutaneous adipose tissue to expand in response to positive energy balance.

Pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis.

PubMed

Lancaster, Lisa H; de Andrade, Joao A; Zibrak, Joseph D; Padilla, Maria L; Albera, Carlo; Nathan, Steven D; Wijsenbeek, Marlies S; Stauffer, John L; Kirchgaessler, Klaus-Uwe; Costabel, Ulrich

2017-12-31

Pirfenidone is one of two approved therapies for the treatment of idiopathic pulmonary fibrosis (IPF). Randomised controlled clinical trials and subsequent post hoc analyses have demonstrated that pirfenidone reduces lung function decline, decreases mortality and improves progression-free survival. Long-term extension trials, registries and real-world studies have also shown similar treatment effects with pirfenidone. However, for patients with IPF to obtain the maximum benefits of pirfenidone treatment, the potential adverse events (AEs) associated with pirfenidone need to be managed. This review highlights the well-known and established safety profile of pirfenidone based on randomised controlled clinical trials and real-world data. Key strategies for preventing and managing the most common pirfenidone-related AEs are described, with the goal of maximising adherence to pirfenidone with minimal AEs. Copyright ©ERS 2017.

[Analysis of after-vacination side-effects occurred in Teresina].

PubMed

de Araújo, Telma Maria Evangelista; de Carvalho, Patrícia Maria Gomes; Vieira, Raimunda Damasceno Ferreira

2007-01-01

This study focuses the profile of the adverse events after-vaccine occurrences in Teresina in 2006. The data had been collected by means of the form application with 73 participants in 18 Basic Units of Health. The results show that the vaccines that had more produced events adverse had been tetravalente, BCG and DPT The events most frequent had been: fever, hiporresponsivo hipotonic episode, moderate irritability and local manifestations. Amongst the behaviors adopted for the health professionals, 80% had been approximately adjusted. The year minors had been accomitted by the events. All the events had evolved for the cure. It was concluded that the action of vaccination still continues requiring constant qualification of the professionals of the area. It is suggested to deepen the knowledge with relation to the handling, diagnosis, inquiry and treatment.

Adverse Effects of the Common Treatments for Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

PubMed Central

Domecq, Juan Pablo; Prutsky, Gabriela; Mullan, Rebecca J.; Sundaresh, Vishnu; Wang, Amy T.; Erwin, Patricia J.; Welt, Corrine; Ehrmann, David; Montori, Victor M.

2013-01-01

Context: Polycystic ovary syndrome (PCOS) is common among women of childbearing age and the available pharmacological therapies have different side-effect profiles. Objective: We summarized the evidence about the side effects of oral contraceptive pills, metformin, and anti-androgens in women with PCOS. Data Source: Sources included Ovid Medline, OVID EMBASE, OVID Cochrane Library, Web of Science, Scopus, PsycInfo, and CINAHL from inception through April 2011. Study Selection: We included comparative observational studies enrolling women with PCOS who received the agents of choice for at least 6 months and reported adverse effects. Data Extraction: Using a standardized, piloted, and Web-based data extraction form and working in duplicate, we abstracted data from each study and performed meta-analysis when possible. Data Synthesis: We found 22 eligible studies of which 20 were randomized. No study reported severe side effects (eg, lactic acidosis, thromboembolic episodes, liver toxicity, cancer incidence, or pregnancy loss). Meta-analysis demonstrated no significant change in weight in oral contraceptive pills or flutamide users. Indirect evidence from populations without PCOS demonstrated no increased risk of lactic acidosis with metformin, only case reports of liver toxicity with flutamide (no comparative evidence), and increased relative risk difference of venous thromboembolism with oral contraceptive pills but very low absolute risk. Evidence on mortality, cardiovascular mortality, and cancer was inconclusive. Conclusions: Drugs commonly used to treat PCOS appear to be associated with very low risk of severe adverse effects although data are extrapolated from other populations. PMID:24092830

Adverse effects of the common treatments for polycystic ovary syndrome: a systematic review and meta-analysis.

PubMed

Domecq, Juan Pablo; Prutsky, Gabriela; Mullan, Rebecca J; Sundaresh, Vishnu; Wang, Amy T; Erwin, Patricia J; Welt, Corrine; Ehrmann, David; Montori, Victor M; Murad, Mohammad Hassan

2013-12-01

Polycystic ovary syndrome (PCOS) is common among women of childbearing age and the available pharmacological therapies have different side-effect profiles. We summarized the evidence about the side effects of oral contraceptive pills, metformin, and anti-androgens in women with PCOS. Sources included Ovid Medline, OVID EMBASE, OVID Cochrane Library, Web of Science, Scopus, PsycInfo, and CINAHL from inception through April 2011. We included comparative observational studies enrolling women with PCOS who received the agents of choice for at least 6 months and reported adverse effects. Using a standardized, piloted, and Web-based data extraction form and working in duplicate, we abstracted data from each study and performed meta-analysis when possible. We found 22 eligible studies of which 20 were randomized. No study reported severe side effects (eg, lactic acidosis, thromboembolic episodes, liver toxicity, cancer incidence, or pregnancy loss). Meta-analysis demonstrated no significant change in weight in oral contraceptive pills or flutamide users. Indirect evidence from populations without PCOS demonstrated no increased risk of lactic acidosis with metformin, only case reports of liver toxicity with flutamide (no comparative evidence), and increased relative risk difference of venous thromboembolism with oral contraceptive pills but very low absolute risk. Evidence on mortality, cardiovascular mortality, and cancer was inconclusive. Drugs commonly used to treat PCOS appear to be associated with very low risk of severe adverse effects although data are extrapolated from other populations.

Analysis of non-Gaussian laser mode guidance and evolution in leaky plasma channels

NASA Astrophysics Data System (ADS)

Djordjevic, Blagoje; Benedetti, Carlo; Schroeder, Carl; Esarey, Eric; Leemans, Wim

2016-10-01

The evolution and propagation of a non-Gaussian laser pulse under varying circumstances, including a typical matched parabolic channel as well as leaky channels, are investigated. It has previously been shown for a Gaussian pulse that matched guiding can be achieved using parabolic plasma channels. In the low power regime, it can be shown directly that for multi-mode pulses there is significant transverse beating. Given the adverse behavior of non-Gaussian pulses in traditional guiding designs, we examine the use of leaky channels to filter out higher modes as a means of optimizing laser conditions. The interaction between different modes can have an adverse effect on the laser pulse as it propagates through the primary channel. To improve guiding of the pulse we propose using leaky channels. Realistic plasma channel profiles are considered. Higher order mode content is lost through the leaky channel, while the fundamental mode remains well-guided. This is demonstrated using both numerical simulations as well as the source-dependent Laguerre-Gaussian modal expansion. In conclusion, an idealized plasma lens based on leaky channels is found to filter out the higher order modes and leave a near-Gaussian profile before the pulse enters the primary channel.

[Intractable diarrhoea and severe weight loss by roflumilast].

PubMed

Horna, Oihana; Toyas, Carla

2013-08-04

Roflumilast is a recently marketed drug, indicated for maintenance treatment of severe chronic obstructive pulmonary disease associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment. The safety data of this drug have always been subjected to controversy and concerns. The Food and Drug Administration rejected the drug after the first evaluation, asking the company to clarify the adverse reactions during the investigation process, the European Medicines Agency approved the drug including a Risk Management Plan, designed to promote a safe use of the drug. During the first months after the marketing process, the Spanish Pharmacovigilance System has already been acquainted of several adverse events notifications; therefore, these patients may be closely monitored, mainly because of digestive and psychiatric disorders. Here we report the case of a female patient who showed a serious digestive clinical profile and a severe weight loss, more than 25% of her initial weight, when a treatment with roflumilast was started. The suspicion of a side effect as the cause of the reported clinical profile and its resolution required 3 hospital admissions. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Transcriptomic and phenotypic profiling in developing zebrafish exposed to thyroid hormone receptor agonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haggard, Derik E.; Noyes, Pamela D.; Waters, Katrina M.

There is a need to develop novel, high-throughput screening and prioritization methods to identify chemicals with adverse estrogen, androgen, and thyroid activity to protect human health and the environment and is of interest to the Endocrine Disruptor Screening Program. The current aim is to explore the utility of zebrafish as a testing paradigm to classify endocrine activity using phenotypically anchored transcriptome profiling. Transcriptome analysis was conducted on embryos exposed to 25 estrogen-, androgen-, or thyroid-active chemicals at a concentration that elicited adverse malformations or mortality at 120 hours post-fertilization in 80% of the animals exposed. Analysis of the top 1000more » significant differentially expressed transcripts across all treatments identified a unique transcriptional and phenotypic profile for thyroid hormone receptor agonists, which can be used as a biomarker screen for potential thyroid hormone agonists.« less

Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: A sex-specific gene profiling analysis.

PubMed

Wang, Hao; Sun, Xuming; Chou, Jeff; Lin, Marina; Ferrario, Carlos M; Zapata-Sudo, Gisele; Groban, Leanne

2017-08-01

Activation of G protein-coupled estrogen receptor (GPER) by its agonist, G1, protects the heart from stressors such as pressure-overload, ischemia, a high-salt diet, estrogen loss, and aging, in various male and female animal models. Due to nonspecific effects of G1, the exact functions of cardiac GPER cannot be concluded from studies using systemic G1 administration. Moreover, global knockdown of GPER affects glucose homeostasis, blood pressure, and many other cardiovascular-related systems, thereby confounding interpretation of its direct cardiac actions. We generated a cardiomyocyte-specific GPER knockout (KO) mouse model to specifically investigate the functions of GPER in cardiomyocytes. Compared to wild type mice, cardiomyocyte-specific GPER KO mice exhibited adverse alterations in cardiac structure and impaired systolic and diastolic function, as measured by echocardiography. Gene deletion effects on left ventricular dimensions were more profound in male KO mice compared to female KO mice. Analysis of DNA microarray data from isolated cardiomyocytes of wild type and KO mice revealed sex-based differences in gene expression profiles affecting multiple transcriptional networks. Gene Set Enrichment Analysis (GSEA) revealed that mitochondrial genes are enriched in GPER KO females, whereas inflammatory response genes are enriched in GPER KO males, compared to their wild type counterparts of the same sex. The cardiomyocyte-specific GPER KO mouse model provides us with a powerful tool to study the functions of GPER in cardiomyocytes. The gene expression profiles of the GPER KO mice provide foundational information for further study of the mechanisms underlying sex-specific cardioprotection by GPER. Copyright © 2016 Elsevier B.V. All rights reserved.

Mechanisms of crystalline silica-induced pulmonary toxicity revealed by global gene expression profiling

PubMed Central

Sellamuthu, Rajendran; Umbright, Christina; Li, Shengqiao; Kashon, Michael; Joseph, Pius

2015-01-01

A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatics analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top ranking biological functions perturbed by silica exposure in A549 cells and rat lungs. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study may result in better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure. PMID:22087542

17D yellow fever vaccines: new insights. A report of a workshop held during the World Congress on medicine and health in the tropics, Marseille, France, Monday 12 September 2005.

PubMed

Barrett, Alan D T; Monath, Thomas P; Barban, Veronique; Niedrig, Matthias; Teuwen, Dirk E

2007-04-12

Yellow fever (YF) is a major health problem in endemic regions of Africa and South America. It also poses a serious health risk to travellers to areas with endemic disease. Currently, there is no effective drug treatment for YF; however, 17D YF vaccines have demonstrated high rates of effectiveness and good safety profiles. This workshop was organized to review key data and issues about YF disease and currently available 17D YF vaccines. Starting with an overview of the current disease epidemiology in Africa and South America and a review of the safety data of 17D YF vaccines, data were then presented demonstrating the genetic stability of multiple production lots of a 17D YF vaccine, the immunological responses of healthy subjects post-vaccination and the long-term immunogenicity of 17D YF vaccines. Finally, the findings of the molecular characterization of 17D YF virus sub-strains recovered from rare, fatal cases of post-vaccination serious adverse events were presented. There was unanimous agreement that current 17D YF vaccines have a highly favourable benefit-risk profile when used in persons at risk of exposure to the YF virus, and that appropriate use of 17D YF vaccines will minimize the occurrence of serious adverse events post-vaccination.

Evaluation of Cytotoxicity, Genotoxicity and Hematotoxicity of the Recombinant Spore-Crystal Complexes Cry1Ia, Cry10Aa and Cry1Ba6 from Bacillus thuringiensis in Swiss Mice

PubMed Central

de Souza Freire, Ingrid; Miranda-Vilela, Ana Luisa; Barbosa, Lilian Carla Pereira; Martins, Erica Soares; Monnerat, Rose Gomes; Grisolia, Cesar Koppe

2014-01-01

The insecticidal properties of Cry-endotoxins from Bacillus thuringiensis (Bt) have long been used as spore-crystals in commercial spray formulations for insect control. Recently, some Bt-endotoxin genes have been cloned in many different plants. Toxicological evaluations of three spore-crystal endotoxins, BtCry1Ia, BtCry10Aa and BtCry1Ba6 from B. thuringiensis, were carried out on mice to understand their adverse effects on hematological systems and on genetic material. These three spore-crystals have shown toxic activity to the boll weevil, which is one of the most aggressive pests of the cotton crop. Cry1Ia, Cry10Aa and Cry1Ba6 did not increase the micronucleus frequency in the peripheral erythrocytes of mice and did not cause changes in the frequency of polychromatic erythrocytes. However, some hematologic disburbances were observed, specifically related to Cry1Ia and Cry1Ba6, respectively, for the erythroid and lymphoid lineage. Thus, although the profile of such adverse side effects can be related to their high level of exposure, which is not commonly found in the environment, results showed that these Bt spore-crystals were not harmless to mice, indicating that each spore-crystal endotoxin presents a characteristic profile of toxicity and might be investigated individually. PMID:25268978

The safety of escitalopram during pregnancy and breastfeeding: a comprehensive review.

PubMed

Bellantuono, Cesario; Bozzi, Francesca; Orsolini, Laura; Catena-Dell'Osso, Mario

2012-11-01

Escitalopram (ESC) is considered one of the most effective selective serotonin reuptake inhibitors for the treatment of major depression. However, little is known on its potential risk of inducing major malformations (MMs) and perinatal complications (PCs). Hence, aim of the present study is to provide a comprehensive review of the available literature on the safety profile of ESC during pregnancy and breastfeeding. MEDLINE and PubMed databases were searched for English language articles by using the following keywords: escitalopram, selective serotonin reuptake inhibitors, major malformations, perinatal complications, pregnancy, and breastfeeding. Although some cases of MMs have been reported after maternal exposure to ESC during early pregnancy, the rate of these adverse events is substantially in the range of those reported in unexposed women. On the contrary, exposure to ESC seems to be significantly associated with some PCs. No adverse effects have been reported in the few studies evaluating its safety during breastfeeding. The available data seem to support the notion that ESC might be considered safe during pregnancy, in particular as far as MMs is concerned. However, similar to other selective serotonin reuptake inhibitors, it could be associated with an increased risk of PCs. Given the paucity of the studies published so far, no definitive conclusions can be drawn on its safety profile during breastfeeding. Copyright © 2012 John Wiley & Sons, Ltd.

Toxicity Profile of a Nutraceutical Formulation Derived from Green Mussel Perna viridis

PubMed Central

Joseph, Deepu; Chakkalakal, Selsa J.

2014-01-01

The short-term (acute) and long-term (subchronic) toxicity profile, mean lethal dose 50 (LD50), and no-observed-adverse-effect level (NOAEL) of a nutraceutical formulation developed from green mussel Perna viridis, which showed in vitro and in vivo anti-inflammatory properties, were evaluated in the present study. The formulation was administered to the male and female Wistar rats at graded doses (0.5, 1.0, and 2.5 g/kg body weight) for two weeks of acute toxicity study and 0.5, 1.0, and 2.0 g/kg body weight for 90 days in subchronic toxicity study. The LD50, variations in clinical signs, changes in body weight, body weight, food/water consumption, organ weight (liver, kidney, spleen, and brain), hematology, serum chemistry, and histopathological changes were evaluated. The LD50 of the formulation was 5,000 mg/kg BW. No test article related mortalities as well as change in body weight, and food and water consumption were observed. No toxicity related significant changes were noted in renal/hepatic function, hematological indices, and serum biochemical parameters between the control and treated groups. Histopathological alterations were not observed in the vital organs of rats. The subchronic NOAEL for the formulation in rats is greater than 2000 mg/kg. This study demonstrated that the green mussel formulation is safe to consume without any adverse effects in the body. PMID:24995298

Aflatoxin effect on erythrocyte profile and histopathology of broilers given different additives

NASA Astrophysics Data System (ADS)

Karimy, M. F.; Sutrisno, B.; Agus, A.; Suryani, A. E.; Istiqomah, L.; Damayanti, E.

2017-12-01

The aim of this study was to evaluate erythrocyte profile and microscopic changes effect of AF induces by low level (57.18 ppb) and chronic exposure (34 days) with administration of additive (Lactobacillus plantarum G7 and methionine). Aflatoxin-contaminated corn was prepared by inoculate Aspergillus flavus FNCC 6002 on corn. Total number of 576 broiler Lohman strain (MB202) unsexed DOC were allocated completely randomized into four treatments and 12 replicates, with 12 broiler chicks each. The treatments as follows: T1 = aflatoxin-contaminated diet, T2 = aflatoxin-contaminated diet + 1% of LAB (w/w), T3 = aflatoxin-contaminated diet + 0.8% of methionine (w/w), and T4 = aflatoxin-contaminated diet + 1% of LAB + 0.8% of methionine (w/w). The effect of treatments was evaluated using ANOVA and the difference among mean treatments were analyzed using DMRT. The result showed that administration of additives had no significant effect (P>0.05) on erythrocyte profile, liver, and bursa of Fabricius. The dose of additive in each treatment (T2, T3, T4) were insufficient to reduce adverse effect of chronic aflatoxicosis. It was concluded that the LAB dose for binding AF (57.18%) should be evaluated and the dose for methionine should be reduced for chronic treatment of aflatoxicosis.

Association of height and pubertal timing with lipoprotein subclass profile: exploring the role of genetic and environmental effects.

PubMed

Jelenkovic, Aline; Bogl, Leonie H; Rose, Richard J; Kangas, Antti J; Soininen, Pasi; Ala-Korpela, Mika; Kaprio, Jaakko; Silventoinen, Karri

2013-01-01

Little is known about the relationship between growth and lipoprotein profile. We aimed to analyze common genetic and environmental factors in the association of height from late childhood to adulthood and pubertal timing with serum lipid and lipoprotein subclass profile. A longitudinal cohort of Finnish twin pairs (FinnTwin12) was analyzed using self-reported height at 11-12, 14, 17 years and measured stature at adult age (21-24 years). Data were available for 719 individual twins including 298 complete pairs. Serum lipids and lipoprotein subclasses were measured by proton nuclear magnetic resonance spectroscopy. Multivariate variance component models for twin data were fitted. Cholesky decomposition was used to partition the phenotypic covariation among traits into additive genetic and unique environmental correlations. In men, the strongest associations for both adult height and puberty were observed with total cholesterol, low-density lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, and low-density lipoprotein particle subclasses (max. r = -0.19). In women, the magnitude of the correlations was weaker (max. r = -0.13). Few associations were detected between height during adolescence and adult lipid profile. Early onset of puberty was related to an adverse lipid profile, but delayed pubertal development in girls was associated with an unfavorable profile, as well. All associations were mediated mainly by additive genetic factors, but unique environmental effects cannot be disregarded. Early puberty and shorter adult height relate to higher concentrations of atherogenic lipids and lipoprotein particles in early adulthood. Common genetic effects behind these phenotypes substantially contribute to the observed associations. Copyright © 2013 Wiley Periodicals, Inc.

Association between Pesticide Profiles Used on Agricultural Fields near Maternal Residences during Pregnancy and IQ at Age 7 Years

PubMed Central

Coker, Eric; Gunier, Robert; Bradman, Asa; Harley, Kim; Kogut, Katherine; Molitor, John; Eskenazi, Brenda

2017-01-01

We previously showed that potential prenatal exposure to agricultural pesticides was associated with adverse neurodevelopmental outcomes in children, yet the effects of joint exposure to multiple pesticides is poorly understood. In this paper, we investigate associations between the joint distribution of agricultural use patterns of multiple pesticides (denoted as “pesticide profiles”) applied near maternal residences during pregnancy and Full-Scale Intelligence Quotient (FSIQ) at 7 years of age. Among a cohort of children residing in California’s Salinas Valley, we used Pesticide Use Report (PUR) data to characterize potential exposure from use within 1 km of maternal residences during pregnancy for 15 potentially neurotoxic pesticides from five different chemical classes. We used Bayesian profile regression (BPR) to examine associations between clustered pesticide profiles and deficits in childhood FSIQ. BPR identified eight distinct clusters of prenatal pesticide profiles. Two of the pesticide profile clusters exhibited some of the highest cumulative pesticide use levels and were associated with deficits in adjusted FSIQ of −6.9 (95% credible interval: −11.3, −2.2) and −6.4 (95% credible interval: −13.1, 0.49), respectively, when compared with the pesticide profile cluster that showed the lowest level of pesticides use. Although maternal residence during pregnancy near high agricultural use of multiple neurotoxic pesticides was associated with FSIQ deficit, the magnitude of the associations showed potential for sub-additive effects. Epidemiologic analysis of pesticides and their potential health effects can benefit from a multi-pollutant approach to analysis. PMID:28486423

Asthma pharmacogenetics and the development of genetic profiles for personalized medicine

PubMed Central

Ortega, Victor E; Meyers, Deborah A; Bleecker, Eugene R

2015-01-01

Human genetics research will be critical to the development of genetic profiles for personalized or precision medicine in asthma. Genetic profiles will consist of gene variants that predict individual disease susceptibility and risk for progression, predict which pharmacologic therapies will result in a maximal therapeutic benefit, and predict whether a therapy will result in an adverse response and should be avoided in a given individual. Pharmacogenetic studies of the glucocorticoid, leukotriene, and β2-adrenergic receptor pathways have focused on candidate genes within these pathways and, in addition to a small number of genome-wide association studies, have identified genetic loci associated with therapeutic responsiveness. This review summarizes these pharmacogenetic discoveries and the future of genetic profiles for personalized medicine in asthma. The benefit of a personalized, tailored approach to health care delivery is needed in the development of expensive biologic drugs directed at a specific biologic pathway. Prior pharmacogenetic discoveries, in combination with additional variants identified in future studies, will form the basis for future genetic profiles for personalized tailored approaches to maximize therapeutic benefit for an individual asthmatic while minimizing the risk for adverse events. PMID:25691813

Androgen deprivation therapy impact on quality of life and cardiovascular health, monitoring therapeutic replacement.

PubMed

Trost, Landon W; Serefoglu, Ege; Gokce, Ahmet; Linder, Brian J; Sartor, Alton O; Hellstrom, Wayne J G

2013-02-01

Androgen deprivation therapy (ADT) is commonly utilized in the management of both localized and advanced adenocarcinoma of the prostate. The use of ADT is associated with several adverse events, physical changes, and development of medical comorbidities/mortality. The current article reviews known adverse events associated with ADT as well as treatment options, where available. Current recommendations and guidelines are cited for ongoing monitoring of patients receiving ADT. A PubMed search of topics relating to ADT and adverse outcomes was performed, with select articles highlighted and reviewed based on level of evidence and overall contribution. Reported outcomes of studies detailing adverse effects of ADT were reviewed and discussed. Where available, randomized trials and meta-analyses were reported. ADT may result in several adverse events including decreased libido, erectile dysfunction, vasomotor symptoms, cognitive, psychological and quality of life impairments, weight gain, sarcopenia, increased adiposity, gynecomastia, reduced penile/testicular size, hair changes, periodontal disease, osteoporosis, increased fracture risk, diabetes and insulin resistance, hyperlipidemia, and anemia. The definitive impact of ADT on lipid profiles, cardiovascular morbidity/mortality, and all-cause mortality is currently unknown with available data. Treatment options to reduce ADT-related adverse events include changing to an intermittent treatment schedule, biophysical therapy, counseling, and pharmacotherapy. Patients treated with ADT are at increased risk of several adverse events and should be routinely monitored for the development of potentially significant morbidity/mortality. Where appropriate, physicians should reduce known risk factors and counsel patients as to known risks and benefits of therapy. © 2013 International Society for Sexual Medicine.

Mitigating adverse event reporting bias in spine surgery.

PubMed

Auerbach, Joshua D; McGowan, Kevin B; Halevi, Marci; Gerling, Michael C; Sharan, Alok D; Whang, Peter G; Maislin, Greg

2013-08-21

Recent articles in the lay press and literature have raised concerns about the ability to report honest adverse event data from industry-sponsored spine surgery studies. To address this, clinical trials may utilize an independent Clinical Events Committee (CEC) to review adverse events and readjudicate the severity and relatedness accordingly. We are aware of no prior study that has quantified either the degree to which investigator bias is present in adverse event reporting or the effect that an independent CEC has on mitigating this potential bias. The coflex Investigational Device Exemption study is a prospective randomized controlled trial comparing coflex (Paradigm Spine) stabilization with lumbar spinal fusion to treat spinal stenosis and spondylolisthesis. Investigators classified the severity of adverse events (mild, moderate, or severe) and their relationship to the surgery and device (unrelated, unlikely, possibly, probably, or definitely). An independent CEC, composed of three spine surgeons without affiliation to the study sponsor, reviewed and reclassified all adverse event reports submitted by the investigators. The CEC reclassified the level of severity, relation to the surgery, and/or relation to the device in 394 (37.3%) of 1055 reported adverse events. The proportion of adverse events that underwent reclassification was similar in the coflex and fusion groups (37.9% compared with 36.0%, p = 0.56). The CEC was 5.3 (95% confidence interval [CI], 2.6 to 10.7) times more likely to upgrade than downgrade the adverse event. The CEC was 7.3 (95% CI, 5.1 to 10.6) times more likely to upgrade than downgrade the relationship to the surgery and 11.6 (95% CI, 7.5 to 18.8) times more likely to upgrade than downgrade the relationship to the device. The status of the investigator's financial interest in the company had little effect on the reclassification of adverse events. Thirty-seven percent of adverse events were reclassified by the CEC; the large majority of the reclassifications were an upgrade in the level of severity or a designation of greater relatedness to the surgery or device. An independent CEC can identify and mitigate potential inherent investigator bias and facilitate an accurate assessment of the safety profile of an investigational device, and a CEC should be considered a requisite component of future clinical trials.

Impact of Life History on Fear Memory and Extinction

PubMed Central

Remmes, Jasmin; Bodden, Carina; Richter, S. Helene; Lesting, Jörg; Sachser, Norbert; Pape, Hans-Christian; Seidenbecher, Thomas

2016-01-01

Behavioral profiles are strongly shaped by an individual's whole life experience. The accumulation of negative experiences over lifetime is thought to promote anxiety-like behavior in adulthood (“allostatic load hypothesis”). In contrast, the “mismatch hypothesis” of psychiatric disease suggests that high levels of anxiety-like behavior are the result of a discrepancy between early and late environment. The aim of the present study was to investigate how different life histories shape the expression of anxiety-like behavior and modulate fear memory. In addition, we aimed to clarify which of the two hypotheses can better explain the modulation of anxiety and fear. For this purpose, male mice grew up under either adverse or beneficial conditions during early phase of life. In adulthood they were further subdivided in groups that either matched or mismatched the condition experienced before, resulting in four different life histories. The main results were: (i) Early life benefit followed by late life adversity caused decreased levels of anxiety-like behavior. (ii) Accumulation of adversity throughout life history led to impaired fear extinction learning. Late life adversity as compared to late life benefit mainly affected extinction training, while early life adversity as compared to early life benefit interfered with extinction recall. Concerning anxiety-like behavior, the results do neither support the allostatic load nor the mismatch hypothesis, but rather indicate an anxiolytic effect of a mismatched early beneficial and later adverse life history. In contrast, fear memory was strongly affected by the accumulation of adverse experiences over the lifetime, therefore supporting allostatic load hypothesis. In summary, this study highlights that anxiety-like behavior and fear memory are differently affected by specific combinations of adverse or beneficial events experienced throughout life. PMID:27757077

Cyclooxygenase-2 inhibitors: promise or peril?

PubMed Central

Mengle-Gaw, Laurel J; Schwartz, Benjamin D

2002-01-01

The discovery of two isoforms of the cyclooxygenase enzyme, COX-1 and COX-2, and the development of COX-2-specific inhibitors as anti-inflammatories and analgesics have offered great promise that the therapeutic benefits of NSAIDs could be optimized through inhibition of COX-2, while minimizing their adverse side effect profile associated with inhibition of COX-1. While COX-2 specific inhibitors have proven to be efficacious in a variety of inflammatory conditions, exposure of large numbers of patients to these drugs in postmarketing studies have uncovered potential safety concerns that raise questions about the benefit/risk ratio of COX-2-specific NSAIDs compared to conventional NSAIDs. This article reviews the efficacy and safety profiles of COX-2-specific inhibitors, comparing them with conventional NSDAIDs. PMID:12467519

Dietary Glutamate Supplementation Ameliorates Mycotoxin-Induced Abnormalities in the Intestinal Structure and Expression of Amino Acid Transporters in Young Pigs

PubMed Central

Wu, Miaomiao; Liao, Peng; Deng, Dun; Liu, Gang; Wen, Qingqi; Wang, Yongfei; Qiu, Wei; Liu, Yan; Wu, Xingli; Ren, Wenkai; Tan, Bie; Chen, Minghong; Xiao, Hao; Wu, Li; Li, Tiejun; Nyachoti, Charles M.; Adeola, Olayiwola; Yin, Yulong

2014-01-01

The purpose of this study was to investigate the hypothesis that dietary supplementation with glutamic acid has beneficial effects on growth performance, antioxidant system, intestinal morphology, serum amino acid profile and the gene expression of intestinal amino acid transporters in growing swine fed mold-contaminated feed. Fifteen pigs (Landrace×Large White) with a mean body weight (BW) of 55 kg were randomly divided into control group (basal feed), mycotoxin group (contaminated feed) and glutamate group (2% glutamate+contaminated feed). Compared with control group, mold-contaminated feed decreased average daily gain (ADG) and increased feed conversion rate (FCR). Meanwhile, fed mold-contaminated feed impaired anti-oxidative system and intestinal morphology, as well as modified the serum amino acid profile in growing pigs. However, supplementation with glutamate exhibited potential positive effects on growth performance of pigs fed mold-contaminated feed, ameliorated the imbalance antioxidant system and abnormalities of intestinal structure caused by mycotoxins. In addition, dietary glutamate supplementation to some extent restored changed serum amino acid profile caused by mold-contaminated feed. In conclusion, glutamic acid may be act as a nutritional regulating factor to ameliorate the adverse effects induced by mycotoxins. PMID:25405987

Molindone for schizophrenia and severe mental illness.

PubMed

Bagnall, A; Fenton, M; Lewis, R; Leitner, M L; Kleijnen, J

2000-01-01

Typical antipsychotic drugs are widely used as the first line treatment for people with schizophrenia. However, the atypical class of antipsychotic drugs is making important inroads into this approach. 'Atypical' is a term widely used to describe some antipsychotics which have a low propensity to produce movement disorders, sedation and raised serum prolactin. There is some suggestion that the different adverse effect profiles of the atypical antipsychotic group make them more acceptable to people with schizophrenia. Molindone has a similar profile to quetiapine (a novel atypical antipsychotic), with very low binding to all receptors. Some authors have suggested that molindone is safer than other 'typical' antipsychotics in that extrapyramidal adverse effects are not usually seen at clinically effective antipsychotic doses and that it should therefore be classed as an atypical antipsychotic. To determine the effects of molindone compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. Electronic searches of Biological Abstracts (1980-1999), The Cochrane Library CENTRAL (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), CINAHL (1982-1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1999), PSYNDEX (1977-1999), and PsycLIT (1974-1999) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. The manufacturer of molindone and authors of trials were contacted. All randomised controlled trials that compared molindone to other treatments for schizophrenia and schizophrenia-like psychoses were included by independent assessment. Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted. Data were excluded if loss to follow up was greater than 50%. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, weighted mean differences (WMD) were calculated. All data were inspected for heterogeneity. Thirteen studies were included in the review. Data for this compound range from very short (10 day) studies of the intramuscular preparation to trials lasting over three months. For measures of global state available data do not justify any conclusions on the comparative efficacy of molindone and placebo. When compared to other typical antipsychotics no difference in effectiveness was evidenced (doctors' RR 1.13, CI 0.69 to 1.86; nurses' RR 1.23, CI 0.82 to 1.86). It is no more or less likely than typical drugs to cause movement disorders, but causes significantly more weight loss (RR 2.78, CI 1.10 to 6.99). The strength of the evidence relating to this compound is limited, owing to small sample size, poor study design, limited outcomes and incomplete reporting. Molindone may be an effective antipsychotic; however, its adverse effect profile does not differ significantly from that of typical antipsychotics, apart from the event of weight loss. At present there is no evidence to suggest that it may have an atypical profile.

Clinical Implications of Cluster Analysis-Based Classification of Acute Decompensated Heart Failure and Correlation with Bedside Hemodynamic Profiles.

PubMed

Ahmad, Tariq; Desai, Nihar; Wilson, Francis; Schulte, Phillip; Dunning, Allison; Jacoby, Daniel; Allen, Larry; Fiuzat, Mona; Rogers, Joseph; Felker, G Michael; O'Connor, Christopher; Patel, Chetan B

2016-01-01

Classification of acute decompensated heart failure (ADHF) is based on subjective criteria that crudely capture disease heterogeneity. Improved phenotyping of the syndrome may help improve therapeutic strategies. To derive cluster analysis-based groupings for patients hospitalized with ADHF, and compare their prognostic performance to hemodynamic classifications derived at the bedside. We performed a cluster analysis on baseline clinical variables and PAC measurements of 172 ADHF patients from the ESCAPE trial. Employing regression techniques, we examined associations between clusters and clinically determined hemodynamic profiles (warm/cold/wet/dry). We assessed association with clinical outcomes using Cox proportional hazards models. Likelihood ratio tests were used to compare the prognostic value of cluster data to that of hemodynamic data. We identified four advanced HF clusters: 1) male Caucasians with ischemic cardiomyopathy, multiple comorbidities, lowest B-type natriuretic peptide (BNP) levels; 2) females with non-ischemic cardiomyopathy, few comorbidities, most favorable hemodynamics; 3) young African American males with non-ischemic cardiomyopathy, most adverse hemodynamics, advanced disease; and 4) older Caucasians with ischemic cardiomyopathy, concomitant renal insufficiency, highest BNP levels. There was no association between clusters and bedside-derived hemodynamic profiles (p = 0.70). For all adverse clinical outcomes, Cluster 4 had the highest risk, and Cluster 2, the lowest. Compared to Cluster 4, Clusters 1-3 had 45-70% lower risk of all-cause mortality. Clusters were significantly associated with clinical outcomes, whereas hemodynamic profiles were not. By clustering patients with similar objective variables, we identified four clinically relevant phenotypes of ADHF patients, with no discernable relationship to hemodynamic profiles, but distinct associations with adverse outcomes. Our analysis suggests that ADHF classification using simultaneous considerations of etiology, comorbid conditions, and biomarker levels, may be superior to bedside classifications.

Metabolic signatures of birthweight in 18 288 adolescents and adults

PubMed Central

Würtz, Peter; Wang, Qin; Niironen, Marjo; Tynkkynen, Tuulia; Tiainen, Mika; Drenos, Fotios; Kangas, Antti J; Soininen, Pasi; Skilton, Michael R; Heikkilä, Kauko; Pouta, Anneli; Kähönen, Mika; Lehtimäki, Terho; Rose, Richard J; Kajantie, Eero; Perola, Markus; Kaprio, Jaakko; Eriksson, Johan G; Raitakari, Olli T; Lawlor, Debbie A; Davey Smith, George; Järvelin, Marjo-Riitta; Ala-Korpela, Mika; Auro, Kirsi

2016-01-01

Background: Lower birthweight is associated with increased susceptibility to cardiometabolic diseases in adulthood, but the underlying molecular pathways are incompletely understood. We examined associations of birthweight with a comprehensive metabolic profile measured in adolescents and adults. Methods: High-throughput nuclear magnetic resonance metabolomics and biochemical assays were used to quantify 87 circulating metabolic measures in seven cohorts from Finland and the UK, comprising altogether 18 288 individuals (mean age 26 years, range 15–75). Metabolic associations with birthweight were assessed by linear regression models adjusted for sex, gestational age and age at blood sampling. The metabolic associations with birthweight were compared with the corresponding associations with adult body mass index (BMI). Results: Lower birthweight adjusted for gestational age was adversely associated with cardiometabolic biomarkers, including lipoprotein subclasses, fatty acids, amino acids and markers of inflammation and impaired liver function (P < 0.0015 for 46 measures). Associations were consistent across cohorts with different ages at metabolic profiling, but the magnitudes were weak. The pattern of metabolic deviations associated with lower birthweight resembled the metabolic signature of higher adult BMI (R2 = 0.77) assessed at the same time as the metabolic profiling. The resemblance indicated that 1 kg lower birthweight is associated with similar metabolic aberrations as caused by 0.92 units higher BMI in adulthood. Conclusions: Lower birthweight adjusted for gestational age is associated with adverse biomarker aberrations across multiple metabolic pathways. Coherent metabolic signatures between lower birthweight and higher adult adiposity suggest that shared molecular pathways may potentially underpin the metabolic deviations. However, the magnitudes of metabolic associations with birthweight are modest in comparison to the effects of adiposity, implying that birthweight is only a weak indicator of the metabolic risk profile in adulthood. PMID:27892411

Profile of deferasirox for the treatment of patients with non-transfusion-dependent thalassemia syndromes.

PubMed

Ricchi, Paolo; Marsella, Maria

2015-01-01

It has been clearly shown that iron overload adds progressively significant morbidity and mortality in patients with non-transfusion-dependent thalassemia (NTDT). The lack of physiological mechanisms to eliminate the excess of iron requires effective iron chelation therapy. The reduced compliance to deferoxamine and the risk of severe hematological adverse events during deferiprone treatment have limited the use of both these drugs to correct iron imbalance in NTDT. According to the principles of evidence-based medicine, following the demonstration of the effectiveness and the safety of deferasirox (Exjade(®)) in a prospective, randomized, controlled trial, deferasirox was approved by the US Food and Drug Administration in May 2013 for the treatment of iron overload associated with NTDT. This review, assessing the available scientific literature, will focus on the profile of DFX in the treatment of non-transfusional hemosiderosis in patients with NTDT.

Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stachel, Shawn J.; Zerbinatti, Celina; Rudd, Michael T.

2016-04-14

Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with anmore » improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.« less

Command generator tracker based direct model reference adaptive tracking guidance for Mars atmospheric entry

NASA Astrophysics Data System (ADS)

Li, Shuang; Peng, Yuming

2012-01-01

In order to accurately deliver an entry vehicle through the Martian atmosphere to the prescribed parachute deployment point, active Mars entry guidance is essential. This paper addresses the issue of Mars atmospheric entry guidance using the command generator tracker (CGT) based direct model reference adaptive control to reduce the adverse effect of the bounded uncertainties on atmospheric density and aerodynamic coefficients. Firstly, the nominal drag acceleration profile meeting a variety of constraints is planned off-line in the longitudinal plane as the reference model to track. Then, the CGT based direct model reference adaptive controller and the feed-forward compensator are designed to robustly track the aforementioned reference drag acceleration profile and to effectively reduce the downrange error. Afterwards, the heading alignment logic is adopted in the lateral plane to reduce the crossrange error. Finally, the validity of the guidance algorithm proposed in this paper is confirmed by Monte Carlo simulation analysis.

Evaluation of safety in clinical use of generic paclitaxel [NK] for injection.

PubMed

Tsukiyama, Ikuto; Hotta, Kazuo; Takeuchi, Masayuki; Onishi, Masahumi; Toyama, Yukio; Saito, Hiroko; Sai, Yoshimichi; Miyamoto, Ken-Ichi; Hasegawa, Takaaki

2012-04-01

The introduction of generic drugs is a favored strategy in reducing medical costs, but some clinicians are often reluctant to use them because of lack of information with regard to their side effects. Generic paclitaxel [NK] differs from the proprietary version, Taxol®, in containing added citric acid and a more pure form of castor oil. However, little information exists regarding the effects of these additives on adverse events such as vascular pain, phlebitis, hypersensitivity and hepatic dysfunction. To compensate for this lack of information and to validate the safety of using generic paclitaxel, we investigated adverse events in response to generic paclitaxel [NK]. Our investigation focused on patients treated with both the proprietary formulation (Taxol® for injection) and the generic version(paclitaxel [NK] for injection)sequentially from April 2008 to March 2009. Adverse events were investigated retrospectively. Incidence of vascular pain, phlebitis and hypersensitivity was similar to that with the original product. Although the expression of some liver enzymes was slightly increased and some gastrointestinal events were reduced following generic paclitaxel [NK] treatment there was no statistically significant difference. The profiles of other adverse events were not significantly different. Increased vascular pain and phlebitis, predicted due to low pH conditions caused by citric acid, were not observed. Similarly, the pure castor oil included in generic paclitaxel [NK] did not influence hypersensitivity and hepatic function. We found no significant differences in our study of proprietary and generic paclitaxel [NK]. Thus, clinicians have no reason for prejudice against using generic paclitaxel [NK] on the basis of increased risk of side effects.

Safety profile of bilastine: 2nd generation H1-antihistamines.

PubMed

Scaglione, F

2012-12-01

Bilastine is a new H1 antagonist with no sedative side effects, no cardiotoxic effects, and no hepatic metabolism. In addition, bilastine has proved to be effective for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. Pharmacological studies have shown that bilastine is highly selective for the H1 receptor in both in vivo and in vitro studies, and with no apparent affinity for other receptors. The absorption of bilastine is fast, linear and dose-proportional; it appears to be safe and well tolerated at all doses levels in healthy population. Multiple administration of bilastine has confirmed the linearity of the kinetic parameters. The distribution in the brain is undetectable. The safety profile in terms of adverse effects is very similar to placebo in all Phase I, II and III clinical trials. Bilastine (20 mg), unlike cetirizine, does not increase alcohol effects on the CNS. Bilastine 20 mg does not increase the CNS depressant effect of lorazepam. Bilastine 20 mg is similar to placebo in the driving test. Therefore, it meets the current criteria for medication used in the treatment of allergic rhinitis and urticaria.

Can Disproportionality Analysis of Post-marketing Case Reports be Used for Comparison of Drug Safety Profiles?

PubMed

Michel, Christiane; Scosyrev, Emil; Petrin, Michael; Schmouder, Robert

2017-05-01

Clinical trials usually do not have the power to detect rare adverse drug reactions. Spontaneous adverse reaction reports as for example available in post-marketing safety databases such as the FDA Adverse Event Reporting System (FAERS) are therefore a valuable source of information to detect new safety signals early. To screen such large data-volumes for safety signals, data-mining algorithms based on the concept of disproportionality have been developed. Because disproportionality analysis is based on spontaneous reports submitted for a large number of drugs and adverse event types, one might consider using these data to compare safety profiles across drugs. In fact, recent publications have promoted this practice, claiming to provide guidance on treatment decisions to healthcare decision makers. In this article we investigate the validity of this approach. We argue that disproportionality cannot be used for comparative drug safety analysis beyond basic hypothesis generation because measures of disproportionality are: (1) missing the incidence denominators, (2) subject to severe reporting bias, and (3) not adjusted for confounding. Hypotheses generated by disproportionality analyses must be investigated by more robust methods before they can be allowed to influence clinical decisions.

Safety of herpes zoster vaccine in the shingles prevention study: a randomized trial.

PubMed

Simberkoff, Michael S; Arbeit, Robert D; Johnson, Gary R; Oxman, Michael N; Boardman, Kathy D; Williams, Heather M; Levin, Myron J; Schmader, Kenneth E; Gelb, Lawrence D; Keay, Susan; Neuzil, Kathleen; Greenberg, Richard N; Griffin, Marie R; Davis, Larry E; Morrison, Vicki A; Annunziato, Paula W

2010-05-04

The herpes zoster vaccine is effective in preventing herpes zoster and postherpetic neuralgia in immunocompetent older adults. However, its safety has not been described in depth. To describe local adverse effects and short- and long-term safety profiles of herpes zoster vaccine in immunocompetent older adults. Randomized, placebo-controlled trial with enrollment from November 1998 to September 2001 and follow-up through April 2004 (mean, 3.4 years). A Veterans Affairs Coordinating Center generated the permutated block randomization scheme, which was stratified by site and age. Participants and follow-up study personnel were blinded to treatment assignments. (ClinicalTrials.gov registration number: NCT00007501) 22 U.S. academic centers. 38 546 immunocompetent adults 60 years or older, including 6616 who participated in an adverse events substudy. Single dose of herpes zoster vaccine or placebo. Serious adverse events and rashes in all participants and inoculation-site events in substudy participants during the first 42 days after inoculation. Thereafter, vaccination-related serious adverse events and deaths were monitored in all participants, and hospitalizations were monitored in substudy participants. After inoculation, 255 (1.4%) vaccine recipients and 254 (1.4%) placebo recipients reported serious adverse events. Local inoculation-site side effects were reported by 1604 (48%) vaccine recipients and 539 (16%) placebo recipients in the substudy. A total of 977 (56.6%) of the vaccine recipients reporting local side effects were aged 60 to 69 years, and 627 (39.2%) were older than 70 years. After inoculation, herpes zoster occurred in 7 vaccine recipients versus 24 placebo recipients. Long-term follow-up (mean, 3.39 years) showed that rates of hospitalization or death did not differ between vaccine and placebo recipients. Participants in the substudy were not randomly selected. Confirmation of reported serious adverse events with medical record data was not always obtained. Herpes zoster vaccine is well tolerated in older, immunocompetent adults. Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development; grants from Merck to the Veterans Affairs Cooperative Studies Program; and the James R. and Jesse V. Scott Fund for Shingles Research.

Adverse morphological development in embryonic zebrafish exposed to environmental concentrations of contaminants individually and in mixture.

PubMed

Kinch, Cassandra D; Kurrasch, Deborah M; Habibi, Hamid R

2016-06-01

Exposure to environmental contaminants has been linked to developmental and reproductive abnormalities leading to infertility, spontaneous abortion, reduced number of offspring, and metabolic disorders. In addition, there is evidence linking environmental contaminants and endocrine disruption to abnormal developmental rate, defects in heart and eye morphology, and alterations in behavior. Notably, these effects could not be explained by interaction with a single hormone receptor. Here, using a whole-organism approach, we investigated morphological changes to developing zebrafish caused by exposure to a number of environmental contaminants, including bisphenol A (BPA), di(2-ethylhexyl)phthalate (DEHP), nonylphenol, and fucosterol at concentrations measured in a local water body (Oldman River, AB), individually and in mixture. Exposure to nanomolar contaminant concentrations resulted in abnormal morphological development, including changes to body length, pericardia (heart), and the head. We also characterize the spatiotemporal expression profiles of estrogen, androgen, and thyroid hormone receptors to demonstrate that localization of these receptors might be mediating contaminant effects on development. Finally, we examined the effects of contaminants singly and in mixture. Combined, our results support the hypothesis that adverse effects of contaminants are not mediated by single hormone receptor signaling, and adversity of contaminants in mixture could not be predicted by simple additive effect of contaminants. The findings provide a framework for better understanding of developmental toxicity of environmental contaminants in zebrafish and other vertebrate species. Copyright © 2016 Elsevier B.V. All rights reserved.

Reporting natural health product related adverse drug reactions: is it the pharmacist's responsibility?

PubMed

Walji, Rishma; Boon, Heather; Barnes, Joanne; Welsh, Sandy; Austin, Zubin; Baker, G Ross

2011-12-01

Herbal medicines and other natural health products (NHPs) are sold in Canadian pharmacies as over-the-counter products, yet there is limited information on their safety and adverse effect profile. Signals of safety concerns associated with medicines can arise through analysis of reports of suspected adverse drug reactions (ADRs) submitted to national pharmacovigilance centres by health professionals, including pharmacists and the public. However, typically such systems experience substantial under-reporting for NHPs. The objective of this paper is to explore pharmacists' experiences with and responses to receiving or identifying reports of suspected ADRs associated with NHPs from pharmacy customers. A qualitative study in which in-depth, semi-structured interviews were conducted with 12 community pharmacists in Toronto, Canada. Pharmacists generally did not submit reports of adverse events associated with NHPs to the national ADR reporting system and cited several barriers, including lack of time, complexity of the reporting process and lack of knowledge about NHPs. Pharmacists who accepted responsibility for adverse event reporting appeared to have different perceptions of their professional role: they saw themselves as 'knowledge generators', contributing to overall healthcare knowledge. Reporting behaviour for suspected ADRs associated with NHPs may be explained by a pharmacist's perception of his/her professional role and perceptions of the relative importance of generating knowledge to share in the wider system of health care. © 2011 The Authors. IJPP © 2011 Royal Pharmaceutical Society.

The Japanese Postmarketing Adverse Event Relief System: A Confluence of Regulatory Science, the Legal System, and Clinical Pharmacology.

PubMed

Tominaga, T; Miyazaki, S; Oniyama, Y; Weber, A D; Kondo, T

2017-08-01

The Japanese Postmarketing Relief System provides for compensation to patients with adverse reactions, based on the acknowledgment that unpredicted adverse events occur inevitably once a drug is marketed. The system also provides new knowledge about the benefit-risk profile of a drug that may be incorporated into product labeling. The system relies on causality assessments that are based on sound clinical pharmacology principles. The system may serve as a model for other countries' healthcare systems. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Latent Classes and Cumulative Impacts of Adverse Childhood Experiences.

PubMed

Barboza, Gia Elise

2018-05-01

Studies of adverse childhood experiences (ACEs) have gauged severity using a cumulative risk (CR) index. Few studies have focused on the nature of the context of adversity and their association with psychosocial outcomes. The objective of this study was to examine the patterning of ACEs and to explore the resultant patterns' association with HIV risk-taking, problem drinking, and depressive symptoms in adulthood. Latent class analysis (LCA) was used to identify homogeneous, mutually exclusive "classes" of 11 of the most commonly used ACEs. The LCA resulted in four high-risk profiles and one low-risk profile, which were labeled: (1) highly abusive and dysfunctional (3.3%; n = 1,983), (2) emotionally abusive alcoholic with parental conflict (6%, n = 3,303), (3) sexual abuse only (4.3%, n = 2,260), (4) emotionally abusive and alcoholic (30.3%, n = 17,460), and (5) normative, low risk (56.3%, n = 32,950). Compared to the low-risk class, each high-risk profile was differentially associated with adult psychosocial outcomes even when the conditional CR within that class was similar. The results further our understanding about the pattern of ACEs and the unique pathways to poor health. Implications for child welfare systems when dealing with individuals who have experienced multiple forms of early childhood maltreatment and/or household dysfunction are discussed.

[Antiepileptic drugs in North America].

PubMed

Akiyama, Tomoyuki; Otsubo, Hiroshi

2010-05-01

In this review study, second-generation antiepileptic drugs (AEDs) (levetiracetam, gabapentin, topiramate, lamotrigine, zonisamide, oxcarbazepine, vigabatrin, pregabalin, rufinamide, tiagabine, lacosamide, and felbamate) and injectable AEDs (levetiracetam, lacosamide, fosphenytoin, lorazepam, and valproic acid) available in North America were compared with those available in Japan. Three second-generation AEDs (gabapentin, topiramate, and lamotrigine) were recently approved in Japan. Levetiracetam is currently under review for approval by the Japanese regulatory agency. An ideal AED would have a broad-spectrum activity to control multiple types of seizures, favorable safety profile, limited potential for drug-drug interaction, many bioequivalent formulations, long half life to allow infrequent administration, and antiepileptogenic effects that may provide a fundamental cure of epileptic patients by suppressing the development of epileptogenic network and neutralizing previously established epileptogenic foci in the brain. The second-generation AEDs have been developed to possess some of these ideal properties. All the second-generation AEDs are efficacious for the treatment of patients with partial seizures. In addition, levetiracetam, topiramate, lamotrigine, and zonisamide are effective for the treatment of patients with generalized tonic-clonic seizures, absences, myoclonic seizures, Lennox-Gastaut syndrome, and West syndrome; however, lamotrigine is not effective for the treatment of patients with myoclonic seizures. Rufinamide and felbamate are useful for the treatment of patients with Lennox-Gastaut syndrome; however owing to its serious adverse effects, including aplastic anemia and hepatic failure, felbamate is used as the last resort for the treatment of patients with intractable seizures. Vigabatrin is particularly effective for the treatment of patients with West syndrome; however, the patients need to be regularly monitored for the development of peripheral visual field defect. Gabapentin, oxcarbazepine, vigabatrin, and tiagabine are ineffective for the treatment of patients with absences and/or myoclonic seizures and may aggravate these conditions. Treatment with levetiracetam or topiramate (off-label use) is the new option for patients with refractory status epilepticus, which is characterized by downregulation of the inhibitory gamma-aminobutyric acid system, because these drugs act via different mechanisms and are rapidly titratable, especially intravenous levetiracetam. The pharmacokinetic profiles of levetiracetam, gabapentin, and pregabalin are favorable: these drugs exhibit minimal protein binding, do not undergo hepatic metabolism, are not involved in any clinically relevant drug interactions, and rarely lead to the development of serious adverse effects. In general, levetiracetam is probably the closest to being the ideal AED because of its broad-spectrum favorable pharmacokinetic profile and safety profile as well as because of the availability of its parenteral formulation. Among the injectable AEDs, fosphenytoin is a water-soluble prodrug and is used to treat patients with status epilepticus. Systemic and local side effects of this drug are fewer than those of phenytoin. Lorazepam, a benzodiazepine is used as the first-line AED for the treatment of patients with status epilepticus. The effects of this drug are more prolonged than those of diazepam. Intravenous administration of valproic acid is regarded as a new treatment option for patients with status epilepticus, because sedative and negative effects on the cardiorespiratory system of this drug are lesser than those of the traditional injectable AEDs. These novel medications will aid the improvement of the quality of life of epileptic patients through improved seizure control and reduced adverse effects.

A network meta-analysis of randomized controlled trials for comparing the effectiveness and safety profile of treatments with marketing authorization for relapsing multiple sclerosis.

PubMed

Hadjigeorgiou, G M; Doxani, C; Miligkos, M; Ziakas, P; Bakalos, G; Papadimitriou, D; Mprotsis, T; Grigoriadis, N; Zintzaras, E

2013-12-01

The relative effectiveness and safety profile of the treatments with marketing authorization for relapsing multiple sclerosis (MS) are not well known because randomized controlled trials with head-to-head comparisons between these treatments do not exist. Thus, a network of multiple-treatments meta-analysis was performed using four clinical outcomes: 'patients free of relapse', 'patients without disease progression', 'patients without MRI progression' and 'patients with adverse events'. Randomized controlled trials (RCTs) on MS were systematically searched in PubMed and Cochrane Central Register of Controlled Trial. The network analysis performed pairwise comparisons between the marketed treatments (Betaferon 250mcg, Avonex 30mcg, Rebif 44mcg, Rebif 22mcg, Aubagio 7 mg, Aubagio 14 mg, Copaxone 20 mg, Tysabri 300 mg, Gilenya 0·5 mg and Novantrone 12 mg/m(2)) using direct and indirect analyses. The analysis included 48 articles, involving 20 455 patients with MS. The direct analysis showed better response for more than one outcome for Gilenya compared with Avonex ('patients free of relapse' and 'patients without MRI progression') and for Betaferon compared with Avonex ('patients without disease progression' and 'patients without MRI progression'). The indirect analysis indicated that Tysabri may have better relative effectiveness compared with the other treatments for two outcomes: 'patients free of relapse' and 'patients without MRI progression'. Regarding 'patients with adverse events', no data were available for all comparisons to make fair inferences. This was an attempt, for the first time, to compare the efficacy and safety profile of existing approved treatments for relapsing MS. Although some treatments have shown better response, the results of the network analysis should be interpreted with caution because of the lack of RCTs with head-to-head comparisons between treatments. © 2013 John Wiley & Sons Ltd.

New antibiotics for healthcare-associated pneumonia.

PubMed

Neuner, Elizabeth A; Ritchie, David J; Micek, Scott T

2009-02-01

Current antibiotics available for the treatment of healthcare-associated pneumonia (HCAP) may result in clinical failure due to resistance development, side effect intolerance, or poor pharmacokinetic-pharmacodynamic profiles. New agents active against common HCAP pathogens are needed. The mechanism of action, spectrum of activity, pharmacokinetics, adverse effects, and clinical efficacy of seven new agents in clinical development or recently approved with either methicillin-resistant Staphylococcus aureus (MRSA) or pseudomonal activity are reviewed. They include doripenem, a new antipseudomonal carbapenem; ceftobiprole and ceftaroline, two anti-MRSA cephalosporins; iclaprim, a selective dihydrofolate reductase antagonist; and three glycopeptides, dalbavancin, telavancin, and oritavancin.

Pharmacological profiling of zebrafish behavior using chemical and genetic classification of sleep-wake modifiers.

PubMed

Nishimura, Yuhei; Okabe, Shiko; Sasagawa, Shota; Murakami, Soichiro; Ashikawa, Yoshifumi; Yuge, Mizuki; Kawaguchi, Koki; Kawase, Reiko; Tanaka, Toshio

2015-01-01

Sleep-wake states are impaired in various neurological disorders. Impairment of sleep-wake states can be an early condition that exacerbates these disorders. Therefore, treating sleep-wake dysfunction may prevent or slow the development of these diseases. Although many gene products are likely to be involved in the sleep-wake disturbance, hypnotics and psychostimulants clinically used are limited in terms of their mode of action and are not without side effects. Therefore, there is a growing demand for developing new hypnotics and psychostimulants with high efficacy and few side effects. Toward this end, animal models are indispensable for use in genetic and chemical screens to identify sleep-wake modifiers. As a proof-of-concept study, we performed behavioral profiling of zebrafish treated with chemical and genetic sleep-wake modifiers. We were able to demonstrate that behavioral profiling of zebrafish treated with hypnotics or psychostimulants from 9 to 10 days post-fertilization was sufficient to identify drugs with specific modes of action. We were also able to identify behavioral endpoints distinguishing GABA-A modulators and hypocretin (hcrt) receptor antagonists and between sympathomimetic and non-sympathomimetic psychostimulants. This behavioral profiling can serve to identify genes related to sleep-wake disturbance associated with various neuropsychiatric diseases and novel therapeutic compounds for insomnia and excessive daytime sleep with fewer adverse side effects.

Double whammy: Adverse childhood events and pain reflect symptomology and quality of life in women in substance abuse treatment.

PubMed

Zlotnick, Cheryl; Lawental, Maayan; Pud, Dorit

2017-03-01

This study examined the profiles of symptoms and health-related quality of life (QOL) of women in substance abuse treatment, comparing those with higher versus lower histories of adverse childhood events (ACE), and those with versus without current pain. Adult women in outpatient substance abuse treatment (n = 30) completed questionnaires (cross-sectional study) on topics including drug use, adverse childhood events (ACE), QOL, functional ability, current pain, and depression. Women with pain indicated significant differences in emotional (p < 0.05), and functional ability (p < 0.01); but no significant differences were found between women with high versus low levels of ACE. Yet, radar plots of women with both current pain and high levels of ACE, versus those without, portrayed a distinctive profile indicating high levels of anxiety and depression. Rather than a checklist, visual composites of symptoms experienced by women in substance abuse treatment illustrates areas of concern in the overall status of women in substance abuse treatment.

Evaluation of the Expression Profile of Extrapyramidal Symptoms Due to Antipsychotics by Data Mining of Japanese Adverse Drug Event Report (JADER) Database.

PubMed

Kose, Eiji; Uno, Kana; Hayashi, Hiroyuki

2017-01-01

 Typical antipsychotics are easily expressed as adverse events such as extrapyramidal symptom (EPS). On the other hand, incidence of adverse events due to atypical antipsychotics is low. Therefore, currently, atypical antipsychotics are widely used to treat schizophrenia. However, it has been reported that there is no difference in the frequency of EPS in atypical and typical antipsychotics. This study aimed to evaluate the expression profile of EPS in atypical and typical antipsychotics treatment using the Japanese Adverse Drug Event Report (JADER) database. We analyzed reports of EPS in the JADER database and calculated the reporting odds ratio (ROR) of antipsychotics potentially associated with EPS. We applied the Weibull shape parameter to time-to-event data in the JADER database. Consequently, there was little information to distinguish between the ROR of atypical and typical antipsychotics. A significant difference related to the time of onset of EPS in both antipsychotics was not recognized. However, when comparing each drug, Paliperidone, Perospirone, Blonanserin, and Aripiprazole were relatively developed as EPS in the early stage. On the other hand, Risperidone, Clozapine, Olanzapine, and Quetiapine were developed as EPS not only at an early stage but also after long-term use. In addition, this finding was suggested from the result of the cumulative incidence of EPS in each drug and of the time-to-onset analysis using Weibull distribution. These findings may contribute to future clinical practice because we revealed the expression profile of EPS in treatment with atypical and typical antipsychotics.

Differential pathway dependency discovery associated with drug response across cancer cell lines* | Office of Cancer Genomics

Cancer.gov

The effort to personalize treatment plans for cancer patients involves the identification of drug treatments that can effectively target the disease while minimizing the likelihood of adverse reactions. In this study, the gene-expression profile of 810 cancer cell lines and their response data to 368 small molecules from the Cancer Therapeutics Research Portal (CTRP) are analyzed to identify pathways with significant rewiring between genes, or differential gene dependency, between sensitive and non-sensitive cell lines.

The use of intraosseous infusions in the operating room.

PubMed

Joseph, Gayatri; Tobias, Joseph D

2008-09-01

The use of an intraosseous (IO) infusion during the anesthetic care of an 8-month-old, 5.4-kg infant with cyanotic congenital heart disease (CHD) is presented. Previous vascular access had resulted in thrombotic occlusion of the upper and lower venous systems. When intravenous access could not be achieved, an IO needle was placed and IO access was used during the surgical procedure. The role of the IO route in the perioperative period is discussed and its adverse effect profile is reviewed.

Species Profiles: Life Histories and Environmental Requirements of Coastal Fishes and Invertebrates (Pacific Southwest). Steelhead.

DTIC Science & Technology

1986-06-01

planning, trout in the Lemhi River, Idaho . The and acquisition of interests in ecological requirements of the two streams threatened with adverse devel...and its effects on insects and fish. B. C., Inst. of Fish., Vancouver. Univ. Idaho Coop. Fish. Res. Unit Bull. 17. Completion Rep. Proj. Anderson, H.W...J. Morris, ed. Symposium, Idaho . Coll. of Forestry, Wildl., ForesT Land Uses and Stream and Range Sciences, Univ. of Idaho , Environment. Oregon State

Treatment of ballism and pseudobulbar affect with sertraline.

PubMed

Okun, M S; Riestra, A R; Nadeau, S E

2001-10-01

The pathogenesis of ballism is uncertain and may involve more than one mechanism; treatment is not always efficacious. To provide evidence of a nondopaminergic mechanism and the potential for a prompt and nearly complete response to a serotonergic agent. Report of 2 separate trials of sertraline hydrochloride in a single patient. Complete remission of symptoms within 48 hours of each drug trial. Sertraline may offer an alternative with a better adverse effect profile than dopamine receptor blockers in the treatment of patients with ballism.

Effects of a low-carbohydrate diet on weight loss and cardiovascular risk factor in overweight adolescents.

PubMed

Sondike, Stephen B; Copperman, Nancy; Jacobson, Marc S

2003-03-01

To compare the effects of a low-carbohydrate (LC) diet with those of a low-fat (LF) diet on weight loss and serum lipids in overweight adolescents. A randomized, controlled 12-week trial. Atherosclerosis prevention referral center. Random, nonblinded assignment of participants referred for weight management. The study group (LC) (n = 16) was instructed to consume <20 g of carbohydrate per day for 2 weeks, then <40 g/day for 10 weeks, and to eat LC foods according to hunger. The control group (LF) (n = 14) was instructed to consume <30% of energy from fat. Diet composition and weight were monitored and recorded every 2 weeks. Serum lipid profiles were obtained at the start of the study and after 12 weeks. The LC group lost more weight (mean, 9.9 +/- 9.3 kg vs 4.1 +/- 4.9 kg, P <.05) and had improvement in non-HDL cholesterol levels (P <.05). There was improvement in LDL cholesterol levels (P <.05) in the LF group but not in the LC group. There were no adverse effects on the lipid profiles of participants in either group. The LC diet appears to be an effective method for short-term weight loss in overweight adolescents and does not harm the lipid profile.

Effectiveness and adverse events of tolvaptan in octogenarians with heart failure. Interim analyses of Samsca Post-Marketing Surveillance In Heart faiLurE (SMILE study).

PubMed

Kinugawa, Koichiro; Inomata, Takayuki; Sato, Naoki; Yasuda, Moriyoshi; Shimakawa, Toshiyuki; Bando, Kosuke; Mizuguchi, Kazuki

2015-01-01

The vasopressin receptor 2 (V2) receptor antagonist tolvaptan is an aquaretic agent that has been found to improve symptoms in patients with congestive heart failure. In this study (SMILE study), we administered tolvaptan to patients aged ≥ 80 years with heart failure accompanied by congestive symptoms and compared its effectiveness and safety profiles in this group with those in patients < 80 years (U-80). The results showed that the effectiveness of tolvaptan in the aged patients was similar to that in U-80 patients. In the safety profile, the incidence rate of thirst was lower in the aged patients than that in U-80 patients (9.6% versus 11.6%, P = 0.0023). Furthermore, the incidence of hypernatremia, defined as ≥ 150 mEq/L in aged patients, was comparable with that in U-80 patients (2.9% versus 3.6%, respectively, P = 0.3657). Based on these findings, tolvaptan has similar effectiveness and safety profiles in aged patients compared with U-80 patients. In addition, we found that a higher starting dose of tolvaptan was markedly associated with the occurrence of hypernatremia exclusively in the aged population; therefore, we recommend that tolvaptan should be started at lower doses in aged patients.

A safety assessment of Coriolus versicolor biomass as a food supplement

PubMed Central

Barros, Ana B.; Ferrão, Jorge; Fernandes, Tito

2016-01-01

Background Coriolus versicolor (CV) is a common mushroom with antitumor, anti-inflammatory, antioxidant, antiviral, antibacterial, and immunomodulatory properties. The existence of these properties has been extensively proven mainly using CV extract; research on the biomass form is scarce. Objective The aim of this study was to investigate the safety of the CV biomass form, as it is commonly used as a food supplement. Design CV biomass powder was dissolved in distilled water and administered daily (2.5, 5.0, and 7.5 g/kg live weight) in single doses by gavage to both female and male Charles River albino rats. Results No adverse or lethal effects were observed as a consequence of the daily administration of CV biomass. In addition, compared with the control group, no abnormal findings were observed at necropsy and histopathological examination. Conclusions A safe profile of CV biomass for human consumption can be inferred from the absence of any remarkable adverse effects in rats. PMID:26969586

Adverse events associated with apremilast use and withdrawal for psoriasis in a real-world setting.

PubMed

Lee, Erica B; Amin, Mina; Egeberg, Alexander; Wu, Jashin J

2018-05-06

Apremilast, a phosphodiesterase-4 inhibitor, is an oral therapy for treatment of psoriasis. Its safety profile is favorable, with side effects including diarrhea, nausea, vomiting, depression, and weight decrease, primarily based on clinical trial data. However, limited research exists on the side effect frequency and subsequent adverse events (AEs) in real-world practice. This retrospective chart review included patients who presented to the dermatology clinic at Kaiser Permanente Los Angeles Medical Center and were treated with apremilast at any time between January 1, 2015 and January 11, 2018. Patients were not included if they did not have at least one follow-up by clinic visit, telephone, or email correspondence after being prescribed apremilast. A total of 77 patients were included. AEs and withdrawal due to AEs were assessed throughout the treatment period from each patient's respective medical record. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) promotes the transgenerational inheritance of adult-onset reproductive dysfunctions through the female germline in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pocar, Paola, E-mail: paola.pocar@unimi.it; Fianda

Endocrine disruptors (EDs) are compounds known to promote transgenerational inheritance of adult-onset disease in subsequent generations after maternal exposure during fetal gonadal development. This study was designed to establish whether gestational and lactational exposure to the plasticizer di(2-ethylhexyl)phthalate (DEHP) at environmental doses promotes transgenerational effects on reproductive health in female offspring, as adults, over three generations in the mouse. Gestating F0 mouse dams were exposed to 0, 0.05, 5 mg/kg/day DEHP in the diet from gestational day 0.5 until the end of lactation. The incidence of adult-onset disease in reproductive function was recorded in F1, F2 and F3 female offspring.more » In adult F1 females, DEHP exposure induced reproductive adverse effects with: i) altered ovarian follicular dynamics with reduced primordial follicular reserve and a larger growing pre-antral follicle population, suggesting accelerated follicular recruitment; ii) reduced oocyte quality and embryonic developmental competence; iii) dysregulation of the expression profile of a panel of selected ovarian and pre-implantation embryonic genes. F2 and F3 female offspring displayed the same altered reproductive morphological phenotype and gene expression profiles as F1, thus showing transgenerational transmission of reproductive adverse effects along the female lineage. These findings indicate that in mice exposure to DEHP at doses relevant to human exposure during gonadal sex determination significantly perturbs the reproductive indices of female adult offspring and subsequent generations. Evidence of transgenerational transmission has important implications for the reproductive health and fertility of animals and humans, significantly increasing the potential biohazards of this toxicant. - Highlights: • Maternal exposure to DEHP transgenerationally affects female reproductive health. • DEHP reduced ovarian follicular reserve up to the third generation. • DEHP reduced oocyte and blastocyst developmental competence up to F3. • DEHP altered expression levels for key genes in ovary and blastocysts up to F4. • DEHP's adverse effects were observed at doses relevant for human exposure.« less

Minimizing adverse events while maintaining clinical improvement in a pediatric attention-deficit/hyperactivity disorder crossover trial with dextroamphetamine and methylphenidate.

PubMed

Ramtvedt, Bjørn E; Aabech, Henning S; Sundet, Kjetil

2014-04-01

The purpose of this study was to investigate whether the availability of both dextroamphetamine and methylphenidate provides an opportunity to minimize adverse events in a pediatric attention-deficit/hyperactivity disorder (ADHD) stimulant trial. Thirty-six medication-naïve children 9-14 years of age, diagnosed with ADHD, were enrolled for 6 weeks in a crossover trial, with 2 weeks of methylphenidate, dextroamphetamine, and a placebo in a randomly assigned, counterbalanced sequence. Barkley's Side-Effect Rating Scale (SERS), rated by parents, was used to assess adverse events. SERS were available for 34 children, and data were analyzed both at the group and the single-subject level. The side-effect profiles of dextroamphetamine and methylphenidate appeared similar at the group level. Overall, insomnia and decreased appetite were the only adverse events associated with the stimulants as compared with placebo. No significant increase from placebo to stimulant conditions was detected on SERS items reflecting emotional symptoms. Furthermore, dextroamphetamine and methylphenidate did not differ from each other on any SERS item, except that dextroamphetamine was associated with higher severity of "insomnia" and a higher prevalence of "unusually happy." Single-subject analyses showed that one or more adverse events were reported in 14 children (41%), and were evenly distributed between those with dextroamphetamine as the drug that showed the greatest reduction in their ADHD symptoms ("best drug") and those with methylphenidate as their best drug. Among children in whom both stimulants were associated with a decrease in ADHD symptoms, a clinically valid difference between the two stimulants in total adverse events score was found in 7 (39%) of the 18 cases. In these children, the availability of both stimulants provided an opportunity to minimize adverse events, while maintaining a reduction in ADHD symptoms. The availability of both dextroamphetamine and methylphenidate may contribute to minimize adverse events in a subsample of children in pediatric ADHD stimulant trials. The study was first registered in clinical trials September 28, 2010. Clinical Trials.gov Identifier: NCT01220440.

Minimizing Adverse Events While Maintaining Clinical Improvement in a Pediatric Attention-Deficit/Hyperactivity Disorder Crossover Trial with Dextroamphetamine and Methylphenidate

PubMed Central

Aabech, Henning S.; Sundet, Kjetil

2014-01-01

Abstract Objective: The purpose of this study was to investigate whether the availability of both dextroamphetamine and methylphenidate provides an opportunity to minimize adverse events in a pediatric attention-deficit/hyperactivity disorder (ADHD) stimulant trial. Methods: Thirty-six medication-naïve children 9–14 years of age, diagnosed with ADHD, were enrolled for 6 weeks in a crossover trial, with 2 weeks of methylphenidate, dextroamphetamine, and a placebo in a randomly assigned, counterbalanced sequence. Barkley's Side-Effect Rating Scale (SERS), rated by parents, was used to assess adverse events. SERS were available for 34 children, and data were analyzed both at the group and the single-subject level. Results: The side-effect profiles of dextroamphetamine and methylphenidate appeared similar at the group level. Overall, insomnia and decreased appetite were the only adverse events associated with the stimulants as compared with placebo. No significant increase from placebo to stimulant conditions was detected on SERS items reflecting emotional symptoms. Furthermore, dextroamphetamine and methylphenidate did not differ from each other on any SERS item, except that dextroamphetamine was associated with higher severity of “insomnia” and a higher prevalence of “unusually happy.” Single-subject analyses showed that one or more adverse events were reported in 14 children (41%), and were evenly distributed between those with dextroamphetamine as the drug that showed the greatest reduction in their ADHD symptoms (“best drug”) and those with methylphenidate as their best drug. Among children in whom both stimulants were associated with a decrease in ADHD symptoms, a clinically valid difference between the two stimulants in total adverse events score was found in 7 (39%) of the 18 cases. In these children, the availability of both stimulants provided an opportunity to minimize adverse events, while maintaining a reduction in ADHD symptoms. Conclusions: The availability of both dextroamphetamine and methylphenidate may contribute to minimize adverse events in a subsample of children in pediatric ADHD stimulant trials. Clinical Trials Registry: The study was first registered in clinical trials September 28, 2010. Clinical Trials.gov Identifier: NCT01220440. PMID:24666268

Spotlight on perampanel in the management of seizures: design, development and an update on place in therapy.

PubMed

Faulkner, Michele A

2017-01-01

Perampanel is a first-in-class antiepileptic medication approved for the treatment of partial (focal) seizures, and as adjunctive treatment for primarily generalized tonic-clonic seizures. The pharmacology, efficacy data, adverse-effect profile, pharmacokinetics and place in therapy are reviewed. Perampanel is indicated for use in patients with epilepsy who are 12 years of age or older. It is the first medication designed specifically to be a non-competitive antagonist at post-synaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors. Efficacy in refractory seizures has been established, and ongoing efficacy demonstrated by post-marketing data. The drug is completely absorbed, and exhibits a half-life that allows for once-daily administration in doses up to 12 mg/day. Drug interactions are minimal, but increased doses may be necessary when given with strong inducers of cytochrome P450 enzymes, including when perampanel is co-administered with other antiepileptics that exhibit this property. The most common adverse effects noted in both clinical trials and post-marketing are dizziness and somnolence. Psychiatric and behavioral adverse events have been documented in both adult and pediatric patients, including those with no corresponding diagnostic history. Perampanel is a novel adjunctive antiepileptic medication that is an effective option for adolescents and adults with partial seizures, and primarily generalized tonic-clonic seizures uncontrolled with other medications.

Spotlight on perampanel in the management of seizures: design, development and an update on place in therapy

PubMed Central

Faulkner, Michele A

2017-01-01

Purpose Perampanel is a first-in-class antiepileptic medication approved for the treatment of partial (focal) seizures, and as adjunctive treatment for primarily generalized tonic–clonic seizures. The pharmacology, efficacy data, adverse-effect profile, pharmacokinetics and place in therapy are reviewed. Summary Perampanel is indicated for use in patients with epilepsy who are 12 years of age or older. It is the first medication designed specifically to be a non-competitive antagonist at post-synaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors. Efficacy in refractory seizures has been established, and ongoing efficacy demonstrated by post-marketing data. The drug is completely absorbed, and exhibits a half-life that allows for once-daily administration in doses up to 12 mg/day. Drug interactions are minimal, but increased doses may be necessary when given with strong inducers of cytochrome P450 enzymes, including when perampanel is co-administered with other antiepileptics that exhibit this property. The most common adverse effects noted in both clinical trials and post-marketing are dizziness and somnolence. Psychiatric and behavioral adverse events have been documented in both adult and pediatric patients, including those with no corresponding diagnostic history. Conclusion Perampanel is a novel adjunctive antiepileptic medication that is an effective option for adolescents and adults with partial seizures, and primarily generalized tonic–clonic seizures uncontrolled with other medications. PMID:29042752

Beyond Ether and Chloroform-A Major Breakthrough With Halothane.

PubMed

Huang, Lisa; Sang, Christine N; Desai, Manisha S

2017-07-01

The use of equipment powered by electricity in the operating room increased the risk of fires in the presence of flammable agents such as ether and cyclopropane. Chloroform was associated with cardiac arrhythmias and liver damage. The introduction of halothane in the late 1950s was heralded as a solution to many problems facing the specialty of anesthesia. We explore whether the manufacturer promptly reported halothane's adverse effects to regulatory agencies and practitioners. We consulted documents submitted by Ayerst Laboratories to federal authorities through the Freedom of Information Act, promotional advertisements, package inserts, published articles, and textbooks. Two major complications associated with the use of halothane, cardiac arrhythmias and the risk of hepatotoxicity, were disclosed by the manufacturer when the drug was first introduced to the US market. Reports appeared timely and complete; there was no apparent attempt to conceal or otherwise downplay these risks. The process of drug discovery and approval for clinical use has always been a lengthy, complex, and extremely expensive undertaking, with only a small minority of compounds receiving approval. The risk of adverse effects or drug interaction directly impacts commercial viability. In the case of halothane, the manufacturer disclosed major adverse effects, and the drug enjoyed decades of popularity until it was replaced by agents with a better drug profile. Copyright © 2017 Elsevier Inc. All rights reserved.

Tiagabine May Reduce Bruxism and Associated Temporomandibular Joint Pain

PubMed Central

Kast, R. E.

2005-01-01

Tiagabine is an anticonvulsant gamma-aminobutyric acid reuptake inhibitor commonly used as an add-on treatment of refractory partial seizures in persons over 12 years old. Four of the 5 cases reported here indicate that tiagabine might also be remarkably effective in suppressing nocturnal bruxism, trismus, and consequent morning pain in the teeth, masticatory musculature, jaw, and temporomandibular joint areas. Tiagabine has a benign adverse-effect profile, is easily tolerated, and retains effectiveness over time. Bed partners of these patients report that grinding noises have stopped; therefore, the tiagabine effect is probably not simply antinociceptive. The doses used to suppress nocturnal bruxism at bedtime (4–8 mg) are lower than those used to treat seizures. PMID:16252740

Effect of penguin and seal excrement on mercury distribution in sediments from the Ross Sea region, East Antarctica.

PubMed

Nie, Yaguang; Liu, Xiaodong; Sun, Liguang; Emslie, Steven D

2012-09-01

Total mercury (Hg) concentration and several other geochemical parameters were determined for five sediment profiles from the Antarctic Ross Sea region. Our data exhibit significant positive correlations between Hg concentration and total organic carbon (TOC) content in all profiles, suggesting the predominant role of organic matter (OM) as a Hg carrier. The OM in the sediments originates primarily from penguin guano and algae. High Hg content in guano and a positive correlation between Hg and a guano bio-element (phosphorus, P) in the ornithogenic sediment profiles (MB6, BI and CC) indicate that Hg was strongly influenced by guano input. The bottom sediments of MB6 with seal hairs contain relatively high Hg. This increase is attributed to the input of seal excrement, suggesting that sedimentary Hg may be an effective trophic-level indicator from seals to penguins. The enrichment factor (EF) for Hg was calculated and the results indicated apparent Hg enrichment in the sediment profiles from the Ross Sea region caused by bio-vectors such as penguins and seals. Compared with typical sediments from other sites in Antarctica and the SQGs (sediment quality guidelines), the total amount of Hg in our study area is still not considered to be adversely high. Copyright © 2012 Elsevier B.V. All rights reserved.

Cutaneous Side-effects of Immunomodulators in MS.

PubMed

Lebrun, C; Bertagna, M; Cohen, M

2011-09-01

Local skin reactions to subcutaneous injections of interferon beta (IFNB) or glatiramer acetate (GA) in multiple sclerosis (MS) are frequent, while severe cutaneous toxicity is rare. Both IFNB and GA are immunomodulatory drugs that have excellent safety profiles and are currently used for treatment of MS. They are administered by SC injection every other day for IFNB-1b, three times a week for IFNB-1a or daily for 20 mg for GA. The most common adverse effects, which occur in approximately 20-60% of patients, include pain, inflammation and induration at the injection sites. Another adverse effect is frank panniculitis followed by localized lipoatrophy at the injection sites, which has been described in half of the patients receiving GA injections but is also described with Subcutaneous IFNB-1b. No guidelines have yet been established for the treatment of skin reactions, which is a frequent point for discussion between neurologists and dermatologists. In addition, no treatment has been found for established lipoatrophy. The prevention and management of cutaneous side-effects include patient education, regular examination and manual palpation of all injection sites. Non-steroid antiinflammatory gels, local corticosteroids or endermology can help patients to resolve side-effects and to continue immunomodulatory treatment.

β-Arrestins: Regulatory Role and Therapeutic Potential in Opioid and Cannabinoid Receptor-Mediated Analgesia

PubMed Central

Bohn, Laura M.

2016-01-01

Pain is a complex disorder with neurochemical and psychological components contributing to the severity, the persistence, and the difficulty in adequately treating the condition. Opioid and cannabinoids are two classes of analgesics that have been used to treat pain for centuries and are arguably the oldest of “pharmacological” interventions used by man. Unfortunately, they also produce several adverse side effects that can complicate pain management. Opioids and cannabinoids act at G protein-coupled receptors (GPCRs), and much of their effects are mediated by the mu-opioid receptor (MOR) and cannabinoid CB1 receptor (CB1R), respectively. These receptors couple to intracellular second messengers and regulatory proteins to impart their biological effects. In this chapter, we review the role of the intracellular regulatory proteins, β-arrestins, in modulating MOR and CB1R and how they influence the analgesic and side-effect profiles of opioid and cannabinoid drugs in vivo. This review of the literature suggests that the development of opioid and cannabinoid agonists that bias MOR and CB1R toward G protein signaling cascades and away from β-arrestin interactions may provide a novel mechanism by which to produce analgesia with less severe adverse effects. PMID:24292843

Safety and effectiveness of iguratimod in patients with rheumatoid arthritis: Final report of a 52-week, multicenter postmarketing surveillance study.

PubMed

Mimori, Tsuneyo; Harigai, Masayoshi; Atsumi, Tatsuya; Fujii, Takao; Kuwana, Masataka; Matsuno, Hiroaki; Momohara, Shigeki; Takei, Syuji; Tamura, Naoto; Takasaki, Yoshinari; Yamamoto, Kazuhiko; Ikeuchi, Satoshi; Kushimoto, Satoru; Koike, Takao

2018-04-27

We evaluated the long-term (52 weeks) safety and effectiveness of iguratimod (IGU) in patients with rheumatoid arthritis (RA). This multicenter, prospective, observational study included all evaluable RA patients who received IGU since its market launch in 2012. We evaluated adverse events (AEs); adverse drug reactions (ADRs); ADRs of special interest, including liver and renal dysfunctions, interstitial lung disease, gastrointestinal and blood disorders, and infection; and change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) at week 52. Safety and effectiveness were analyzed in 2666 and 1614 patients, respectively. The incidences of AEs, serious AEs, ADRs, and serious ADRs were 46.92, 7.35, 38.26, and 4.58%, respectively. The incidence of ADRs peaked at approximately 4 weeks of treatment. Subsequently, the ADR incidence did not increase over time. Improvement of RA activity was shown up to week 52. Long-term treatment with IGU in patients with RA resulted in a tolerable safety profile and an improvement in RA activity. IGU could be considered a useful treatment option for patients with RA.

Levetiracetam for the treatment of alcohol withdrawal syndrome: a multicenter, prospective, randomized, placebo-controlled trial.

PubMed

Richter, Christoph; Hinzpeter, Axel; Schmidt, Folkhard; Kienast, Thorsten; Preuss, Ulrich W; Plenge, Thomas; Heinz, Andreas; Schaefer, Martin

2010-12-01

Treatment of alcohol withdrawal syndrome (AWS) with benzodiazepines is limited by risk of abuse, intoxication, respiratory problems, and liver toxicity. Alternatives such as carbamazepine and valproate may also have safety problems, such as hepatotoxicity or central nervous adverse effects. We therefore investigated the safety and efficacy of levetiracetam (LV), a newer antiepileptic with a potentially favorable adverse-effect profile, for the treatment of AWS. One hundred six patients were enrolled in a prospective, randomized, double-blind, multicenter, placebo-controlled trial. Levetiracetam was administered in a fixed dose schedule over 6 days. Diazepam was added when symptom triggered as rescue medication. Severity of the AWS was measured with the AWS and Clinical Institute Withdrawal Assessment Scale. Although tolerability and safety data were similar in the LV group when compared with placebo, the total daily and weekly dose of diazepam as rescue medication and the severity of alcohol withdrawal symptoms did not differ significantly between groups. Our data so far do not support an additional effect of LV on the reduction of alcohol withdrawal symptoms.

Ontology-Based Combinatorial Comparative Analysis of Adverse Events Associated with Killed and Live Influenza Vaccines

PubMed Central

Sarntivijai, Sirarat; Xiang, Zuoshuang; Shedden, Kerby A.; Markel, Howard; Omenn, Gilbert S.; Athey, Brian D.; He, Yongqun

2012-01-01

Vaccine adverse events (VAEs) are adverse bodily changes occurring after vaccination. Understanding the adverse event (AE) profiles is a crucial step to identify serious AEs. Two different types of seasonal influenza vaccines have been used on the market: trivalent (killed) inactivated influenza vaccine (TIV) and trivalent live attenuated influenza vaccine (LAIV). Different adverse event profiles induced by these two groups of seasonal influenza vaccines were studied based on the data drawn from the CDC Vaccine Adverse Event Report System (VAERS). Extracted from VAERS were 37,621 AE reports for four TIVs (Afluria, Fluarix, Fluvirin, and Fluzone) and 3,707 AE reports for the only LAIV (FluMist). The AE report data were analyzed by a novel combinatorial, ontology-based detection of AE method (CODAE). CODAE detects AEs using Proportional Reporting Ratio (PRR), Chi-square significance test, and base level filtration, and groups identified AEs by ontology-based hierarchical classification. In total, 48 TIV-enriched and 68 LAIV-enriched AEs were identified (PRR>2, Chi-square score >4, and the number of cases >0.2% of total reports). These AE terms were classified using the Ontology of Adverse Events (OAE), MedDRA, and SNOMED-CT. The OAE method provided better classification results than the two other methods. Thirteen out of 48 TIV-enriched AEs were related to neurological and muscular processing such as paralysis, movement disorders, and muscular weakness. In contrast, 15 out of 68 LAIV-enriched AEs were associated with inflammatory response and respiratory system disorders. There were evidences of two severe adverse events (Guillain-Barre Syndrome and paralysis) present in TIV. Although these severe adverse events were at low incidence rate, they were found to be more significantly enriched in TIV-vaccinated patients than LAIV-vaccinated patients. Therefore, our novel combinatorial bioinformatics analysis discovered that LAIV had lower chance of inducing these two severe adverse events than TIV. In addition, our meta-analysis found that all previously reported positive correlation between GBS and influenza vaccine immunization were based on trivalent influenza vaccines instead of monovalent influenza vaccines. PMID:23209624

Wear-Induced Changes in FSW Tool Pin Profile: Effect of Process Parameters

NASA Astrophysics Data System (ADS)

Sahlot, Pankaj; Jha, Kaushal; Dey, G. K.; Arora, Amit

2018-06-01

Friction stir welding (FSW) of high melting point metallic (HMPM) materials has limited application due to tool wear and relatively short tool life. Tool wear changes the profile of the tool pin and adversely affects weld properties. A quantitative understanding of tool wear and tool pin profile is crucial to develop the process for joining of HMPM materials. Here we present a quantitative wear study of H13 steel tool pin profile for FSW of CuCrZr alloy. The tool pin profile is analyzed at multiple traverse distances for welding with various tool rotational and traverse speeds. The results indicate that measured wear depth is small near the pin root and significantly increases towards the tip. Near the pin tip, wear depth increases with increase in tool rotational speed. However, change in wear depth near the pin root is minimal. Wear depth also increases with decrease in tool traverse speeds. Tool pin wear from the bottom results in pin length reduction, which is greater for higher tool rotational speeds, and longer traverse distances. The pin profile changes due to wear and result in root defect for long traverse distance. This quantitative understanding of tool wear would be helpful to estimate tool wear, optimize process parameters, and tool pin shape during FSW of HMPM materials.

A Review of the Novel Application and Potential Adverse Effects of Proton Pump Inhibitors.

PubMed

Yu, Li-Yuan; Sun, Lu-Ning; Zhang, Xue-Hui; Li, Yue-Qi; Yu, Lei; Yuan, Zi-Qing-Yun; Meng, Ling; Zhang, Hong-Wen; Wang, Yong-Qing

2017-05-01

Proton pump inhibitors (PPIs) are known as a class of pharmaceutical agents that target H + /K + -ATPase, which is located in gastric parietal cells. PPIs are widely used in the treatment of gastric acid-related diseases including peptic ulcer disease, erosive esophagitis and gastroesophageal reflux disease, and so on. These drugs present an excellent safety profile and have become one of the most commonly prescribed drugs in primary and specialty care. Except for gastric acid-related diseases, PPIs can also be used in the treatment of Helicobacter pylori infection, viral infections, respiratory system diseases, cancer and so on. Although PPIs are mainly used short term in patients with peptic ulcer disease, nowadays these drugs are increasingly used long term, and frequently for a lifetime, for instance in patients with typical or atypical symptoms of gastroesophageal reflux disease and in NSAID or aspirin users at risk of gastrotoxicity and related complications including hemorrhage, perforation and gastric outlet obstruction. Long-term use of PPIs may lead to potential adverse effects, such as osteoporotic fracture, renal damage, infection (pneumonia and clostridium difficile infection), rhabdomyolysis, nutritional deficiencies (vitamin B12, magnesium and iron), anemia and thrombocytopenia. In this article, we will review some novel uses of PPIs in other fields and summarize the underlying adverse reactions.

Statistical and Ontological Analysis of Adverse Events Associated with Monovalent and Combination Vaccines against Hepatitis A and B Diseases

PubMed Central

Xie, Jiangan; Zhao, Lili; Zhou, Shangbo; He, Yongqun

2016-01-01

Vaccinations often induce various adverse events (AEs), and sometimes serious AEs (SAEs). While many vaccines are used in combination, the effects of vaccine-vaccine interactions (VVIs) on vaccine AEs are rarely studied. In this study, AE profiles induced by hepatitis A vaccine (Havrix), hepatitis B vaccine (Engerix-B), and hepatitis A and B combination vaccine (Twinrix) were studied using the VAERS data. From May 2001 to January 2015, VAERS recorded 941, 3,885, and 1,624 AE case reports where patients aged at least 18 years old were vaccinated with only Havrix, Engerix-B, and Twinrix, respectively. Using these data, our statistical analysis identified 46, 69, and 82 AEs significantly associated with Havrix, Engerix-B, and Twinrix, respectively. Based on the Ontology of Adverse Events (OAE) hierarchical classification, these AEs were enriched in the AEs related to behavioral and neurological conditions, immune system, and investigation results. Twenty-nine AEs were classified as SAEs and mainly related to immune conditions. Using a logistic regression model accompanied with MCMC sampling, 13 AEs (e.g., hepatosplenomegaly) were identified to result from VVI synergistic effects. Classifications of these 13 AEs using OAE and MedDRA hierarchies confirmed the advantages of the OAE-based method over MedDRA in AE term hierarchical analysis. PMID:27694888

An open-label study to assess safety, tolerability, and effectiveness of dextromethorphan/quinidine for pseudobulbar affect in dementia: PRISM II results.

PubMed

Doody, Rachelle S; D'Amico, Stephen; Cutler, Andrew J; Davis, Charles S; Shin, Paul; Ledon, Fred; Yonan, Charles; Siffert, João

2016-12-01

Dextromethorphan (DM)/quinidine (Q) is an approved treatment for pseudobulbar affect (PBA) based on trials in amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness and tolerability for PBA secondary to dementia, stroke, or traumatic brain injury; dementia cohort results are reported. This was an open-label, multicenter, 90 day trial; patients received DM/Q 20/10 mg twice daily. Primary outcome was change in Center for Neurologic Study-Lability Scale (CNS-LS) score. Secondary outcomes included PBA episode count and Clinical and Patient/Caregiver Global Impression of Change scores with respect to PBA (CGI-C/PGI-C). 134 patients were treated. CNS-LS improved by a mean (SD) of 7.2 (6.0) points at Day 90/Endpoint (P<.001) vs. baseline. PBA episodes were reduced 67.7% (P<.001) vs. baseline; global measures showed 77.5% CGI-C and 76.5% PGI-C "much"/"very much" improved. Adverse events included headache (7.5%), urinary tract infection (4.5%), and diarrhea (3.7%); few patients dropped out for adverse events (10.4%). DM/Q significantly reduced PBA symptoms in patients with dementia; reported adverse events were consistent with the known safety profile of DM/Q. Trial Registration clinicaltrials.gov identifier: NCT01799941.

Psychosocial Outcomes 3 to 10 Years After Donation in the Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL)

PubMed Central

Dew, Mary Amanda; DiMartini, Andrea F.; Ladner, Daniela P.; Simpson, Mary Ann; Pomfret, Elizabeth A.; Gillespie, Brenda W.; Merion, Robert M.; Zee, Jarcy; Smith, Abigail R.; Holtzman, Susan; Sherker, Averell H.; Weinrieb, Robert; Fisher, Robert A.; Emond, Jean C.; Freise, Chris E.; Burton, James R.; Butt, Zeeshan

2016-01-01

Background Studies of liver donors’ psychosocial outcomes focus on the short-term and rely largely on quality-of-life measures not specific to donation. We sought to examine long-term donation effects on three psychosocial domains: perceived physical, emotional, and socioeconomic outcomes. Methods Individuals donating 3–10 years previously at nine centers were eligible for telephone surveys. Survey responses were examined descriptively. Cluster analysis was used to identify distinct donor groups based on response profiles across psychosocial domains. Potential predictors of response profiles were evaluated with regression analysis. Results 517 donors (66%) participated (M=5.8 years postdonation, SD=1.9). 15%–48% of donors endorsed current donation-related physical health problems and concerns, and 7%–60% reported socioeconomic concerns (e.g., insurance difficulties, financial expenditures). However, on average, donors experienced high psychological growth, and 90% felt positively about donation. Cluster analysis revealed five donor groups. One group showed high psychological benefit, with little endorsement of physical or socioeconomic concerns (15% of donors). Four groups showed less favorable profiles, with varying combinations of difficulties. The largest such group showed high endorsement of physical concerns and financial expenditures, and only modest psychological benefit (31% of donors). Men and non-Hispanic whites were most likely to have unfavorable response profiles (p<.01). Compared with donors aged 19–30, older donors were less likely to have unfavorable profiles; these differences were significant for donors aged >40–50 (p’s<.008). Conclusions Even many years postdonation, donors report adverse physical and socioeconomic effects, but positive emotional effects as well. Identification of response profiles and predictors may improve targeting of postdonation surveillance and care. PMID:27152918

Adverse Events During a Randomized Trial of Ketamine Versus Co-Administration of Ketamine and Propofol for Procedural Sedation in a Pediatric Emergency Department.

PubMed

Weisz, Keith; Bajaj, Lalit; Deakyne, Sara J; Brou, Lina; Brent, Alison; Wathen, Joseph; Roosevelt, Genie E

2017-07-01

The co-administration of ketamine and propofol (CoKP) is thought to maximize the beneficial profile of each medication, while minimizing the respective adverse effects of each medication. Our objective was to compare adverse events between ketamine monotherapy (KM) and CoKP for procedural sedation and analgesia (PSA) in a pediatric emergency department (ED). This was a prospective, randomized, single-blinded, controlled trial of KM vs. CoKP in patients between 3 and 21 years of age. The attending physician administered either ketamine 1 mg/kg i.v. or ketamine 0.5 mg/kg and propofol 0.5 mg/kg i.v. The physician could administer up to three additional doses of ketamine (0.5 mg/kg/dose) or ketamine/propofol (0.25 mg/kg/dose of each). Adverse events (e.g., respiratory events, cardiovascular events, unpleasant emergence reactions) were recorded. Secondary outcomes included efficacy, recovery time, and satisfaction scores. Ninety-six patients were randomized to KM and 87 patients were randomized to CoKP. There was no difference in adverse events or type of adverse event, except nausea was more common in the KM group. Efficacy of PSA was higher in the KM group (99%) compared to the CoKP group (90%). Median recovery time was the same. Satisfaction scores by providers, including nurses, were higher for KM, although parents were equally satisfied with both sedation regimens. We found no significant differences in adverse events between the KM and CoKP groups. While CoKP is a reasonable choice for pediatric PSA, our study did not demonstrate an advantage of this combination over KM. Copyright © 2017 Elsevier Inc. All rights reserved.

[Analysis of Time-to-onset of Interstitial Lung Disease after the Administration of Small Molecule Molecularly-targeted Drugs].

PubMed

Komada, Fusao

2018-01-01

　The aim of this study was to investigate the time-to-onset of drug-induced interstitial lung disease (DILD) following the administration of small molecule molecularly-targeted drugs via the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report database. DILD datasets for afatinib, alectinib, bortezomib, crizotinib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, temsirolimus, and tofacitinib were used to calculate the median onset times of DILD and the Weibull distribution parameters, and to perform the hierarchical cluster analysis. The median onset times of DILD for afatinib, bortezomib, crizotinib, erlotinib, gefitinib, and nilotinib were within one month. The median onset times of DILD for dasatinib, everolimus, lapatinib, osimertinib, and temsirolimus ranged from 1 to 2 months. The median onset times of the DILD for alectinib, imatinib, and tofacitinib ranged from 2 to 3 months. The median onset times of the DILD for sunitinib and sorafenib ranged from 8 to 9 months. Weibull distributions for these drugs when using the cluster analysis showed that there were 4 clusters. Cluster 1 described a subgroup with early to later onset DILD and early failure type profiles or a random failure type profile. Cluster 2 exhibited early failure type profiles or a random failure type profile with early onset DILD. Cluster 3 exhibited a random failure type profile or wear out failure type profiles with later onset DILD. Cluster 4 exhibited an early failure type profile or a random failure type profile with the latest onset DILD.

Acute and Subchronic Toxicological Evaluations of Allium rotundum L.: A Dietary Plant from Iran.

PubMed

Hosseinzadeh, Leila; Farhangian, Sajad; Hajialyani, Marziyeh; Bahari, Arash; Farzaei, Mohammad Hosein

2018-04-25

Allium rotundum L. is a dietary plant with diverse nutritional and herbal applications. According to its widespread application in Iranians' diets, understanding the possible adverse effects and toxic activities could be of major importance. The aim of this study was to establish the acute and subchronic toxicity profile of the hydroalcoholic extract of Allium rotundum on male and female Wistar rats. The acute study indicated no adverse effect or toxic activity after administration of the extract, suggesting that the LD 50 value is up to 5,000 mg/kg body weight for the extract. The subchronic study at three doses (250, 500, and 750 mg/kg body weight/day) supported the results of acute study and revealed that no abnormal change or toxicity was induced by the extract in both male and female Wistar rats. All the biochemical and hematological parameters of the treated rats were in historical range after long-term administration of the extract. The histopathological examination also revealed no lesion or alteration in the tissue of vital organs (kidney, liver, heart, lung, and spleen). The NOAEL (no observed adverse effect level) value was high enough (greater than 750 mg/kg body weight/ day) to conclude the nontoxic nature of this extract. The safety of this extract was affirmed by the acute and subchronic toxic studies and suggested that this plant could be a proper and effective dietary plant due to its high nutritive value and inherent therapeutic properties.

Intermittent blood pressure control: potential consequences for outcome.

PubMed

Leenen, F H

1999-05-01

Although both blood pressure (BP) and left ventricular (LV) mass at initial evaluation predict future cardiovascular risk, the actual BP and LV mass achieved over years of treatment more clearly relate to cardiovascular event rates. Intermittent compliance or noncompliance is the major reason for uncontrolled hypertension and presumably persistent LV hypertrophy. In general, drugs with rapid onset and short duration of action are not desirable because this profile may lead to large variations in BP lowering effect during actual drug intake and rapid disappearance of the antihypertensive effect with missed doses. In addition, intermittent compliance per se introduces the potential for adverse events. For drugs requiring several dose-titrations (e.g., alpha1-blockers), restarting at full doses may lead to excessive drug action and symptomatic hypotension. For other drugs (e.g., short acting beta-blockers or clonidine-like drugs), sudden discontinuation with intermittent compliance may lead to rebound-enhanced sympathetic responsiveness after one to two days, resulting not only in side effects, but also in adverse events, particularly in patients with (silent) coronary artery disease. The rapid onset, short acting dihydropyridines cause intermittent BP control at each dosing, particularly at higher doses. This intermittent control of BP is even more apparent at dosing intervals that are long relative to the duration of action. Thus, sympathetic activation and potential for adverse events can be anticipated at each dosing unless these drugs are being taken frequently at relatively low doses. For diuretics, angiotensin-converting enzyme inhibitors and angiotensin I receptor blockers, no adverse effects have been identified with intermittent compliance. Intermittent BP control is, in general, not an appropriate approach to the management of hypertension and introduces additional risks depending on the type of antihypertensive drug. In contrast, drugs with slow onset and long duration of action provide a more consistent effect during actual drug intake and a more persistent effect during short periods of noncompliance.

Cumulative trauma, adversity and grief symptoms associated with fronto-temporal regions in life-course persistent delinquent boys.

PubMed

Lansing, Amy E; Virk, Agam; Notestine, Randy; Plante, Wendy Y; Fennema-Notestine, Christine

2016-08-30

Delinquent youth have substantial trauma exposure, with life-course persistent delinquents [LCPD] demonstrating notably elevated cross-diagnostic psychopathology and cognitive deficits. Because adolescents remain in the midst of brain and neurocognitive development, tailored interventions are key to improving functional outcomes. This structural magnetic resonance imaging study compared neuroanatomical profiles of 23 LCPD and 20 matched control adolescent boys. LCPD youth had smaller overall gray matter, and left hippocampal, volumes alongside less cortical surface area and folding within the left pars opercularis and supramarginal cortex. LCPD youth had more adversity-related exposures, and their higher Cumulative Trauma, Adversity and Grief [C-TAG] symptoms were associated with less surface area and folding in the pars opercularis and lingual gyrus. Neuroanatomical differences between LCPD and control youth overlap with data from both maltreatment and antisocial literatures. The affected left frontal regions also share connections to language- and executive-related functions, aligning well with LCPD youths' cognitive and behavioral difficulties. These data also dovetail with research suggesting the possibility of neurodevelopmental delays or disruptions related to cumulative adversity burden. Thus, concurrent treatment of LCPD youths' C-TAG symptoms and, cognitive deficits with overlapping neuroanatomical bases, may be most effective in improving outcomes and optimizing neurodevelopmental trajectories. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A meta-analysis of efficacy and safety of antibodies targeting PD-1/PD-L1 in treatment of advanced nonsmall cell lung cancer

PubMed Central

Wang, Cuihua; Yu, Xuetao; Wang, Wei

2016-01-01

Abstract Background: Nonsmall cell lung cancer (NSCLC)-patients treated with standard chemotherapy experienced progression rapidly. A novel therapy based on programed death 1 (PD-1)/programed death ligand 1 (PD-L1) inhibitors showed an increasing potential in several malignancies including advanced NSCLC. Objectives: This article is a meta-analysis aiming to systematically evaluate the efficacy and safety profiles of PD-1/PD-L1 agents in patients with NSCLC. Data sources: Data were collected from eligible studies searched from PubMed, ScienceDirect, and Web of Science. Synthesis methods: Pooled hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) was estimated to assess the efficacy of PD-1/PD-L1 inhibitors versus docetaxel, pooled odds ratio (OR) was calculated for objective response rate (ORR). The overall frequency was estimated for 1-year OS, 1-year progression-free survival, and ORR. A subgroup analysis among NSCLC patients tested with different epidermal growth factor receptor (EGFR) status was also performed to figure out the relationship between EGFR status and efficacy of PD-1/PD-L1 therapies. OR for occurrence of any grade and grade 3 to 5 treatment-related adverse effect was calculated for evaluating the safety of PD-1/PD-L1 therapies. Results: Nine studies were included in this analysis. The pooled HRs for OS and PFS were 0.68 (95% confidence interval [CI] 0.61–0.75) and 0.83 (95% CI 0.75–0.91), respectively, the pooled OR for ORR was 1.83 (95% CI 1.41–2.36), indicating a significant improvement in OS, PFS, and ORR. In the results of subgroup analysis, the HR for OS in NSCLC patients was 1.05 (95% CI 0.69–1.59) in patients with mutant EGFR and 0.66 (95% CI 0.57–0.77) in patients with wild-type EGFR status. OR for occurrence was 0.36 (95% CI 0.28–0.46) in any grade treatment-related adverse effect and 0.18 (95% CI 0.14–0.22) in grade 3 to 5 treatment-related adverse effect, suggesting a superior safety profile of PD-1/PD-L1 inhibitors. Conclusion: The PD-1/PD-L1 therapy significantly prolonged the OS and improved the ORR, simultaneously lowering the treatment-related adverse effect events versus docetaxel. PMID:28033249

Dual-opioid therapy: changing the paradigm. Introduction.

PubMed

Nicholson, Bruce D

2012-03-01

Morphine sulfate and oxycodone hydrochloride are commonly used for pain management because of their pharmacologic profile, pharmacokinetics, and analgesic potency. However, opioids are associated with a significant adverse event (AE) burden that limits their use in both the acute and the chronic pain settings. Co-administration of opioids demonstrated synergistic analgesia and reduced side effects. Thus, dual-opioid therapy has the potential to enhance the positive analgesic benefits of opioids, while limiting the burden of opioid-related AEs. This symposium proceedings was based on presentations at the 13th World Congress on Pain in August 2010. This program will review the rationale for dual-opioid therapy based on preclinical findings and data from clinical studies showing the efficacy and tolerability profile of a dual-opioid formulation when used to treat acute postoperative pain. Wiley Periodicals, Inc.

Prospective evaluation of 1-day polyethylene glycol-3350 bowel preparation regimen in children.

PubMed

Abbas, Mazen I; Nylund, Cade M; Bruch, Carol J; Nazareno, Luzviminda G; Rogers, Philip L

2013-02-01

The aim of the present study was to evaluate efficacy, safety, and tolerability of a pediatric colonoscopy bowel preparation regimen composed of polyethylene glycol-3350 (PEG-3350) and a sports drink completed in a few hours. A prospective, open-label trial of a colonoscopy bowel preparation in children ages 8 to 18 years that included 238 g of PEG-3350 mixed with 1.9 L of Gatorade completed in a few hours. Efficacy was determined using the Boston Bowel Preparation Scale. Basic metabolic profiles and questionnaires were obtained that assessed for safety, adverse effects, tolerability, and patient acceptability. Forty-six patients completed the study. Patients were predominately boys (56.5%) with a mean age of 14.50 years (SD ± 2.9 years). Forty-three (93.5%) were able to complete the regimen. All of the colonoscopies were completed to the cecum and 84% had terminal ileum visualization. Seventy-seven percent were found to be effective preparations. Nausea/vomiting were the most common reported adverse effect (60%) followed by abdominal pain/cramping (44%) and fatigue/weakness (40%). Overall, the regimen was acceptable with 1 exception being the large volume to drink. There were no clinically significant changes in basic metabolic profiles, although there was a statistically significant decrease in the mean potassium (0.16 mEq/L; P = 0.016), blood urea nitrogen (2.68 mg/dL; P < 0.0001), and carbon dioxide (1.89 mmol/L; P < 0.0001). This study demonstrated that PEG-3350 + Gatorade administered in a few hours is an effective, safe, and moderately tolerable bowel preparation regimen for colonoscopy in children.

Efficacy and safety of biologic therapies for systemic lupus erythematosus treatment: systematic review and meta-analysis.

PubMed

Borba, Helena Hiemisch Lobo; Wiens, Astrid; de Souza, Thais Teles; Correr, Cassyano Januário; Pontarolo, Roberto

2014-04-01

The objectives of this study were to evaluate the efficacy, safety, and tolerability of biologic drugs compared with placebo for systemic lupus erythematosus (SLE) treatment. A systematic review evaluating the efficacy and safety of biologic therapies compared with placebo in adult SLE patients treatment was performed. Data from studies performed before September 2013 were collected from several databases (MEDLINE, Cochrane Library, SCIELO, Scopus, and International Pharmaceutical Abstracts). Study eligibility criteria included randomized, double-blind, placebo-controlled trials; regarding treatment with biologic agents in SLE adult patients; and published in English, German, Portuguese, and Spanish. Extracted data were statistically analyzed in a meta-analysis using the Review Manager (RevMan) 5.1 software. Efficacy outcomes included the SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index) score, the SRI (Systemic Lupus Erythematosus Responder Index), normalization of low C3 (<90 mg/dL), anti-double-stranded DNA positive to negative, and no new BILAG (British Isles Lupus Assessment Group index) 1A or 2B flares. Data on safety profile included adverse events, serious and severe adverse events, death, malignancy, infections, and infusion reactions. We also evaluated withdrawals from treatment due to lack of efficacy or adverse events. Thirteen randomized placebo-controlled trials met the criteria for data extraction for systematic review. A meta-analysis regarding the efficacy and safety of belimumab compared with placebo involving four of these trials was undertaken and the remainder contributed to a meta-analysis of the safety of biologic agents. In addition, two trials allowed the performance of a meta-analysis regarding the efficacy and safety of rituximab compared with placebo. Belimumab was more effective than placebo in most evaluated outcomes. No significant differences in the safety and tolerability data were observed between the belimumab and placebo groups. No differences were observed between the rituximab and placebo groups for the efficacy outcomes or safety parameters. Extracted data from the 13 studies were pooled, allowing assessment of the safety of biologic drugs. The meta-analysis revealed a satisfactory safety profile of these agents when used for SLE treatment, as there were no significant differences between the two evaluated groups (biologic agents and placebo) for all outcomes analyzed. Belimumab exhibited a satisfactory profile regarding efficacy, safety, and tolerability. Rituximab showed no superiority over placebo in terms of efficacy, despite its suitable safety profile. Biologic agents exhibited a good safety profile for SLE treatment, indicating that these agents are promising therapies and should be further investigated.

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

PubMed Central

Solmi, Marco; Murru, Andrea; Pacchiarotti, Isabella; Undurraga, Juan; Veronese, Nicola; Fornaro, Michele; Stubbs, Brendon; Monaco, Francesco; Vieta, Eduard; Seeman, Mary V; Correll, Christoph U; Carvalho, André F

2017-01-01

Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis. PMID:28721057

Effects of air pollution exposure on glucose metabolism in Los Angeles minority children

PubMed Central

Toledo-Corral, CM; Alderete, TL; Habre, R; Berhane, K; Lurmann, FW; Weigensberg, MJ; Goran, MI; Gilliland, FD

2017-01-01

Objective Growing evidence indicates that ambient (AAP: NO2, PM2.5, and O3) and traffic-related (TRAP) air pollutants contribute to metabolic disease risk in adults; however, few studies have examined these relationships in children. Methods Metabolic profiling was performed in 429 overweight and obese African-American and Latino youth living in urban Los Angeles, California. This cross-sectional study estimated individual residential air pollution exposure and used linear regression to examine relationships between air pollution and metabolic outcomes. Results AAP and TRAP exposure were associated with adverse effects on glucose metabolism independent of body fat percent. PM2.5 was associated with 25.0% higher fasting insulin (p<0.001), 8.3% lower insulin sensitivity (SI) (p<0.001), 14.7% higher acute insulin response to glucose (AIRg) (p=0.001), and 1.7% higher fasting glucose (p<0.001). Similar associations were observed for increased NO2 exposure. TRAP from non-freeway roads was associated with 12.1% higher insulin (p<0.001), 6.9% lower SI (p=0.02), 10.8% higher AIRg (p=0.003), and 0.7% higher fasting glucose (p=0.047). Conclusions Elevated air pollution exposure was associated with a metabolic profile that is characteristic of increased risk for type 2 diabetes. These results indicate that increased prior year exposure to air pollution may adversely affect type 2 diabetes-related pathophysiology in overweight and obese minority children. PMID:27923100

Effects of air pollution exposure on glucose metabolism in Los Angeles minority children.

PubMed

Toledo-Corral, C M; Alderete, T L; Habre, R; Berhane, K; Lurmann, F W; Weigensberg, M J; Goran, M I; Gilliland, F D

2018-01-01

Growing evidence indicates that ambient (AAP: NO 2 , PM 2.5 and O 3 ) and traffic-related air pollutants (TRAP) contribute to metabolic disease risk in adults; however, few studies have examined these relationships in children. Metabolic profiling was performed in 429 overweight and obese African-American and Latino youth living in urban Los Angeles, California. This cross-sectional study estimated individual residential air pollution exposure and used linear regression to examine relationships between air pollution and metabolic outcomes. AAP and TRAP exposure were associated with adverse effects on glucose metabolism independent of body fat percent. PM 2.5 was associated with 25.0% higher fasting insulin (p < 0.001), 8.3% lower insulin sensitivity (p < 0.001), 14.7% higher acute insulin response to glucose (p = 0.001) and 1.7% higher fasting glucose (p < 0.001). Similar associations were observed for increased NO 2 exposure. TRAP from non-freeway roads was associated with 12.1% higher insulin (p < 0.001), 6.9% lower insulin sensitivity (p = 0.02), 10.8% higher acute insulin response to glucose (p = 0.003) and 0.7% higher fasting glucose (p = 0.047). Elevated air pollution exposure was associated with a metabolic profile that is characteristic of increased risk for type 2 diabetes. These results indicate that increased prior year exposure to air pollution may adversely affect type 2 diabetes-related pathophysiology in overweight and obese minority children. © 2016 World Obesity Federation.

Double disadvantage: the influence of childhood maltreatment and community violence exposure on adolescent mental health.

PubMed

Cecil, Charlotte A M; Viding, Essi; Barker, Edward D; Guiney, Jo; McCrory, Eamon J

2014-07-01

Childhood maltreatment is a key risk factor for maladjustment and psychopathology. Although maltreated youth are more likely to experience community violence, both forms of adversity are generally examined separately. Consequently, little is known about the unique and interactive effects that characterize maltreatment and community violence exposure (CVE) on mental health. Latent Profile Analysis (LPA) was applied to data from a community sample of high-risk adolescents and young adults (n = 204, M = 18.85) to categorize groups of participants with similar patterns of childhood (i.e. past) maltreatment exposure. Associations between childhood maltreatment, CVE and mental health outcomes were then explored using multivariate regression and moderation analyses. Latent Profile Analysis identified three groups of individuals with low, moderate and severe levels of childhood maltreatment. Maltreatment was associated with more internalizing, externalizing, and trauma-related symptoms. By contrast, CVE showed independent associations with only externalizing and trauma-related symptoms. Typically, childhood maltreatment and CVE exerted additive effects; however, these forms of adversity interacted to predict levels of anger. Exposure to maltreatment and community violence is associated with increased levels of clinical symptoms. However, while maltreatment is associated with increased symptoms across a broad range of mental health domains, the impact of community violence is more constrained, suggesting that these environmental risk factors differentially impact mental health functioning. © 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.

An index of the ratio of inflammatory to antiviral cell types mediates the effects of social adversity and age on chronic illness.

PubMed

Simons, Ronald L; Lei, Man-Kit; Beach, Steven R H; Barr, Ashley B; Cutrona, Carolyn E; Gibbons, Frederick X; Philibert, Robert A

2017-07-01

It is assumed that both social stress and chronological age increase the risk of chronic illness, in part, through their effect on systemic inflammation. Unfortunately, observational studies usually employ single-marker measures of inflammation (e.g., Interleukin-6, C-reactive protein) that preclude strong tests for mediational effects. The present study investigated the extent to which the effects of socioeconomic disadvantage and age on onset of chronic illness is mediated by dominance of the innate (inflammatory) over the acquired (antiviral) components of the immune system. We assessed inflammation using the ratio of inflammatory to antiviral cell types (ITACT Ratio). This approach provided a stronger test of evolutionary arguments regarding the effect of social stress on chronic inflammation than is the case with cytokine measures, and afforded an opportunity to replicate findings obtained utilizing mRNA. We used structural equation modeling and longitudinal data from a sample of 100 middle-age African American women to perform our analyses. Dominance of inflammatory over antiviral cell activity was associated with each of the eight illnesses included in our chronic illness measure. Both socioeconomic disadvantage and age were also associated with inflammatory dominance. Pursuant to the central focus of the study, the effects of socioeconomic adversity and age on increased illness were mediated by our measure of inflammatory dominance. The indirect effect of these variables through inflammatory cell profile was significant, with neither socioeconomic disadvantage nor age showing a significant association with illness once the impact of inflammatory cell profile was taken into account. First, the analysis provides preliminary validation of a new measure of inflammation that is calculated based on the ratio of inflammatory to antiviral white blood cells. Second, our results support the hypothesis that socioeconomic disadvantage and chronological age increase risk for chronic illness in part through their effect on inflammatory processes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Antihistamines and other prognostic factors for adverse outcome in hyperemesis gravidarum

PubMed Central

Fejzo, Marlena S.; Magtira, Aromalyn; Schoenberg, Frederic Paik; MacGibbon, Kimber; Mullin, Patrick; Romero, Roberto; Tabsh, Khalil

2014-01-01

Objective The purpose of this study is to determine the frequency of adverse perinatal outcome in women with hyperemesis gravidarum and identify prognostic factors. Study design This is a case-control study in which outcomes of first pregnancies were compared between 254 women with hyperemesis gravidarum treated with intravenous fluids and 308 controls. Prognostic factors were identified by comparing the clinical profile of patients with hyperemesis gravidarum with a normal and an adverse pregnancy outcome. Binary responses were analyzed using either a Chi-square or Fisher exact test and continuous responses were analyzed using a t-test. Results Women with hyperemesis gravidarum have over a 4-fold increased risk of poor outcome including preterm birth and lower birth weight (p < 0.0001). Among maternal characteristics, only gestational hypertension had an influence on outcome (p < 0.0001). Treatment as an outpatient and/or by alternative medicine (acupuncture/acupressure/Bowen massage) was associated with a positive outcome (p < 0.0089). Poor outcomes were associated with early start of symptoms (p < 0.019), and treatment with methylprednisolone (p < 0.0217), promethazine (p < 0.0386), and other antihistamines [diphenhy- dramine (Benadryl), dimenhydrinate (Gravol), doxylamine (Unisom), hydroxyzine (Vistaril/Atarax), doxylamine and pyridoxine (Diclectin/Bendectin)] (p < 0.0151) independent of effectiveness. Among these medications, only the other antihistamines were prescribed independent of severity: they were effective in less than 20% of cases and were taken by almost 50% of patients with an adverse outcome. Conclusion Poor outcomes are significantly greater in women with HG and are associated with gestational hypertension, early symptoms, and antihistamine use. Given these results, there is an urgent need to address the safety and effectiveness of medications containing antihistamines in women with severe nausea of pregnancy. PMID:23751910

What's Tramadol Got to Do with It? A Case Report of Rebound Hypoglycemia, a Reappraisal and Review of Potential Mechanisms.

PubMed

Odonkor, Charles A; Chhatre, Akhil

2016-01-01

Tramadol has gained traction as an analgesic of choice among pain practicing physicians. However some concerns regarding a previously unlabeled adverse reaction - hypoglycemia - have cast it in a dim light. Prior reports have noted an associated risk of hospitalization for hypoglycemia after tramadol use, but whether tramadol is the main causal agent is poorly understood and the underlying mechanisms are not well delineated. We present a unique case of rebound hypoglycemia as a variation of the theme of tramadol's adverse effect profile in a patient with type 1 diabetes mellitus, and reappraise potential mechanisms underlying this underappreciated phenomenon. A 71-year-old woman presented with right buttock pain and right lateral leg discomfort of 9-month duration. Her physical exam suggested sacroiliac joint (SIJ) etiology, confirmed by magnetic resonance imaging (MRI). She was scheduled for an SIJ-diagnostic and therapeutic block and started on tramadol 50 mg 3 times daily on as needed basis. The patient subsequently developed severe hypoglycemia initially resistant to euglycemia restorative interventions with a rebound episode. Hypoglycemia resolved with oral ingestion of high levels of glucose and the patient was taken off tramadol. Fortunately, she did not require hospitalization. The clinical scenario described is a case of rebound hypoglycemia after tramadol use in a patient with type-1 diabetes naïve to opioid analgesics. The episodes of hypoglycemia aligned perfectly with the anticipated pharmacodynamic and pharmacokinetic properties of tramadol. The specificity and temporality of events after tramadol use in this patient fulfilled causality criteria. Tramadol may cause rebound hypoglycemia in patients via interference of the intrinsic euglycemia-restoration pathways and a blunted autonomic counter-regulatory response to antecedent hypoglycemia. Its use must be tempered by this underappreciated adverse effect profile.Key words: Tramadol, hypoglycemia, sacroiliac joint arthritis, type 1 diabetes mellitus, serotonin uptake inhibitors, glutamate receptor 4.

Monitoring long-term oral corticosteroids

PubMed Central

Mundell, Lewis; Lindemann, Roberta; Douglas, James

2017-01-01

Corticosteroids are synthetic analogues of human hormones normally produced by the adrenal cortex. They have both glucocorticoid and mineralocorticoid properties. The glucocortoid components are anti-inflammatory, immunosuppressive, anti-proliferative and vasoconstrictive. They influence the metabolism of carbohydrate and protein, in addition to playing a key role in the body’s stress response. Mineralocorticoid’s main significance is in the balance of salt and water concentrations. Due to the combination of these effects, corticosteroids can cause many adverse effects. Oral corticosteroids are absorbed systemically and are therefore more likely to cause adverse effects than topical or inhaled corticosteroids. Furthermore, it is assumed that greater duration of treatment will lead to a greater number of adverse effects, and therefore the most at risk group are those taking high dose, long-term oral corticosteroids (LTOC). High dose is defined as a prescription of >5 mg oral prednisolone and long term as duration of treatment >1 month (based on National Institute for Health and Care Excellence guidance for patient’s ’at risk' of systemic side effects). Parameters to be monitored in primary care include weight, blood pressure, triglycerides, glucose and urea and electrolytes. From clinical experience within the general practice setting, the authors propose that these patients do not receive adequate baseline monitoring before starting corticosteroids nor are these markers monitored consistently thereafter. This project intended to evidence this claim, evaluate the adverse effect profile and improve monitoring in this patient group. The initial audit of 22 patients, within a single general practice, detected at least one documented adverse effect in 64% of patients, while 41% reported more than one adverse effect. 45% had recorded weight gain, 18% had recorded osteoporosis, 18% had at least one recorded cataract, 14% had recorded Hypertension, 14% had recorded diabetes mellitus, 9% had recorded dyspepsia and 5% had a recorded psychiatric complaint. All of these recorded conditions were either directly attributed to steroid medication or occurred since LTOC were prescribed. The aim of this project was to increase the percentage of patients on LTOC with complete baseline monitoring to 100%. ’Baseline monitoring' was defined as a measurement taken within the previous 5 years. Although somewhat arbitrary, 5 years was felt to be the maximum timeframe in which monitoring would still be relevant for comparison following introduction of LTOC. Quality improvement methodology was used throughout this project with multiple PDSA (Plan, Study, Do and Act) cycles. Through this, a monitoring system and protocol for patients taking LTOC was developed. As a result of this project, five adverse effects were detected in five different patients. These included two cases of secondary hypertension, one case of diabetes mellitus, one cataract and one case of adrenal insufficiency. 12 out of 20 patients achieved complete baseline monitoring. While this study did not fully achieve its aim, the aim was deliberately ambitious. As not all patients in this study attended for monitoring, a figure of 100% was impossible to achieve. The remaining ’incompletely monitored patients' had some but not all parameters measured. The creation of a staff protocol and increased clinical experience will ensure that complete monitoring takes place in the future. In conclusion, this project has shown that adverse effects from LTOC are prevalent in a single general practice population. It is also shown that monitoring for LTOC adverse effects is inadequate but can be improved relatively easily as skills and competencies from other medication monitoring systems already exist within healthcare settings and are immediately transferable. PMID:29450303

Monitoring long-term oral corticosteroids.

PubMed

Mundell, Lewis; Lindemann, Roberta; Douglas, James

2017-01-01

Corticosteroids are synthetic analogues of human hormones normally produced by the adrenal cortex. They have both glucocorticoid and mineralocorticoid properties. The glucocortoid components are anti-inflammatory, immunosuppressive, anti-proliferative and vasoconstrictive. They influence the metabolism of carbohydrate and protein, in addition to playing a key role in the body's stress response. Mineralocorticoid's main significance is in the balance of salt and water concentrations. Due to the combination of these effects, corticosteroids can cause many adverse effects. Oral corticosteroids are absorbed systemically and are therefore more likely to cause adverse effects than topical or inhaled corticosteroids. Furthermore, it is assumed that greater duration of treatment will lead to a greater number of adverse effects, and therefore the most at risk group are those taking high dose, long-term oral corticosteroids (LTOC). High dose is defined as a prescription of >5 mg oral prednisolone and long term as duration of treatment >1 month (based on National Institute for Health and Care Excellence guidance for patient's 'at risk' of systemic side effects). Parameters to be monitored in primary care include weight, blood pressure, triglycerides, glucose and urea and electrolytes. From clinical experience within the general practice setting, the authors propose that these patients do not receive adequate baseline monitoring before starting corticosteroids nor are these markers monitored consistently thereafter. This project intended to evidence this claim, evaluate the adverse effect profile and improve monitoring in this patient group. The initial audit of 22 patients, within a single general practice, detected at least one documented adverse effect in 64% of patients, while 41% reported more than one adverse effect. 45% had recorded weight gain, 18% had recorded osteoporosis, 18% had at least one recorded cataract, 14% had recorded Hypertension, 14% had recorded diabetes mellitus, 9% had recorded dyspepsia and 5% had a recorded psychiatric complaint. All of these recorded conditions were either directly attributed to steroid medication or occurred since LTOC were prescribed. The aim of this project was to increase the percentage of patients on LTOC with complete baseline monitoring to 100%. 'Baseline monitoring' was defined as a measurement taken within the previous 5 years. Although somewhat arbitrary, 5 years was felt to be the maximum timeframe in which monitoring would still be relevant for comparison following introduction of LTOC. Quality improvement methodology was used throughout this project with multiple PDSA (Plan, Study, Do and Act) cycles. Through this, a monitoring system and protocol for patients taking LTOC was developed. As a result of this project, five adverse effects were detected in five different patients. These included two cases of secondary hypertension, one case of diabetes mellitus, one cataract and one case of adrenal insufficiency. 12 out of 20 patients achieved complete baseline monitoring. While this study did not fully achieve its aim, the aim was deliberately ambitious. As not all patients in this study attended for monitoring, a figure of 100% was impossible to achieve. The remaining 'incompletely monitored patients' had some but not all parameters measured. The creation of a staff protocol and increased clinical experience will ensure that complete monitoring takes place in the future. In conclusion, this project has shown that adverse effects from LTOC are prevalent in a single general practice population. It is also shown that monitoring for LTOC adverse effects is inadequate but can be improved relatively easily as skills and competencies from other medication monitoring systems already exist within healthcare settings and are immediately transferable.

Safety profile of levetiracetam.

PubMed

Arroyo, Santiago; Crawford, Pamela

2003-05-01

A good balance between safety and tolerability is necessary for an antiepileptic drug (AED) to be successful in the management of patients with epilepsy. Levetiracetam is one of the new generation of AEDs licensed as an add-on therapy for the treatment of patients with partial-onset seizures. Leveti-racetam's mechanisms of action are not fully understood. Controlled clinical trials, open-label studies, and postmarketing surveillance indicate that leveti-racetam has a favorable safety profile characterized by little effect on vital signs or clinical laboratory values, reported adverse events that are mild to moderate, and no known drug-drug interactions. The tolerability of levetiracetam may extend to both pediatric and elderly patients based on analyses of small numbers of patients. Tolerability is maintained over the long term. Levetirac-etam does not appear to have a different safety profile in learning-disabled patients. Levetiracetam appears to have a good balance between tolerability and efficacy in the treatment of a wide variety of patients with partial epilepsy.

Rationale for combination therapy in hypertension management: focus on angiotensin receptor blockers and thiazide diuretics.

PubMed

Nash, David T

2007-04-01

Despite recognition that hypertension is a major risk factor for cardiovascular events and mortality, blood pressure control rates remain low in the US population. Reflecting clinical trial results, hypertension management guidelines assert the clinical benefit of achieving current blood pressure goals and indicate that most patients will require 2 or more drugs to reach goal. Well-designed drug combinations counter hypertension via complementary mechanisms that increase antihypertensive efficacy, potentially with lower rates of adverse events than higher dose monotherapy regimens. Lower adverse event rates, in turn, may contribute to greater adherence with treatment. The combination of a low-dose diuretic with agents that block the effects of the renin-angiotensin system (RAS), such as angiotensin receptor blockers, has been found in numerous clinical trials to be highly effective for lowering blood pressure in patients with uncomplicated as well as high-risk hypertension, with a comparable favorable side effect profile compared with monotherapy. Moreover, agents that block the RAS are associated with a lower risk of new-onset diabetes mellitus than other antihypertensive classes. Complementary combinations of antihypertensive agents provide an efficient and effective approach to hypertension management.

Wild Blueberries (Vaccinium myrtillus) Alleviate Inflammation and Hypertension Associated with Developing Obesity in Mice Fed with a High-Fat Diet

PubMed Central

Mykkänen, Otto T.; Huotari, Anne; Herzig, Karl-Heinz; Dunlop, Thomas W.; Mykkänen, Hannu; Kirjavainen, Pirkka V.

2014-01-01

Background Low-grade metabolic inflammation and hypertension are primary mechanisms involved in obesity-associated adverse health effects. Berries, especially Nordic wild blueberries (hereafter referred to as bilberries), represent an important source of dietary anthocyanins, a group of polyphenols with potential beneficial effects to combat obesity-associated metabolic disturbances. Methods The effects of 5% or 10% (w/w) of whole bilberries (BB) were studied on the development of obesity and its metabolic disturbances in C57BL mice fed with a high-fat diet (HFD) for three months. Cytokines, inflammatory cells, systolic blood pressure, glucose tolerance, insulin sensitivity, weight gain, body fat, food consumption and energy metabolism were assessed. Results Bilberries ameliorated type 1 pro-inflammatory responsiveness induced by HFD. This was indicated by the altered cytokine profile and the reduced prevalence of interferon gamma -producing T-cells, in particular T helper type 1 cells. Bilberries also prevented the progression of obesity associated long term increase in systolic blood pressure in mice. Conclusions Bilberries reduce the development of systemic inflammation and prevent the progression of chronic hypertension, thus supporting their potential role in alleviating the adverse health effects associated with developing obesity. PMID:25501421

Influence of arachidonyl-2'-chloroethylamide, a selective cannabinoid CB1 receptor agonist, on the anticonvulsant and acute side-effect potentials of clobazam, lacosamide, and pregabalin in the maximal electroshock-induced seizure model and chimney test in mice.

PubMed

Florek-Luszczki, Magdalena; Zagaja, Miroslaw; Luszczki, Jarogniew J

2015-08-01

The influence of arachidonyl-2'-chloroethylamide (ACEA - a selective cannabinoid CB1 receptor agonist) on the anticonvulsant potency and acute adverse-effect potentials of clobazam, lacosamide, and pregabalin was determined in the maximal electroshock-induced seizure model and chimney test in mice. ACEA (2.5 mg/kg, i.p.) significantly enhanced the anticonvulsant potency of pregabalin in the mouse maximal electroshock-induced seizure model by decreasing the median effective dose (ED50 ) of pregabalin from 125.39 to 78.06 mg/kg (P < 0.05). In contrast, ACEA (2.5 mg/kg) had no significant impact on the anticonvulsant potency of clobazam and lacosamide in the mouse maximal electroshock-induced seizure model. On the other hand, ACEA (2.5 mg/kg) did not affect acute adverse effects of clobazam, lacosamide or pregabalin, and the median toxic doses (TD50 ) for the studied anti-epileptic drugs in combination with ACEA did not differ from the TD50 values as determined for the drugs administered alone in the chimney test. In conclusion, ACEA ameliorates the pharmacological profile of pregabalin, when considering both the anticonvulsant and the acute adverse effects of the drug in preclinical study on animals. The combination of pregabalin with ACEA can be of pivotal importance for patients with epilepsy as a potentially advantageous combination if the results from this study translate into clinical settings. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Moving beyond a descriptive aquatic toxicology: the value of biological process and trait information.

PubMed

Segner, Helmut

2011-10-01

In order to improve the ability to link chemical exposure to toxicological and ecological effects, aquatic toxicology will have to move from observing what chemical concentrations induce adverse effects to more explanatory approaches, that are concepts which build on knowledge of biological processes and pathways leading from exposure to adverse effects, as well as on knowledge on stressor vulnerability as given by the genetic, physiological and ecological (e.g., life history) traits of biota. Developing aquatic toxicology in this direction faces a number of challenges, including (i) taking into account species differences in toxicant responses on the basis of the evolutionarily developed diversity of phenotypic vulnerability to environmental stressors, (ii) utilizing diversified biological response profiles to serve as biological read across for prioritizing chemicals, categorizing them according to modes of action, and for guiding targeted toxicity evaluation; (iii) prediction of ecological consequences of toxic exposure from knowledge of how biological processes and phenotypic traits lead to effect propagation across the levels of biological hierarchy; and (iv) the search for concepts to assess the cumulative impact of multiple stressors. An underlying theme in these challenges is that, in addition to the question of what the chemical does to the biological receptor, we should give increasing emphasis to the question how the biological receptor handles the chemicals, i.e., through which pathways the initial chemical-biological interaction extends to the adverse effects, how this extension is modulated by adaptive or compensatory processes as well as by phenotypic traits of the biological receptor. 2011 Elsevier B.V. All rights reserved.

Brexpiprazole: A Partial Dopamine Agonist for the Treatment of Schizophrenia.

PubMed

Ekinci, Asli; Ekinci, Okan

2018-01-31

Schizophrenia is a chronic and debilitating mental disorder that affects the patient's and their family's life. The disease remains a complicated disorder that is challenging to treat, despite there being a large antipsychotic armamentarium. Brexpiprazole acts both as a partial agonist at the serotonin 5-HT1A and dopamine D2 receptors and as an antagonist at the serotonin 5- HT2A and noradrenaline alpha1B and alpha2C receptors, all with similar potency. This balanced receptor profile may produce promising antipsychotic effects on positive, negative and cognitive symptoms in schizophrenia with minimal adverse effects. This review summarizes the pharmacodynamics and pharmacokinetic profile of brexpiprazole and the clinical trial information pertaining to its effectiveness and safety and tolerability, discusses its best clinical use, and compares its clinical profile to those of other widely used antipsychotic agents. Brexpiprazole demonstrated significant clinical efficacy and had good safety and tolerability in well-designed trials with patients with schizophrenia. This agent may be a useful treatment alternative. However, it will be valuable to consider a long-term observational study that includes an active comparator, especially other second-generation antipsychotics (SGAs), to further evaluate the efficacy and safety of brexpiprazole in the treatment of schizophrenia. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Therapeutic potential of Hibiscus sabdariffa: a review of the scientific evidence].

PubMed

Guardiola, Soledad; Mach, Núria

2014-05-01

Infusion of Hibiscus sabdariffa (H. sabdariffa) is a very popular drink in many parts of the world. Its phytochemical composition is associated to antioxidant, hypotensive, and antiatherosclerotic effects. However, the molecular mechanisms involved in these processes are not well known. The aim of this review was to report the scientific evidence supporting that regular use of H. sabdariffa decreases oxidative stress, atherosclerosis, lipid profile, and blood pressure. A search of recent publications was made in the following specialized electronic databases: Elsevier Journal, SciELO, FSTA, Science Direct, Springer Link, and NCBI. Results of research conducted in clinical trials in humans and in animal models and cell cultures were recorded. Keywords used included Hibiscus sabdariffa, oxidative stress, polyphenols, hypertension, atherosclerosis, and lipid profile. Results of the different articles suggested a possible therapeutic effect of H. sabdariffa extracts on oxidative stress, lipid profile, hypertension, and atherosclerosis thanks to its composition rich in phenolic compounds. Anthocyanins significantly decrease LDL oxidation, inhibit adipogenesis by regulating adipogenic signaling pathways and transcription factors, and modulate gene expression of certain microRNAs. No adverse events or side effects were reported. Further more homogeneous, placebo-controlled studies in humans are needed to state that H. sabdariffa has therapeutic efficacy in humans. Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.

A Phase 1, Single-center, Double-blind, Placebo-controlled Study in Healthy Subjects to Assess the Safety, Tolerability, Clinical Effects, and Pharmacokinetics-Pharmacodynamics of Intravenous Cyclopropyl-methoxycarbonylmetomidate (ABP-700) after a Single Ascending Bolus Dose.

PubMed

Struys, Michel M R F; Valk, Beatrijs I; Eleveld, Douglas J; Absalom, Anthony R; Meyer, Peter; Meier, Sascha; den Daas, Izaak; Chou, Thomas; van Amsterdam, Kai; Campagna, Jason A; Sweeney, Steven P

2017-07-01

Cyclopropyl-methoxycarbonylmetomidate (ABP-700) is a new "soft" etomidate analog. The primary objectives of this first-in-human study were to describe the safety and efficacy of ABP-700 and to determine its maximum tolerated dose. Secondary objectives were to characterize the pharmacokinetics of ABP-700 and its primary metabolite (cyclopropyl-methoxycarbonyl acid), to assess the clinical effects of ABP-700, and to investigate the dose-response and pharmacokinetic/pharmacodynamic relationships. Sixty subjects were divided into 10 cohorts and received an increasing, single bolus of either ABP-700 or placebo. Safety was assessed by clinical laboratory evaluations, infusion-site reactions, continuous monitoring of vital signs, physical examination, adverse event monitoring, and adrenocorticotropic hormone stimulation testing. Clinical effects were assessed with modified observer's assessment of alertness/sedation and Bispectral Index monitoring. Pharmacokinetic parameters were calculated. Stopping criteria were met at 1.00 mg/kg dose. No serious adverse events were reported. Adverse events were dose-dependent and comprised involuntary muscle movement, tachycardia, and ventilatory effects. Adrenocorticotropic hormone stimulation evoked a physiologic cortisol response in all subjects, no different from placebo. Pharmacokinetics were dose-proportional. A three-compartment pharmacokinetic model described the data well. A rapid onset of anesthesia/sedation after bolus administration and also a rapid recovery were observed. A quantitative concentration-effect relationship was described for the modified observer's assessment of alertness/sedation and Bispectral Index. This first-in-human study of ABP-700 shows that ABP-700 was safe and well tolerated after single-bolus injections up to 1.00 mg/kg. Bolus doses of 0.25 and 0.35 mg/kg were found to provide the most beneficial clinical effect versus side-effect profile.

QT Interval Screening in Methadone Maintenance Treatment: Report of a SAMHSA Expert Panel

PubMed Central

Martin, Judith A.; Campbell, Anthony; Killip, Thomas; Kotz, Margaret; Krantz, Mori J.; Kreek, Mary Jeanne; McCarroll, Brian A.; Mehta, Davendra; Payte, J. Thomas; Stimmel, Barry; Taylor, Trusandra; Wilford, Bonnie B.

2014-01-01

In an effort to enhance patient safety in Opioid Treatment Programs (OTPs), the Substance Abuse and Mental Health Services Administration (SAMHSA) convened a multi-disciplinary Expert Panel on the Cardiac Effects of Methadone. Panel members reviewed the literature, regulatory actions, professional guidances, and OTPs’ experiences regarding adverse cardiac events associated with methadone. The Panel concluded that, to the extent possible, every OTP should have a universal Cardiac Risk Management Plan (incorporating clinical assessment, ECG assessment, risk stratification, and prevention of drug interactions) for all patients, and should strongly consider patient-specific risk minimization strategies (such as careful patient monitoring, obtaining ECGs as indicated by a particular patient’s risk profile, and adjusting the methadone dose as needed) for patients with identified risk factors for adverse cardiac events. The Panel also suggested specific modifications to informed consent documents, patient education, staff education, and methadone protocols. PMID:22026519

Inflammatory and mitochondrial gene expression data in GPER-deficient cardiomyocytes from male and female mice.

PubMed

Wang, Hao; Sun, Xuming; Chou, Jeff; Lin, Marina; Ferrario, Carlos M; Zapata-Sudo, Gisele; Groban, Leanne

2017-02-01

We previously showed that cardiomyocyte-specific G protein-coupled estrogen receptor (GPER) gene deletion leads to sex-specific adverse effects on cardiac structure and function; alterations which may be due to distinct differences in mitochondrial and inflammatory processes between sexes. Here, we provide the results of Gene Set Enrichment Analysis (GSEA) based on the DNA microarray data from GPER-knockout versus GPER-intact (intact) cardiomyocytes. This article contains complete data on the mitochondrial and inflammatory response-related gene expression changes that were significant in GPER knockout versus intact cardiomyocytes from adult male and female mice. The data are supplemental to our original research article "Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: a sex-specific gene profiling" (Wang et al., 2016) [1]. Data have been deposited to the Gene Expression Omnibus (GEO) database repository with the dataset identifier GSE86843.

Novel biotherapies are needed in youth mental health.

PubMed

Amminger, G Paul; Berger, Maximus; Rice, Simon M; Davey, Christopher G; Schäfer, Miriam R; McGorry, Patrick D

2017-04-01

Adverse effects and lack of efficacy in a significant number of patients limit pharmaceutical interventions in youth psychiatry. This is exemplified by the fact that no medication is currently approved for the treatment of non-OCD anxiety disorders or major depressive disorder in young people younger than 18 years of age in Australia. Here, emerging biological therapies for youth with mental health problems are discussed. There is an urgent need for more research into biological interventions with acceptable risk-benefit balances. Omega-3 fatty acids, cannabidiol and N-acetylcysteine are currently being evaluated. If initial findings are confirmed, they may offer alternatives with more benign side-effect profiles than existing treatments.

The effect of pharmaceutical intervention on lipid profile in polycystic ovary syndrome.

PubMed

Diamanti-Kandarakis, E; Kandaraki, E; Christakou, C; Panidis, D

2009-07-01

The polycystic ovary syndrome (PCOS), a prevalent endocrinopathy of women, has been associated with a clustering of adverse metabolic features, which co-exist with reproductive dysfunction. Lipid abnormalities are very common in lean as well as obese women with PCOS and should be cautiously considered in the therapeutic management of the syndrome. Clinicians should also critically assess the lipidemic effect of pharmaceutical intervention, primarily aimed at hyperandrogenism, anovulation or insulin resistance. Because dyslipidemia may contribute to long-term cardiometabolic and reproductive sequelae in PCOS, it should be considered as an additional therapeutic target when these patients are assigned to appropriate pharmaceutical treatment.

A Health Assessment of Technical Grade Dinitrotoluene ...

EPA Pesticide Factsheets

Technical grade dinitrotoluene (tgDNT) is a mixture of dinitrotoluene isomers. It is composed of 76% 2,4 DNT and 19% 2,6 DNT with the remaining 5% a combination of the other four dinitrotoluene isomers (2,3 , 2,5 , 3,4 , and 3,5 DNT). The toxicological effects of tgDNT were reviewed and the critical effects were identified by evaluating available human occupational and animal studies mainly via inhalation and oral exposure routes. In occupational studies of workers from DNT manufacturing plants, tgDNT exposure (predominately via the inhalation route) associates with clinical symptoms, adverse reproductive effects, and adverse effects on the cardiovascular system. However, these occupational studies are limited due to co-exposure to other known and/or unknown chemicals and lack of useful exposure information. Oral studies in F344 rats showed that tgDNT has a broad toxicity profile in both males and females including significantly increased reticulocytes and Heinz bodies, increased relative liver weight and kidney weight, spleen hemosiderin and extramedullary hematopoiesis, increased incidence of chronic interstitial nephritis, and hepatotoxicity characterized by increased incidences of hepatocyte necrosis, hyperbasophilic hepatocytes, and hepatocyte megalocytosis . The incidence of testicular degeneration in male rats is also significantly increased by tgDNT. In order to identify the most sensitive non-cancer effect(s), all toxicological endpoints from subchron

Estradiol uptake, toxicity, metabolism, and adverse effects on cadmium-treated amphibian embryos.

PubMed Central

Fridman, Osvaldo; Corró, Lucrecia; Herkovits, Jorge

2004-01-01

The exposure of Bufo arenarum embryos to 25 micromol/L 17beta-estradiol (E2) resulted in 100% lethality within 48 hr, whereas 10 micromol//L E2 was the no observed effect concentration value for short-term chronic (7 days) exposure. The toxicity profile curves show that lethal effects were proportional to the E2 concentration and the time of exposure. The E2 uptake resulted in 20.1 ng E2/mg embryo at 8 hr posttreatment, but 67.3% of this value was achieved during the first 30 min of incubation with this estrogen. Regarding metabolism, the embryos synthesize estrone (E1) from E2 by means of 17beta-hydroxysteroid dehydrogenase. Simultaneous treatments of Bufo arenarum embryos with 1 mg/L Cd2+ and 0.1, 1, or 10 micromol/L E2 enhanced the lethality exerted by cadmium in 76.7, 80, and 83.3% of embryos, respectively. The results indicate that estrogenic endocrine disruptors could have an adverse effect on amphibian embryos and enhance the toxic effect of Cd on amphibian embryos. This study points to the possibility of using the AMPHITOX test as a screening method for potential endocrine disruption as well as the combined effects of chemical mixtures. PMID:15175173

The impact of herbal drug use on adverse drug reaction profiles of patients on antiretroviral therapy in zimbabwe.

PubMed

Mudzviti, Tinashe; Maponga, Charles C; Khoza, Star; Ma, Qing; Morse, Gene D

2012-01-01

Background. The main objective was to determine the impact of herbal drug use on adverse drug reactions in patients on antiretroviral therapy (ART). Methodology. Patients receiving first-line ART from the national roll-out program participated in this cross-sectional study. Participants were interviewed and a data collection sheet was used to collect information from the corresponding medical record. Results. The majority (98.2%) of participants were using at least one herbal drug together with ART. The most common herbal remedies used were Allium Sativum (72.7%), Bidens pilosa (66.0%), Eucalyptus globulus (52.3%), Moringa oleifera (44.1%), Lippia javanica (36.3%), and Peltoforum africanum (34.3%). Two indigenous herbs, Musakavakadzi (OR = 0.25; 95% CI 0.076-0.828) and Peltoforum africanum (OR = 0.495; 95% CI 0.292-0.839) reduced the occurrence of adverse drug events. Conclusions. The use of herbal drugs is high in the HIV-infected population and there is need for pharmacovigilance programs to recognize the role they play in altering ADR profiles.

The Impact of Herbal Drug Use on Adverse Drug Reaction Profiles of Patients on Antiretroviral Therapy in Zimbabwe

PubMed Central

Mudzviti, Tinashe; Maponga, Charles C.; Khoza, Star; Ma, Qing; Morse, Gene D.

2012-01-01

Background. The main objective was to determine the impact of herbal drug use on adverse drug reactions in patients on antiretroviral therapy (ART). Methodology. Patients receiving first-line ART from the national roll-out program participated in this cross-sectional study. Participants were interviewed and a data collection sheet was used to collect information from the corresponding medical record. Results. The majority (98.2%) of participants were using at least one herbal drug together with ART. The most common herbal remedies used were Allium Sativum (72.7%), Bidens pilosa (66.0%), Eucalyptus globulus (52.3%), Moringa oleifera (44.1%), Lippia javanica (36.3%), and Peltoforum africanum (34.3%). Two indigenous herbs, Musakavakadzi (OR = 0.25; 95% CI 0.076–0.828) and Peltoforum africanum (OR = 0.495; 95% CI 0.292–0.839) reduced the occurrence of adverse drug events. Conclusions. The use of herbal drugs is high in the HIV-infected population and there is need for pharmacovigilance programs to recognize the role they play in altering ADR profiles. PMID:22506106

A pharmacovigilance study of adults on highly active antiretroviral therapy, South Africa: 2007 - 2011.

PubMed

Dube, Nomathemba Michell; Summers, Robert; Tint, Khin-San; Mayayise, Guistee

2012-01-01

Of the 1.6 million South African people infected with human immunodeficiency virus (HIV), approximately 970,000 (55%) have been initiated on HAART. Despite these numbers, very little has been published about the safety profile of antiretroviral (ARV) medicines in the country. This study was performed at the Medunsa National Pharmacovigilance Centre and aimed to describe the demographic characteristics of patients enrolled in the pharmacovigilance surveillance study; highly active antiretroviral therapy (HAART) initiation regimen patterns; reasons for regimen changes; and adverse effects of ARV medicines. A cohort study of HIV-infected individuals aged 15 years or older who were on ARV medicines was conducted at four sentinel sites. After HAART initiation, with an average lapse of 17.8 months (range: 0 - 83.8 months), 2,815 patients were enrolled into the study. Results show that patients were observed for 1,606.2 person-years for pharmacy visits (collection of ARV medicines) and 817.1 person-years for clinical visits (consultation with the doctor). Females constituted 69.6% (1,958/2,815) of the study population. Almost all patients initiated HAART on first-line regimens (2,801/2,815). Some patients (6.7%, 190/2,815) dropped out of the study after HAART initiation. Reasons for regimen changes were not recorded for 2.5% (22/891) of the patients who changed regimens. The primary reason for regimen changes was drug-related toxicity (76.1%, 678/891), mostly evident in patients taking first-line regimens. Adverse effects experienced by patients were polyneuropathy (24.0%, 163/678); lipodystrophy (23.9%, 162/678); neuropathy (10.6%, 72/678); and suspected lactic acidosis (3.8%, 26/678). The majority of prescribers complied with the HAART guidelines and initiated most patients on first-line regimens. However, adverse effects are evident in patients taking first-line regimens. We recommend that the Department of Health should introduce less toxic first-line ARV regimens. Future efforts will aim to initiate patients on HAART and enrol them into the study simultaneously to determine early risk profiles of ARV medicines.

Translation, cross-cultural adaptation, and validation of the Bulgarian version of the Liverpool Adverse Event Profile.

PubMed

Kuzmanova, Rumyana; Stefanova, Irina; Velcheva, Irena; Stambolieva, Katerina

2014-10-01

Adverse effects (AEs) of antiepileptic drugs (AEDs) affect the quality of life of patients with epilepsy and their outcomes. There are no questionnaires or studies on the reliability and validity of instruments measuring AEs of AEDs in patients with epilepsy in Bulgarian language. The aim of the present study was the translation, cross-cultural adaptation, and validation of the LAEP in the Bulgarian language in order to use it in the Bulgarian-speaking population in providing a reliable instrument for the clinical monitoring of patients with epilepsy. One hundred thirty-one patients (57 men and 74 women, mean age: 40.13±13.37 years) took part in the investigation. The internal consistency and test-retest reliability were tested by Cronbach's α and ICC estimations. The convergent construct validity was tested by estimating the correlation of the LAEP-BG with the QOLIE-89 and the discriminant validity by evaluating the difference between LAEP-BG scores and clinical parameters such as the type of epilepsy using Kruskal-Wallis ANOVA. The LAEP-BG showed high internal consistency and reliability. The Cronbach's α of the total scale was 0.86. No significant differences between the Cronbach's α coefficients of the total LAEP-BG and original English, Chinese, Spanish, Korean, and Portuguese-Brazilian versions of the questionnaire were observed. The ICCs, which evaluate the test-retest reliability, were higher than the recommended value of 0.75 and determined the strong positive correlations between the first and second examinations. The creation of two subscales "Neurological and psychiatric side effects" and "Non neurological side effects" of the LAEP-BG proposed by us showed good internal consistency (Cronbach's α of 0.85 and 0.71, respectively). The LAEP-BG scores significantly correlated with other questionnaires such as the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) and showed a good discriminative validity between groups with different levels of self-assessed AEs of AEDs. The Bulgarian version of the Liverpool Adverse Event Profile (LAEP) is a reliable and valid tool in assessing the patient-reported AEs of AEDs and their impact on the patient's outcome. Copyright © 2014 Elsevier Inc. All rights reserved.

Aripiprazole in schizophrenia and schizoaffective disorder: A review.

PubMed

Stip, Emmanuel; Tourjman, Valérie

2010-01-01

During the past decade, there has been some progress in the pharmacotherapy of schizophrenia and schizoaffective disorder. Current evidence supports the use of various second-generation, or atypical, antipsychotic medications, although few of these agents have been associated with long-term efficacy and tolerability. Aripiprazole is an atypical antipsychotic that has been found to improve positive and negative symptoms of schizophrenia with a favorable adverse-effect profile. This article reviews the efficacy and tolerability of aripiprazole in the context of recommended management strategies for schizophrenia and schizoaffective disorder, and in comparison with first-generation and other second-generation antipsychotics. A search of MEDLINE (1999-May 2009) was conducted for reports of short- and long-term clinical studies of atypical antipsychotics (including aripiprazole) and meta-analyses of randomized controlled trials comparing first- and second-generation antipsychotics (including aripiprazole) in the treatment of schizophrenia or schizoaffective disorder. The search terms were schizophrenia; schizoaffective disorder; pharmacogenetics; adverse effects; tardive dyskinesia AND atypical antipsychotics; aripiprazole; aripiprazole, schizophrenia, AND double-blind studies; and atypical antipsychotics AND adverse effects. The reference lists of identified articles were reviewed for additional relevant publications. Only full study publications were included. Based on the clinical evidence, including data from short-term (4-8 weeks) and long-term (26-52 weeks) randomized, double-blind clinical trials, aripiprazole has been associated with improvements in positive, negative, cognitive, and affective symptoms of schizophrenia and schizoaffective disorder. It has been associated with long-term (up to 52 weeks) symptom control in schizophrenia, as well as with efficacy in treatment-resistant schizophrenia. Common adverse effects associated with aripiprazole were nausea, insomnia, and agitation. These effects were usually transient. The evidence suggests that aripiprazole is unlikely to be associated with clinically significant weight gain or dyslipidemia, increased prolactin levels, or prolongation of the QTc interval. Compared with placebo, aripiprazole has been reported to have a relatively low potential for inducing metabolic syndrome. Based on the evidence reviewed, aripiprazole monotherapy appears to be effective and well tolerated in treating the positive, negative, and cognitive symptoms of schizophrenia and schizoaffective disorder. It was associated with a low risk for the common adverse effects of antipsychotic therapy, including metabolic and endocrine alterations. 2010 Excerpta Medica Inc. All rights reserved.

Differences in Antipsychotic-Related Adverse Events in Adult, Pediatric, and Geriatric Populations.

PubMed

Sagreiya, Hersh; Chen, Yi-Ren; Kumarasamy, Narmadan A; Ponnusamy, Karthik; Chen, Doris; Das, Amar K

2017-02-26

In recent years, antipsychotic medications have increasingly been used in pediatric and geriatric populations, despite the fact that many of these drugs were approved based on clinical trials in adult patients only. Preliminary studies have shown that the "off-label" use of these drugs in pediatric and geriatric populations may result in adverse events not found in adults. In this study, we utilized the large-scale U.S. Food and Drug Administration (FDA) Adverse Events Reporting System (AERS) database to look at differences in adverse events from antipsychotics among adult, pediatric, and geriatric populations. We performed a systematic analysis of the FDA AERS database using MySQL by standardizing the database using structured terminologies and ontologies. We compared adverse event profiles of atypical versus typical antipsychotic medications among adult (18-65), pediatric (age < 18), and geriatric (> 65) populations. We found statistically significant differences between the number of adverse events in the pediatric versus adult populations with aripiprazole, clozapine, fluphenazine, haloperidol, olanzapine, quetiapine, risperidone, and thiothixene, and between the geriatric versus adult populations with aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, paliperidone, promazine, risperidone, thiothixene, and ziprasidone (p < 0.05, with adjustment for multiple comparisons). Furthermore, the particular types of adverse events reported also varied significantly between each population for aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone (Chi-square, p < 10 -6 ). Diabetes was the most commonly reported side effect in the adult population, compared to behavioral problems in the pediatric population and neurologic symptoms in the geriatric population. We also found discrepancies between the frequencies of reports in AERS and in the literature. Our analysis of the FDA AERS database shows that there are significant differences in both the numbers and types of adverse events among these age groups and between atypical and typical antipsychotics. It is important for clinicians to be mindful of these differences when prescribing antipsychotics, especially when prescribing medications off-label.

Is Diabetes Mellitus a Risk Factor for Poor Outcomes after Left Ventricular Assist Device Placement?

PubMed

Mohamedali, Burhan; Yost, Gardner; Bhat, Geetha

2017-04-01

Diabetes mellitus is associated with adverse outcomes in patients with cardiovascular diseases, including heart failure. Left ventricular assist devices (LVADs) are increasingly used as life-saving therapy for advanced heart failure. The effects of pre-LVAD diabetes on long-term outcomes after LVAD implantation are not well understood. In this study, we retrospectively evaluated the effect of existing diabetes on post-LVAD outcomes. Data on 288 LVAD recipients from 2006 through 2013 were reviewed. Patients were stratified in accordance with their histories of diabetes. Baseline demographic, laboratory, hemodynamic, and echocardiographic information before LVAD placement were reviewed, together with the post-LVAD incidence of major adverse outcomes. Kaplan-Meier analysis and Cox regression analysis were performed. Our cohort comprised 122 patients with diabetes and 166 patients without. The mean glycosylated hemoglobin A 1c level in the diabetes group was 7.4% ± 1.6%. Diabetic patients at baseline had a more adverse medical profile than did nondiabetic patients. There were no differences in major outcomes between the 2 groups other than a higher incidence of hemolysis in the diabetes group: 12 (10%) vs 5 (3%); P =0.02. There was no difference in survival outcomes between the groups. Diabetic patients did not have worse survival or more adverse outcomes than did nondiabetic patients in this study, perhaps because of improved diabetes control, or improvement in biochemical derangements after normalization of cardiac output with LVAD therapy. A diagnosis of diabetes was an independent predictor of hemolysis. Further studies to evaluate the link between hemolysis and diabetes are indicated.

Safety and Outcomes of Open-Label Deferasirox Iron Chelation Therapy for Mucormycosis▿

PubMed Central

Spellberg, Brad; Andes, David; Perez, Mario; Anglim, Anne; Bonilla, Hector; Mathisen, Glenn E.; Walsh, Thomas J.; Ibrahim, Ashraf S.

2009-01-01

We sought to describe the safety profile of open-label, adjunctive deferasirox iron chelation therapy in eight patients with biopsy-proven mucormycosis. Deferasirox was administered for an average of 14 days (range, 7 to 21) at 5 to 20 mg/kg of body weight/day. The only adverse effects attributable to deferasirox were rashes in two patients. Deferasirox treatment was not associated with changes in renal or liver function, complete blood count, or transplant immunosuppressive levels. Thus, deferasirox appears safe as an adjunctive therapy for mucormycosis. PMID:19433555

Select medications that unexpectedly lower HbA1c levels.

PubMed

Tillman, F; Kim, J

2018-04-19

A variety of medication classes are available for diabetes; however, treatment options become limited due to adverse effect profiles and cost. Current diabetes guidelines include agents not originally developed for diabetes treatment, bromocriptine and colesevelam. Other non-diabetes medications demonstrating haemoglobin A1c lowering, including agents for weight loss, depression, anaemia and coronary artery disease, are described in this review article. More research looking into the impact of non-diabetes medications on blood glucose may offer additional diabetes treatment strategies. © 2018 John Wiley & Sons Ltd.

Progress of pharmacogenomic research related to minerals and trace elements.

PubMed

Zeng, Mei-Zi; Tang, Jie; Liu, Zhao-Qian; Zhou, Hong-Hao; Zhang, Wei

2015-10-01

Pharmacogenomics explores the variations in both the benefits and the adverse effects of a drug among patients in a target population by analyzing genomic profiles of individual patients. Minerals and trace elements, which can be found in human tissues and maintain normal physiological functions, are also in the focus of pharmacogenomic research. Single-nucleotide polymorphisms (SNPs) affect the metabolism, disposition and efficacy of minerals and trace elements in humans, resulting in changes of body function. This review describes some of the recent progress in pharmacogenomic research related to minerals and trace elements.

A comparative safety review between GLP-1 receptor agonists and SGLT2 inhibitors for diabetes treatment.

PubMed

Consoli, Agostino; Formoso, Gloria; Baldassarre, Maria Pompea Antonia; Febo, Fabrizio

2018-03-01

Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose cotransporter 2 inhibitors (SGLT2i) are of particular interest in type 2 diabetes treatment strategies, due to their efficacy in reducing HbA1c with a low risk of hypoglycaemia, to their positive effects on body weight and blood pressure and in light of their effects on cardiovascular risk and on nephroprotection emerged from the most recent cardiovascular outcome trials. Since it is therefore very likely that GLP-1RA and SGLT2i use will become more and more common, it is more and more important to gather and discuss information about their safety profile. Area Covered: adverse events and the safety concerns most often emerged in trials with GLP-1RA namely, exenatide long acting release (LAR), dulaglutide, liraglutide, semaglutide, lixisenatide or SGLT2i, namely empagliflozin, dapagliflozin, canagliflozin and SGLT2i with an attempt at comparing the safety profiles of molecules of these two classes. Expert opinion: GLP-1RA and SGLT2i, although each associated with different specific side effects, share a 'similar' safety profile and are both drugs relatively easy to handle. The potentially complementary mechanisms of action, the cardio and nephroprotective effects demonstrated by molecules of both classes, make these drugs potentially useful even in add on to each other.

Preclinical toxicity profile of oral bilastine.

PubMed

Lucero, María Luisa; Arteche, Joseba K; Sommer, E W; Casadesus, Agustín

2012-06-01

As part of the bilastine development program, and as mandated by regulatory authorities, several studies were performed with oral bilastine in different animal species to evaluate its toxicity profile. Toxicokinetic analyses conducted in tandem to evaluate systemic exposure, gender differences, and dose proportionality in the different animal species indicated that animals were systemically exposed to bilastine during treatment. Repeated-dose toxicity studies in beagle dogs (52 weeks) and in rats and mice (13 weeks) showed that bilastine at doses up to 2,000 mg/kg/day was not associated with any mortality, ocular effects, or nodules/masses. Likewise, no bilastine-associated neoplastic lesions were observed in rats and mice after 104 weeks of treatment with bilastine at doses up to 2,000 mg/kg/day. In general, bilastine-related clinical signs, body-weight changes, food consumption, clinical chemistry, haematology, and macro- and microscopic findings were of low order and reversible, with effects present only at the highest doses administered. Bilastine (up to 1,000 mg/kg/day) was well tolerated in pregnant/lactating rats and in their offspring and subsequent generations. With respect to effects on embryofoetal development in rabbits, bilastine at 400 mg/kg/day (the highest dose evaluated) was assessed to be the no observed adverse effects level. Overall, bilastine demonstrated a favorable toxicity profile in all animal models investigated and at higher doses than the corresponding recommended daily human dosage.

Long-term treatment of Cushing's disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial.

PubMed

Petersenn, S; Salgado, L R; Schopohl, J; Portocarrero-Ortiz, L; Arnaldi, G; Lacroix, A; Scaroni, C; Ravichandran, S; Kandra, A; Biller, B M K

2017-07-01

Treating hypercortisolism in patients with Cushing's disease after failed surgery often requires chronic medication, underlining the need for therapies with favourable long-term efficacy and safety profiles. In a randomised, double-blind study, 162 adult patients with persistent/recurrent or de novo Cushing's disease received pasireotide. Patients with mean urinary free cortisol at/below the upper limit of normal or clinical benefit at month 12 could continue receiving pasireotide during an open-ended, open-label phase, the outcomes of which are described herein. Sixteen patients received 5 years of pasireotide treatment. Among these, median (95% confidence interval) percentage change from baseline in mean urinary free cortisol was -82.6% (-89.0, -41.9) and -81.8% (-89.8, -67.4) at months 12 and 60. Eleven patients had mean urinary free cortisol ≤ upper limit of normal at month 60. Improvements in clinical signs were sustained during long-term treatment. The safety profile of pasireotide at 5 years was similar to that reported after 12 months. Fifteen of 16 patients experienced a hyperglycaemia-related adverse event; glycated haemoglobin levels were stable between months 6 and 60. Adverse events related to hyperglycaemia, bradycardia, gallbladder/biliary tract, and liver safety were most likely to first occur by month 6; adverse event severity did not tend to worsen over time. This represents the longest prospective trial of a medical therapy for Cushing's disease to date. A subset of patients treated with pasireotide maintained biochemical and clinical improvements for 5 years, with no new safety signals emerging. These data support the use of pasireotide as an effective long-term therapy for some patients with Cushing's disease.

The effect of advanced maternal age on maternal and neonatal outcomes of placenta previa: A register-based cohort study.

PubMed

Roustaei, Zahra; Vehviläinen-Julkunen, Katri; Tuomainen, Tomi-Pekka; Lamminpää, Reeta; Heinonen, Seppo

2018-05-19

Advanced maternal age (AMA) at the time of delivery generally worsens obstetric outcomes, but its effects on specific pregnancy problems, such as placenta previa, have not been adequately assessed. Therefore, the objective of the study was to explore the effect of AMA on adverse maternal and neonatal outcomes among pregnancies complicated by placenta previa. The study was a register-based cohort study using data of three Finnish health registries, including information of 283 324 women and their newborns. Separate multivariable logistic regression modeling was performed for women under age 35 and women aged 35 or older to assess the association between placenta previa and adverse maternal and neonatal outcomes. Furthermore, interactions between maternal age and placenta previa were tested. A total of 283 324 deliveries of which 714 (0.3%) were complicated by placenta previa. Adverse maternal and neonatal outcomes increased in women with placenta previa, with different patterns across age groups. The adjusted odds ratios and 95% confidence intervals for AMA and young women with previa were 7.3 (5.0-10.6) and 6.8 (5.2-8.9) in blood transfusion, 11.3 (5.4-23.3) and 10.9 (6.1-19.6) in placental abruption. In neonatal outcomes the adjusted odds ratios for AMA and young women with placenta previa were 8.8 (6.6-11.6) and 11.7 (9.7-14.1) in preterm birth <37 weeks, 4.0 (3.0-5.3) and 4.9 (4.1-5.9) in neonatal intensive care unit (NICU) admission, 4.0 (2.8-5.7) and 5.9 (4.7-7.4) low birth weight <2500 g, 2.7 (1.5-4.9) and 3.3 (2.2-5.0) in low Apgar score at 5 min. The joint effects of maternal age and placenta previa on the risk of adverse maternal and neonatal outcomes were non-significant. The risk of adverse maternal and neonatal outcomes for women with placenta previa was not substantially affected by maternal age if their different risk profiles were taken into account. Copyright © 2018 Elsevier B.V. All rights reserved.

Plasma metabolic profiling analysis of nephrotoxicity induced by acyclovir using metabonomics coupled with multivariate data analysis.

PubMed

Zhang, Xiuxiu; Li, Yubo; Zhou, Huifang; Fan, Simiao; Zhang, Zhenzhu; Wang, Lei; Zhang, Yanjun

2014-08-01

Acyclovir (ACV) is an antiviral agent. However, its use is limited by adverse side effect, particularly by its nephrotoxicity. Metabonomics technology can provide essential information on the metabolic profiles of biofluids and organs upon drug administration. Therefore, in this study, mass spectrometry-based metabonomics coupled with multivariate data analysis was used to identify the plasma metabolites and metabolic pathways related to nephrotoxicity caused by intraperitoneal injection of low (50mg/kg) and high (100mg/kg) doses of acyclovir. Sixteen biomarkers were identified by metabonomics and nephrotoxicity results revealed the dose-dependent effect of acyclovir on kidney tissues. The present study showed that the top four metabolic pathways interrupted by acyclovir included the metabolisms of arachidonic acid, tryptophan, arginine and proline, and glycerophospholipid. This research proves the established metabonomic approach can provide information on changes in metabolites and metabolic pathways, which can be applied to in-depth research on the mechanism of acyclovir-induced kidney injury. Copyright © 2014 Elsevier B.V. All rights reserved.

Topical retinoids in acne vulgaris: update on efficacy and safety.

PubMed

Thielitz, Anja; Gollnick, Harald

2008-01-01

Topical retinoids represent a mainstay of acne treatment because they expel mature comedones, reduce microcomedone formation, and exert anti-inflammatory effects. The first-generation retinoid tretinoin (all-trans retinoic acid) and the synthetic third-generation polyaromatics adapalene and tazarotene are approved for acne treatment by the US FDA, whereas topical tretinoin, isotretinoin (13-cis retinoic acid), and adapalene are accredited in Canada and Europe. Topical retinoids have a favorable safety profile distinct from the toxicity of their systemic counterparts. Local adverse effects, including erythema, dryness, itching, and stinging, occur frequently during the early treatment phase. Their impact varies with the vehicle formation, skin type, frequency and mode of application, use of moisturizers, and environmental factors such as sun exposure or temperature. The broad anti-acne activity and safety profile of topical retinoids justifies their use as first-line treatment in most types of non-inflammatory and inflammatory acne. They are also suitable as long-term medications, with no risk of inducing bacterial resistance, for maintenance of remission after cessation of initial combination therapy.

Supervised extensions of chemography approaches: case studies of chemical liabilities assessment

PubMed Central

2014-01-01

Chemical liabilities, such as adverse effects and toxicity, play a significant role in modern drug discovery process. In silico assessment of chemical liabilities is an important step aimed to reduce costs and animal testing by complementing or replacing in vitro and in vivo experiments. Herein, we propose an approach combining several classification and chemography methods to be able to predict chemical liabilities and to interpret obtained results in the context of impact of structural changes of compounds on their pharmacological profile. To our knowledge for the first time, the supervised extension of Generative Topographic Mapping is proposed as an effective new chemography method. New approach for mapping new data using supervised Isomap without re-building models from the scratch has been proposed. Two approaches for estimation of model’s applicability domain are used in our study to our knowledge for the first time in chemoinformatics. The structural alerts responsible for the negative characteristics of pharmacological profile of chemical compounds has been found as a result of model interpretation. PMID:24868246

Multidimensional profiling platforms reveal metabolic dysregulation caused by organophosphorus pesticides.

PubMed

Medina-Cleghorn, Daniel; Heslin, Ann; Morris, Patrick J; Mulvihill, Melinda M; Nomura, Daniel K

2014-02-21

We are environmentally exposed to countless synthetic chemicals on a daily basis, with an increasing number of these chemical exposures linked to adverse health effects. However, our understanding of the (patho)physiological effects of these chemicals remains poorly understood, due in part to a general lack of effort to systematically and comprehensively identify the direct interactions of environmental chemicals with biological macromolecules in mammalian systems in vivo. Here, we have used functional chemoproteomic and metabolomic platforms to broadly identify direct enzyme targets that are inhibited by widely used organophosphorus (OP) pesticides in vivo in mice and to determine metabolic alterations that are caused by these chemicals. We find that these pesticides directly inhibit over 20 serine hydrolases in vivo leading to widespread disruptions in lipid metabolism. Through identifying direct biological targets of OP pesticides, we show heretofore unrecognized modes of toxicity that may be associated with these agents and underscore the utility of using multidimensional profiling approaches to obtain a more complete understanding of toxicities associated with environmental chemicals.

Metabolic responses to prolonged consumption of glucose- and fructose-sweetened beverages are not associated with postprandial or 24-h glucose and insulin excursions123

PubMed Central

Stanhope, Kimber L; Griffen, Steven C; Bremer, Andrew A; Vink, Roel G; Schaefer, Ernst J; Nakajima, Katsuyuki; Schwarz, Jean-Marc; Beysen, Carine; Berglund, Lars; Keim, Nancy L; Havel, Peter J

2011-01-01

Background: Consumption of sugar-sweetened beverages has been shown to be associated with dyslipidemia, insulin resistance, fatty liver, diabetes, and cardiovascular disease. It has been proposed that adverse metabolic effects of chronic consumption of sugar-sweetened beverages are a consequence of increased circulating glucose and insulin excursions, ie, dietary glycemic index (GI). Objective: We determined whether the greater adverse effects of fructose than of glucose consumption were associated with glucose and insulin exposures. Design: The subjects were studied in a metabolic facility and consumed energy-balanced diets containing 55% of energy as complex carbohydrate for 2 wk (GI = 64). The subjects then consumed 25% of energy requirements as fructose- or glucose-sweetened beverages along with their usual ad libitum diets for 8 wk at home and then as part of energy-balanced diets for 2 wk at the metabolic facility (fructose GI = 38, glucose GI = 83). The 24-h glucose and insulin profiles and fasting plasma glycated albumin and fructosamine concentrations were measured 0, 2, 8, and 10 wk after beverage consumption. Results: Consumption of fructose-sweetened beverages lowered glucose and insulin postmeal peaks and the 23-h area under the curve compared with the baseline diet and with the consumption of glucose-sweetened beverages (all P < 0.001, effect of sugar). Plasma glycated albumin concentrations were lower 10 wk after fructose than after glucose consumption (P < 0.01, effect of sugar), whereas fructosamine concentrations did not differ between groups. Conclusion: The results suggest that the specific effects of fructose, but not of glucose and insulin excursions, contribute to the adverse effects of consuming sugar-sweetened beverages on lipids and insulin sensitivity. This study is registered at clinicaltrials.gov as NCT01165853. PMID:21613559

Potential Adverse Effects of Amphetamine Treatment on Brain and Behavior: A Review

PubMed Central

Berman, Steven M.; Kuczenski, Ronald; McCracken, James T.; London, Edythe D.

2009-01-01

Rationale Amphetamine stimulants have been used medically since early in the twentieth century, but they have a high abuse potential and can be neurotoxic. Although they have long been used effectively to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents, amphetamines are now being prescribed increasingly as maintenance therapy for ADHD and narcolepsy in adults, considerably extending the period of potential exposure. Effects of prolonged stimulant treatment have not been fully explored, and understanding such effects is a research priority 1. Because the pharmacokinetics of amphetamines differ between children and adults, reevaluation of the potential for adverse effects of chronic treatment of adults is essential. Findings Despite information on the effects of stimulants in laboratory animals, profound species differences in susceptibility to stimulant-induced neurotoxicity underscore the need for systematic studies of prolonged human exposure. Early amphetamine treatment has been linked to slowing in height and weight growth in some children. Because the number of prescriptions for amphetamines has increased several-fold over the past decade, an amphetamine-containing formulation is the most commonly prescribed stimulant in North America, and it is noteworthy that amphetamines are also the most abused prescription medications. Although early treatment does not increase risk for substance abuse, few studies have tracked the compliance and usage profiles of individuals who began amphetamine treatment as adults. Overall, there is concern about risk for slowed growth in young patients who are dosed continuously, and for substance abuse in patients first medicated in late adolescence or adulthood. Although most adult patients also use amphetamines effectively and safely, occasional case reports indicate that prescription use can produce marked psychological adverse events, including stimulant-induced psychosis. Assessments of central toxicity and adverse psychological effects during late adulthood and senescence of adults who receive prolonged courses of amphetamine treatment are warranted. Finally, identification of the biological factors that confer risk and those that offer protection are also needed to better specify the parameters of safe, long-term, therapeutic administration of amphetamines to adults. PMID:18698321

Adolescent, parent and societal preferences and willingness to pay for meningococcal B vaccine: A Discrete Choice Experiment.

PubMed

Marshall, H S; Chen, G; Clarke, M; Ratcliffe, J

2016-01-27

Meningococcal B (MenB) vaccines have been licensed in many countries with private purchase the only option until recently, when a funded programme was introduced in the UK. The aim of this study was to explore adolescent/parental values for a variety of salient vaccine attributes (cost, effectiveness, side effect profile) to assess preferences and willingness-to-pay (WTP) for a MenB vaccine. A national cross-sectional population study was conducted in Australia using Discrete Choice Experiment methodology to assess adolescent/parent/adult preferences for attributes related to MenB vaccine. 2003 adults and 502 adolescents completed the survey in 2013. The majority of participants were willing to be vaccinated with MenB vaccine with vaccination opt-out chosen by 11.9% of adolescents and parents, and 18.2% of non-parent adults. A mixed logit regression model examining adolescent/adult preferences indicated consistent findings; the higher the effectiveness, the longer the duration of protection, the less chance of adverse events and the lower the cost, the more likely respondents were to agree to vaccination. For an ideal MenB vaccine, including the most favoured level of each attribute summed together (90% effectiveness, 10 year duration, 1 injection, no adverse events) adolescents would pay AU$251.60 and parents AU$295.10. Adolescents and parents would pay AU$90.70 or AU$127.20 for 90% vaccine effectiveness vs AU$18.50 or AU$16.70 for 70% effectiveness and would want to be financially compensated for 50% effectiveness; pay AU$63.30 or AU$76.40 for 10 years protection; and pay AU$48.50 or AU$49.20 for no vaccine related adverse events. A slight fever post vaccination was a preferred choice with parents and adolescents willing to pay AU$9.60 or AU$12.30 for this attribute. Vaccine effectiveness, adverse events and duration of immunity are important drivers for parental and adolescent decisions about WTP for MenB vaccine and should be included in discussions on the benefits, risks and cost. Copyright © 2015 Elsevier Ltd. All rights reserved.

A rapid nuclear staining test using cationic dyes contributes to efficient STR analysis of telogen hair roots.

PubMed

Lee, So-Yeon; Ha, Eun-Ju; Woo, Seung-Kyun; Lee, So-Min; Lim, Kyung-Hee; Eom, Yong-Bin

2017-07-01

Telogen hairs presented in the crime scene are commonly encountered as trace evidence. However, short tandem repeat (STR) profiling of the hairs currently have low and limited use due to poor success rate. To increase the success rate of STR profiling of telogen hairs, we developed a rapid and cost-effective method to estimate the number of nuclei in the hair roots. Five cationic dyes, Methyl green (MG), Harris hematoxylin (HH), Methylene blue (MB), Toluidine blue (TB), and Safranin O (SO) were evaluated in this study. We conducted a screening test based on microscopy and the percentage of loss with nuclear DNA, in order to select the best dye. MG was selected based on its specific nuclei staining and low adverse effect on the hair-associated nuclear DNA. We examined 330 scalp and 100 pubic telogen hairs with MG. Stained hairs were classified into five groups and analyzed by STR. The fast staining method revealed 70% (head hair) and 33.4% (pubic hair) of full (30 alleles) and high partial (18-29 alleles) STR profiling proportion from the lowest nuclei count group (one to ten nuclei). The results of this study demonstrated a rapid, specific, nondestructive, and high yield DNA profiling method applicable for screening telogen hairs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Potential of gene expression profiling in the management of childhood acute lymphoblastic leukemia.

PubMed

Bhojwani, Deepa; Moskowitz, Naomi; Raetz, Elizabeth A; Carroll, William L

2007-01-01

Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous disease. Current treatment approaches are tailored according to the clinical features of the host, genotypic features of the leukemic blast, and early response to therapy. Although these approaches have been successful in dramatically improving outcomes, approximately 20% of children with ALL still relapse and many of these children do not have an identifiable adverse risk factor at presentation. Further insights into the biologic basis of the disease may contribute to novel, rational treatment strategies. Childhood ALL has served as an example for demonstrating the feasibility and potential of high-throughput technologies such as global gene expression or transcript profiling. In the last decade or so, utilization of these techniques has grown exponentially. As the methodology undergoes refinement and validation, it is plausible that microarrays may be used in the routine management of childhood ALL in the next few years. This article discusses the numerous applications to date of gene expression profiling in childhood ALL. Multiple investigators have made it evident that microarrays can be used as a single platform for the accurate classification of ALL into the various cytogenetic subtypes. Additional promising utilities include prediction of early response to therapy, overall outcome, and adverse effects. Identification of patients who are predicted to have an unfavorable outcome may allow for early intervention such as intensification of therapy or avoidance of drugs that are associated with specific secondary effects such as therapy-related acute myelogenous leukemia. Knowledge has been gained into pathways contributing to leukemogenesis and chemoresistance. Therapeutic targets have been identified, some of which are entering clinical trials following validation in additional preclinical models. These newer methods of genome analyses complemented by studies involving the proteome as well as host polymorphisms will have a profound impact on the diagnosis and management of childhood ALL.

Clinical experiences with cannabinoids in spasticity management in multiple sclerosis.

PubMed

Lorente Fernández, L; Monte Boquet, E; Pérez-Miralles, F; Gil Gómez, I; Escutia Roig, M; Boscá Blasco, I; Poveda Andrés, J L; Casanova-Estruch, B

2014-06-01

Spasticity is a common symptom among patients with multiple sclerosis (MS). This study aims to assess the effectiveness and safety of the combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in clinical practice for the treatment of spasticity in MS. Retrospective observational study with patients treated with inhaled THC/CBD between April 2008 and March 2012. Descriptive patient and treatment variables were collected. Therapeutic response was evaluated based on the doctor's analysis and overall impression. Of the 56 patients who started treatment with THC/CBD, 6 were excluded because of missing data. We evaluated 50 patients (42% male) with a median age 47.8 years (25.6-76.8); 38% were diagnosed with primary progressive MS, 44% with secondary progressive MS, and 18% with relapsing-remitting MS. The reason for prescribing the drug was spasticity (44%), pain (10%), or both (46%). Treatment was discontinued in 16 patients because of ineffectiveness (7 patients), withdrawal (4), and adverse effects (5). The median exposure time in patients whose treatment was discontinued was 30 days vs 174 days in those whose treatment continued at the end of the study. THC/CBD was effective in 80% of patients at a median dose of 5 (2-10) inhalations/day. The adverse event profile consisted of dizziness (11 patients), somnolence (6), muscle weakness (7), oral discomfort (2), diarrhoea (3), dry mouth (2), blurred vision (2), agitation (1), nausea (1), and paranoid ideation (1). THC/CBD appears to be a good alternative to standard treatment as it improves refractory spasticity in MS and has an acceptable toxicity profile. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Medium Chain Triglyceride Oil Consumption as Part of a Weight Loss Diet Does Not Lead to an Adverse Metabolic Profile When Compared to Olive Oil

PubMed Central

St-Onge, Marie-Pierre; Bosarge, Aubrey; Goree, Laura Lee T.; Darnell, Betty

2010-01-01

Objective Medium chain triglyceride (MCT) consumption may have a beneficial impact on weight management, however, some studies point to a negative impact of MCT oil consumption on cardiovascular disease risk. This study examined the effects of MCT oil consumption, as part of a weight loss diet, on metabolic risk profile compared to olive oil. Design Thirty-one men and women, age 19–50 y and body mass index 27–33 kg/m2, completed this randomized, controlled, 16-week weight loss program. Oils were consumed at a level of ~12% of the subjects’ prescribed energy intakes in the form of muffins and liquid oil. Results After controlling for body weight, there was a significant effect of time on fasting serum glucose (P = 0.0177) and total cholesterol (P = 0.0386) concentrations, and on diastolic blood pressure (P = 0.0413), with reductions in these variables occurring over time; there was no time-by-diet interaction for any of the parameters studied. Two of the 3 subjects in the MCT oil group with evidence of the metabolic syndrome at baseline did not have metabolic syndrome at endpoint. In the olive oil group, 6 subjects had the metabolic syndrome at baseline; 2 subjects no longer had metabolic syndrome at endpoint, 1 person developed metabolic syndrome, and 4 subjects did not have any change in their metabolic syndrome status. Conclusions Our results suggest that MCT oil can be incorporated into a weight loss program without fear of adversely affecting metabolic risk factors. Distinction should be made regarding chain length when it comes to discussing the effects of saturated fats on metabolic risk factors. PMID:18845704

Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) promotes the transgenerational inheritance of adult-onset reproductive dysfunctions through the female germline in mice.

PubMed

Pocar, Paola; Fiandanese, Nadia; Berrini, Anna; Secchi, Camillo; Borromeo, Vitaliano

2017-05-01

Endocrine disruptors (EDs) are compounds known to promote transgenerational inheritance of adult-onset disease in subsequent generations after maternal exposure during fetal gonadal development. This study was designed to establish whether gestational and lactational exposure to the plasticizer di(2-ethylhexyl)phthalate (DEHP) at environmental doses promotes transgenerational effects on reproductive health in female offspring, as adults, over three generations in the mouse. Gestating F0 mouse dams were exposed to 0, 0.05, 5mg/kg/day DEHP in the diet from gestational day 0.5 until the end of lactation. The incidence of adult-onset disease in reproductive function was recorded in F1, F2 and F3 female offspring. In adult F1 females, DEHP exposure induced reproductive adverse effects with: i) altered ovarian follicular dynamics with reduced primordial follicular reserve and a larger growing pre-antral follicle population, suggesting accelerated follicular recruitment; ii) reduced oocyte quality and embryonic developmental competence; iii) dysregulation of the expression profile of a panel of selected ovarian and pre-implantation embryonic genes. F2 and F3 female offspring displayed the same altered reproductive morphological phenotype and gene expression profiles as F1, thus showing transgenerational transmission of reproductive adverse effects along the female lineage. These findings indicate that in mice exposure to DEHP at doses relevant to human exposure during gonadal sex determination significantly perturbs the reproductive indices of female adult offspring and subsequent generations. Evidence of transgenerational transmission has important implications for the reproductive health and fertility of animals and humans, significantly increasing the potential biohazards of this toxicant. Copyright © 2017 Elsevier Inc. All rights reserved.

The Biosulin equivalence in standard therapy (BEST) study - a multicentre, open-label, non-randomised, interventional, observational study in subjects using Biosulin 30/70 for the treatment of insulin-dependent type 1 and type 2 diabetes mellitus.

PubMed

Segal, D; Tupy, D; Distiller, L

2013-04-02

The need for more cost-effective insulin therapy is critical in reducing the burden on patients and health systems. Biosimilar insulins have the potential to dramatically lower healthcare costs by delivering insulin with a similar anti-glycaemic effect and adverse reaction profile. The purpose of this study was to confirm equivalence in glycaemic outcomes and side-effect profiles between Biosulin 30/70 and other human premixed insulin preparations on the South African market in a clinical practice setting. Subjects in this interventional, observational, multicentre, open-label, prospective study were switched from their existing human premix insulin (Actraphane, Humulin 30/70 or Insuman) to the study insulin Biosulin 30/70. The primary endpoint was the change in HbA1c from baseline to 6 months. Seventy-seven adult patients with type 1(n=18) or type 2 (n=59) diabetes were enrolled. The baseline HbA1c in the overall cohort was 7.9%, 8.0% at 3 months (p=0.50) and 7.6% at 6 months (p=0.14).There was a small increase in the total daily dose of insulin used in both the type 1 and type 2 cohort, from 0.62 to 0.65 units/kg/day (p=0.0004). There was no significant difference in weight in the study subjects during the 6-month period on Biosulin 30/70 (p=0.67). Biosulin 30/70 achieved at least equivalent glycaemic control to existing human premix insulins, with no reported new or severe adverse events. Increased use of biosimilar insulins has the potential for significant cost savings.

Testicular toxicity in cannabis extract treated mice: association with oxidative stress and role of antioxidant enzyme systems.

PubMed

Mandal, Tapas K; Das, Nildari S

2010-02-01

Intraperitoneal injection of cannabis extract at low doses (total doses ranging from 40 mg to 60 mg per mouse) induced adverse effect on testes and oxidative stress. At low doses, there was a significant increase in lipid peroxidation and decrease in testicular lipid content, but the effects were significantly less at higher doses and at the withdrawal of cannabis treatment (recovery dose). There was a marked decrease in antioxidant enzyme profiles (superoxide dismutase, catalase and glutathione peroxidase) and glutathione content at low doses, but these effects were higher at higher dose and at withdrawal of the treatment (recovery effect). Histology revealed significant shrinkage of tubular diameter and detrimental changes in seminiferous epithelium of testis with resulting lowered serum testosterone and pituitary gonadotropins (follicular stimulating [FSH] and luteinizing hormones [LH]) levels at low doses. But at higher doses and particularly at withdrawal of the treatment, regression of various germ cell layers of testes through the revival of testosterone hormone and pituitary gonadotropins (FSH and LH) were observed, indicating that recovery effects on testes became operative possibly through the corrective measure of endogenous testicular antioxidant enzymes profiles and pituitary gonadotropins hormones feedback mechanisms.

Noisy relativistic quantum games in noninertial frames

NASA Astrophysics Data System (ADS)

Khan, Salman; Khan, M. Khalid

2013-02-01

The influence of noise and of Unruh effect on quantum Prisoners' dilemma is investigated both for entangled and unentangled initial states. The noise is incorporated through amplitude damping channel. For unentangled initial state, the decoherence compensates for the adverse effect of acceleration of the frame and the effect of acceleration becomes irrelevant provided the game is fully decohered. It is shown that the inertial player always out scores the noninertial player by choosing defection. For maximally entangled initially state, we show that for fully decohered case every strategy profile results in either of the two possible equilibrium outcomes. Two of the four possible strategy profiles become Pareto optimal and Nash equilibrium and no dilemma is leftover. It is shown that other equilibrium points emerge for different region of values of decoherence parameter that are either Pareto optimal or Pareto inefficient in the quantum strategic spaces. It is shown that the Eisert et al. (Phys Rev Lett 83:3077, 1999) miracle move is a special move that leads always to distinguishable results compare to other moves. We show that the dilemma like situation is resolved in favor of one player or the other.

Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function.

PubMed

Lundgaard, Iben; Wang, Wei; Eberhardt, Allison; Vinitsky, Hanna Sophia; Reeves, Benjamin Cameron; Peng, Sisi; Lou, Nanhong; Hussain, Rashad; Nedergaard, Maiken

2018-02-02

Prolonged intake of excessive amounts of ethanol is known to have adverse effects on the central nervous system (CNS). Here we investigated the effects of acute and chronic ethanol exposure and withdrawal from chronic ethanol exposure on glymphatic function, which is a brain-wide metabolite clearance system connected to the peripheral lymphatic system. Acute and chronic exposure to 1.5 g/kg (binge level) ethanol dramatically suppressed glymphatic function in awake mice. Chronic exposure to 1.5 g/kg ethanol increased GFAP expression and induced mislocation of the astrocyte-specific water channel aquaporin 4 (AQP4), but decreased the levels of several cytokines. Surprisingly, glymphatic function increased in mice treated with 0.5 g/kg (low dose) ethanol following acute exposure, as well as after one month of chronic exposure. Low doses of chronic ethanol intake were associated with a significant decrease in GFAP expression, with little change in the cytokine profile compared with the saline group. These observations suggest that ethanol has a J-shaped effect on the glymphatic system whereby low doses of ethanol increase glymphatic function. Conversely, chronic 1.5 g/kg ethanol intake induced reactive gliosis and perturbed glymphatic function, which possibly may contribute to the higher risk of dementia observed in heavy drinkers.

Safety assessment of EPA-rich triglyceride oil produced from yeast: genotoxicity and 28-day oral toxicity in rats.

PubMed

Belcher, Leigh A; MacKenzie, Susan A; Donner, Maria; Sykes, Greg P; Frame, Steven R; Gillies, Peter J

2011-02-01

The 28-day repeat-dose oral and genetic toxicity of eicosapentaenoic acid triglyceride oil (EPA oil) produced from genetically modified Yarrowia lipolytica yeast were assessed. Groups of rats received 0 (olive oil), 940, 1880, or 2820 mg EPA oil/kg/day, or fish oil (sardine/anchovy source) by oral gavage. Lower total serum cholesterol was seen in all EPA and fish oil groups. Liver weights were increased in the medium and high-dose EPA (male only), and fish oil groups but were considered non-adverse physiologically adaptive responses. Increased thyroid follicular cell hypertrophy was observed in male high-dose EPA and fish oil groups, and was considered to be an adaptive response to high levels of polyunsaturated fatty acids. No adverse test substance-related effects were observed on body weight, nutritional, or other clinical or anatomic pathology parameters. The oil was not mutagenic in the in vitro Ames or mouse lymphoma assay, and was not clastogenic in the in vivo mouse micronucleus test. In conclusion, exposure for 28 days to EPA oil derived from yeast did not produce adverse effects at doses up to 2820 mg/kg/day and was not genotoxic. The safety profile of the EPA oil in these tests was comparable to a commercial fish oil. Copyright © 2010 Elsevier Inc. All rights reserved.

Oral contraceptives in polycystic ovary syndrome: risk-benefit assessment.

PubMed

Yildiz, Bulent O

2008-01-01

Combined oral contraceptive pills (OCPs) have been a key component of the chronic treatment of polycystic ovary syndrome (PCOS) by improving androgen excess and regulating menstrual cycles. Earlier epidemiologic studies with second- and third-generation OCPs in the general population have raised important questions regarding long-term cardiometabolic effects of these agents. In PCOS, there are only a few short-term studies with contradictory results evaluating potential adverse effects of OCPs on cardiovascular risk factors and glucose homeostasis. These studies included a small number of participants and did not take into account several confounding factors that might influence the outcome. Nevertheless, limited available data support the benefits of long-term OCP use in PCOS. By contrast, solid evidence for cardiometabolic adverse outcome with the use of these agents, especially with newer OCPs containing antiandrogenic progestins, is lacking. More studies are needed to resolve controversies regarding the safety of long-term OCP use in PCOS. Meanwhile, assessment of each PCOS patient's personal cardiometabolic risk profile should be an essential component of the evaluation before prescribing OCPs and also during follow-up.

Safety of polyethylene glycol 3350 for the treatment of chronic constipation in children.

PubMed

Pashankar, Dinesh S; Loening-Baucke, Vera; Bishop, Warren P

2003-07-01

To assess the clinical and biochemical safety profile of long-term polyethylene glycol 3350 (PEG) therapy in children with chronic constipation and to assess pediatric patient acceptance of PEG therapy. Prospective observational study. Pediatric clinics at a referral center. Patients Eighty-three children (44 with chronic constipation, 39 with constipation and encopresis) receiving PEG therapy for more than 3 months. Clinical adverse effects related to PEG therapy and acceptance and compliance with PEG therapy. Serum electrolyte levels, osmolality, albumin levels, and liver and renal function test results were measured. At the time of evaluation, the mean duration of PEG therapy was 8.7 months, and the mean PEG dose was 0.75 g/kg daily. There were no major clinical adverse effects. All blood test results were normal, except for transient minimal alanine aminotransferase elevation unrelated to therapy in 9 patients. All children preferred PEG to previously used laxatives, and daily compliance was measured as good in 90% of children. Long-term PEG therapy is safe and is well accepted by children with chronic constipation with and without encopresis.

Combination of t(4;14), del(17p13), del(1p32) and 1q21 gain FISH probes identifies clonal heterogeneity and enhances the detection of adverse cytogenetic profiles in 233 newly diagnosed multiple myeloma.

PubMed

Smol, Thomas; Dufour, Annika; Tricot, Sabine; Wemeau, Mathieu; Stalnikiewicz, Laure; Bernardi, Franck; Terré, Christine; Ducourneau, Benoît; Bisiau, Hervé; Daudignon, Agnès

2017-01-01

Our aim was to set the FISH combination of del(17p13), t(4;14), 1q21 gain and del(1p32), four adverse cytogenetic factors rarely evaluated together, and compare our technical thresholds with those defined in the literature. Two hundred thirty-three patients with MM at diagnosis were studied using FISH to target 4 unfavorable cytogenetic abnormalities: 17p13 deletion, t(4;14) translocation, 1p32 deletion and 1q21 gain. Technical thresholds were determined for each probe using isolated CD138-expressing PC from patients without MM. The FISH analysis identified abnormalities in 79.0% of patients. Del(17p13) was detected in 15.0% of cases, t(4;14) in 11.5%, 1q21 gain in 37.8% and del(1p32) in 8.7%. Adding 1p32/1q21 FISH probes has enabled us to identify adverse cytogenetic profiles in 39.0% of patients without del(17p13) or t(4;14). Clonal heterogeneity was observed in 51.1% of patients as well as an increase in the number of adverse abnormalities when related clones were greater than or equal to 2 (85.1% against 45.6%). FISH allowed detecting accumulation of adverse abnormalities and clonal heterogeneity in MM with a combination of 4 probes. The impacts of these two parameters need to be evaluated, and could be included in future cytogenetic classifications.

Effect of transcutaneous electrical nerve stimulation therapy for the treatment of primary dysmenorrheal.

PubMed

Bai, Hai-Yan; Bai, Hong-Yan; Yang, Zhi-Qin

2017-09-01

This study aimed to investigate the effect and safety of transcutaneous electrical nerve stimulation (TENS) therapy for relieving pain in women with primary dysmenorrhea (PD). In this study, 134 participants with PD were randomly divided into the intervention group and the sham group, with 67 participants in each group. Participants in the intervention group received TENS, whereas those in the sham group received sham TENS. The primary outcome was measured by the Numeric Rating Scale (NRS). The secondary outcomes were measured by the duration of relief from dysmenorrheal pain, number of ibuprofen tablets taken, and the World Health Organization quality of life (WHOQOL)-BREF score, as well as the adverse events. A total of 122 participants completed the study. Compared to sham TENS, TENS showed a greater effect in pain relief with regard to the NRS (P < .01), duration of relief from dysmenorrheal pain (P < .01), and number of ibuprofen tablets taken (P < .01). However, no significant differences in the quality of life, measured by the WHOQOL-BREF score, were found between 2 groups. The adverse event profiles were also similar between 2 groups. TENS was efficacious and safe in relieving pain in participants with PD.

Advances in treating psoriasis in the elderly with small molecule inhibitors.

PubMed

Cline, Abigail; Cardwell, Leah A; Feldman, Steven R

2017-12-01

Due to the chronic nature of psoriasis, the population of elderly psoriasis patients is increasing. However, many elderly psoriatic patients are not adequately treated because management is challenging as a result of comorbidities, polypharmacy, and progressive impairment of organ systems. Physicians may hesitate to use systemic or biologic agents in elderly psoriasis patients because of an increased risk of adverse events in this patient population. Small molecule medications are emerging as promising options for elderly patients with psoriasis and other inflammatory conditions. Areas covered: Here we review the efficacy, safety and tolerability of small molecule inhibitors apremilast, tofacitinib, ruxolitinib, baricitinib, and peficitinib in the treatment of psoriasis, with focus on their use in the elderly population. Expert opinion: Although small molecule inhibitors demonstrate efficacy in elderly patients with psoriasis, they will require larger head-to-head studies and post-marketing registries to evaluate their effectiveness and safety in specific patient populations. Apremilast, ruxolitinib, and peficitinib are effective agents with favorable side effect profiles; however, physicians should exercise caution when prescribing tofacitinib or baricitinib in elderly populations due to adverse events. The high cost of these drugs in the U.S. is likely to limit their use.

Safety and tolerability of extended-release niacin-laropiprant: Pooled analyses for 11,310 patients in 12 controlled clinical trials.

PubMed

McKenney, James; Bays, Harold; Gleim, Gilbert; Mitchel, Yale; Kuznetsova, Olga; Sapre, Aditi; Sirah, Waheeda; Maccubbin, Darbie

2015-01-01

The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) showed that adding extended-release niacin-laropiprant (ERN-LRPT) to statin provided no incremental cardiovascular benefit vs placebo (PBO). ERN-LRPT was also associated with an excess of serious adverse experiences (AEs), some of which were unexpected (infections and bleeding). These findings led to the withdrawal of ERN-LRPT from all markets. We examined the safety profile of ERN-LRPT vs the comparators ERN alone and statins in the ERN-LRPT development program to assess whether similar safety signals were observed to those seen in HPS-THRIVE and whether these might be attributed to ERN or LRPT. Postrandomization safety data from 12 clinical studies, 12 to 52 weeks in duration and involving 11,310 patients, were analyzed across 3 treatments: (1) ERN-LRPT; (2) ERN-NSP (ERN, Merck & Co, Inc or Niaspan [NSP], Abbott Laboratories); and (3) statin-PBO (statin or PBO). The safety profiles of ERN-LRPT and ERN-NSP were similar, except for less flushing with ERN-LRPT. Nonflushing AEs reported more frequently with ERN-LRPT or ERN-NSP than with statin-PBO were mostly nonserious and typical of niacin (nausea, diarrhea, and increased blood glucose). There was no evidence for an increased risk of serious AEs related to diabetes, muscle, infection, or bleeding. Pooled data from 11,310 patients revealed that, except for reduced flushing, the safety profile of ERN-LRPT was similar to that of ERN-NSP; LRPT did not appear to adversely affect the side-effect profile of ERN. The inability to replicate the unexpected AE findings in HPS2-THRIVE could be because of the smaller sample size and substantially shorter duration of these studies. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Maternal adversities during pregnancy and cord blood oxytocin receptor (OXTR) DNA methylation

PubMed Central

Unternaehrer, Eva; Bolten, Margarete; Nast, Irina; Staehli, Simon; Meyer, Andrea H.; Dempster, Emma; Hellhammer, Dirk H.; Lieb, Roselind

2016-01-01

The aim of this study was to investigate whether maternal adversities and cortisol levels during pregnancy predict cord blood DNA methylation of the oxytocin receptor (OXTR). We collected cord blood of 39 babies born to mothers participating in a cross-sectional study (N = 100) conducted in Basel, Switzerland (2007–10). Mothers completed the Inventory of Life Events (second trimester: T2), the Edinburgh Postnatal Depression Scale (EPDS, third trimester: T3), the Trier Inventory of Chronic Stress (TICS-K, 1–3 weeks postpartum) and provided saliva samples (T2, T3) for maternal cortisol profiles, as computed by the area under the curve with respect to ground (AUCg) or increase (AUCi) for the cortisol awakening response (CAR) and for diurnal cortisol profiles (DAY). OXTR DNA methylation was quantified using Sequenom EpiTYPER. The number of stressful life events (P = 0.032), EPDS score (P = 0.007) and cortisol AUCgs at T2 (CAR: P = 0.020; DAY: P = 0.024) were negatively associated with OXTR DNA methylation. Our findings suggest that distinct prenatal adversities predict decreased DNA methylation in a gene that is relevant for childbirth, maternal behavior and wellbeing of mother and offspring. If a reduced OXTR methylation increases OXTR expression, our findings could suggest an epigenetic adaptation to an adverse early environment. PMID:27107296

Interpersonal polyvictimization and mental health in males.

PubMed

Burns, Carol Rhonda; Lagdon, Susan; Boyda, David; Armour, Cherie

2016-05-01

A consistent conclusion within the extant literature is that victimization and in particular polyvictimization leads to adverse mental health outcomes. A large body of literature exists as it pertains to the association between victimisation and mental health in studies utilising samples of childhood victims, female only victims, and samples of male and female victims; less research exists as it relates to males victims of interpersonal violence. The aim of the current study was therefore to identify profiles of interpersonal victimizations in an exclusively male sample and to assess their differential impact on a number of adverse mental health outcomes. Using data from 14,477 adult males from Wave 2 of the NESARC, we identified interpersonal victimization profiles via Latent Class Analysis. Multinomial Logistic Regression was subsequently utilized to establish risk across mental health disorders. A 4-class solution was optimal. Victimisation profiles showed elevated odds ratios for the presence of mental health disorders; suggesting that multiple life-course victimisation typologies exists, and that victimization is strongly associated with psychopathology. Several additional notable findings are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Aspects of Cardiometabolic Risk in Women with Polycystic Ovary Syndrome.

PubMed

Paterakis, Thomas S; Diamanti-Kandarakis, Evanthia

2014-12-01

Women with polycystic ovary syndrome (PCOS), the most common endocrine disorder among women of reproductive age, exhibit an adverse cardiovascular risk profile characteristic of the cardiometabolic syndrome. These women, compared with age- and body mass index-matched women without PCOS, appear to present a higher risk of insulin resistance, glucose intolerance, and dyslipidemia, and possibly a higher rate of type 2 diabetes mellitus and cardiovascular disease. However, despite the presence of cardiovascular risk factors and increased surrogate markers of cardiovascular disease, it is unclear whether they have accelerated atherosclerosis and greater mortality, the latter mainly because of a lack of endpoint studies. This article addresses, summarizes, and discusses salient data from the existing literature, including gaps and uncertainties, aspects, and mechanisms related to the spectrum of adverse cardiometabolic profile factors in women with PCOS.

Use of atypical antipsychotics in the elderly: a clinical review

PubMed Central

Gareri, Pietro; Segura-García, Cristina; Manfredi, Valeria Graziella Laura; Bruni, Antonella; Ciambrone, Paola; Cerminara, Gregorio; De Sarro, Giovambattista; De Fazio, Pasquale

2014-01-01

The use of atypical antipsychotic drugs in the elderly has become wider and wider in recent years; in fact, these agents have novel receptor binding profiles, good efficacy with regard to negative symptoms, and reduced extrapyramidal symptoms. However, in recent years, the use of both conventional and atypical antipsychotics has been widely debated for concerns about their safety in elderly patients affected with dementia and the possible risks for stroke and sudden death. A MEDLINE search was made using the words elderly, atypical antipsychotics, use, schizophrenia, psychosis, mood disorders, dementia, behavioral disorders, and adverse events. Some personal studies were also considered. This paper reports the receptor binding profiles and the main mechanism of action of these drugs, together with their main use in psychiatry and the possible adverse events in elderly people. PMID:25170260

Cardiovascular risk-benefit profile of sibutramine.

PubMed

Scheen, A J

2010-01-01

Sibutramine is a combined norepinephrine and serotonin reuptake inhibitor used as an antiobesity agent to reduce appetite and promote weight loss in combination with diet and exercise. At a daily dose of 10-20 mg, it was initially considered to have a good safety profile, as it does not induce primary pulmonary hypertension or adverse effects on cardiac valves, in contrast to previous reports relating to some other antiobesity agents. However, it exerts disparate effects on cardiovascular risk factors. On the one hand, sibutramine may have antiatherogenic activities, as it improves insulin resistance, glucose metabolism, dyslipidemia, and inflammatory markers, with most of these effects resulting from weight loss rather than from an intrinsic effect of the drug. On the other hand, because of its specific mode of action, sibutramine exerts a peripheral sympathomimetic effect, which induces a moderate increase in heart rate and attenuates the reduction in BP attributable to weight loss or even slightly increases BP. It may also prolong the QT interval, an effect that could induce arrhythmias. Because of these complex effects, it is difficult to conclude what the final impact of sibutramine on cardiovascular outcomes might be. Sibutramine has been shown to exert favorable effects on some surrogate cardiovascular endpoints such as reduction of left ventricular hypertrophy and improvement of endothelial dysfunction. A good cardiovascular safety profile was demonstrated in numerous 1- to 2-year controlled trials, in both diabetic and nondiabetic well selected patients, as well as in several observational studies. However, since 2002, several cardiovascular adverse events (hypertension, tachycardia, arrhythmias, and myocardial infarction) have been reported in sibutramine-treated patients. This led to a contraindication of the use of this antiobesity agent in patients with established coronary heart disease, previous stroke, heart failure, or cardiac arrhythmias. SCOUT (Sibutramine Cardiovascular and Diabetes Outcome Study) was designed to prospectively evaluate the efficacy/safety ratio of sibutramine in a high-risk population. The efficacy/safety results of the first 6-week lead-in open period of treatment with sibutramine 10 mg/day were reassuring in 10 742 overweight/obese high-risk subjects (97% had cardiovascular disease, 88% had hypertension, and 84% had type 2 diabetes mellitus). However, the final results of SCOUT showed that long-term (5 years') treatment with sibutramine (10-15 mg/day) exposed subjects with pre-existing cardiovascular disease to a significantly increased risk for nonfatal myocardial infarction and nonfatal stroke, but not cardiovascular death or all-cause mortality. Because the benefit of sibutramine as a weight-loss aid seems not to outweigh the cardiovascular risks, the European Medicines Agency recommended the suspension of marketing authorizations for sibutramine across the EU. The US FDA stated that the drug should carry a 'black box' warning due to an increased risk of stroke and heart attack in patients with a history of cardiovascular disease. In conclusion, concern still persists about the safety profile of sibutramine regarding cardiovascular outcomes, and the drug should not be prescribed for overweight/obese patients with a high cardiovascular risk profile.

Herbal medicines supplied by community pharmacies in Lagos, Nigeria: pharmacists’ knowledge

PubMed Central

Oshikoya, Kazeem Adeola; Oreagba, Ibrahim A.; Ogunleye, Olayinka O.; Oluwa, Rashidat; Senbanjo, Idowu O.; Olayemi, Sunday O.

Background The use of herbal medicines is on the increase globally and they are usually supplied in pharmacies as non-prescription medicines. Pharmacists are, therefore, responsible for educating and informing the consumers about rational use of herbal medicines. Objective To evaluate the knowledge of pharmacists in Lagos, Nigeria with regards to the herbal medicines they supplied by their pharmacies. Methods Pharmacists in charge of randomly selected 140 community pharmacies from 20 Local Government Areas in Lagos were required to fill out a self-administered questionnaire. We gathered information on their knowledge of the indications, adverse effects, potential drug-herb interactions and contraindications of the herbal medicines they supply in their pharmacies. Results Of the 140 questionnaires distributed, 103 (72.9%) participants completed the questionnaire appropriately. The majority (74; 71.8%) of the participants were males and 36-50 years (56; 54.4%). The pharmacies supplied mostly Yoyo cleanser bitters® (101; 98.5%), ginseng (97; 98.5%), Jobelyn® (91; 88.3%), Ciklavit® (68; 66.6%), gingko (66; 64.1%), herbal tea (66; 64.1%), and Aloe vera (57; 55.3%). The pharmacists self-rated their knowledge of herbal medicines mostly as fair (39%) and good (42%), but they exhibited poor knowledge with regards to the indications, contraindications and safety profiles. Seventy participants consulted reference materials such as leaflet insert in the herbal medicines (56%) and internet (20%) before supplying herbal medicines. The information most frequently sought was herb-drug interactions (85%), contraindications (75%) and adverse effects (70%). Conclusions Community pharmacists need to be informed about the indications and safety profiles of herbal medicines. PMID:24367462

MAO-inhibitors in Parkinson's Disease

PubMed Central

Laux, Gerd

2011-01-01

Monoamine oxidase inhibitors (MAO-I) belong to the earliest drugs tried in Parkinson's disease (PD). They have been used with or without levodopa (L-DOPA). Non-selective MAO-I due to their side-effect/adverse reaction profile, like tranylcypromine have limited use in the treatment of depression in PD, while selective, reversible MAO-A inhibitors are recommended due to their easier clinical handling. For the treatment of akinesia and motor fluctuations selective irreversible MAO-B inhibitors selegiline and rasagiline are recommended. They are safe and well tolerated at the recommended daily doses. Their main differences are related to (1) metabolism, (2) interaction with CYP-enzymes and (3) quantitative properties at the molecular biological/genetic level. Rasagiline is more potent in clinical practise and has a hypothesis driven more favourable side effect/adverse reaction profile due to its metabolism to aminoindan. Both selegiline and rasagiline have a neuroprotective and neurorestaurative potential. A head-to head clinical trial would be of utmost interest from both the clinical outcome and a hypothesis-driven point of view. Selegiline is available as tablet and melting tablet for PD and as transdermal selegiline for depression, while rasagiline is marketed as tablet for PD. In general, the clinical use of MAO-I nowadays is underestimated. There should be more efforts to evaluate their clinical potency as antidepressants and antidementive drugs in addition to the final proof of their disease-modifying potential. In line with this are recent innovative developments of MAO-I plus inhibition of acetylcholine esterase for Alzheimer's disease as well as combined MAO-I and iron chelation for PD. PMID:22110357

Antidepressants versus placebo for panic disorder in adults.

PubMed

Bighelli, Irene; Castellazzi, Mariasole; Cipriani, Andrea; Girlanda, Francesca; Guaiana, Giuseppe; Koesters, Markus; Turrini, Giulia; Furukawa, Toshi A; Barbui, Corrado

2018-04-05

Panic disorder is characterised by repeated, unexpected panic attacks, which represent a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes, and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. It is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, the National Institute for Health and Care Excellence (NICE) and the British Association for Psychopharmacology consider antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Several classes of antidepressants have been studied and compared, but it is still unclear which antidepressants have a more or less favourable profile in terms of effectiveness and acceptability in the treatment of this condition. To assess the effects of antidepressants for panic disorder in adults, specifically:1. to determine the efficacy of antidepressants in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison to placebo;2. to review the acceptability of antidepressants in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate the adverse effects of antidepressants in panic disorder, with or without agoraphobia, including the general prevalence of adverse effects, compared to placebo. We searched the Cochrane Common Mental Disorders' (CCMD) Specialised Register, and CENTRAL, MEDLINE, EMBASE and PsycINFO up to May 2017. We handsearched reference lists of relevant papers and previous systematic reviews. All double-blind, randomised, controlled trials (RCTs) allocating adults with panic disorder to antidepressants or placebo. Two review authors independently checked eligibility and extracted data using a standard form. We entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details and settings. Primary outcomes included failure to respond, measured by a range of response scales, and treatment acceptability, measured by total number of dropouts for any reason. Secondary outcomes included failure to remit, panic symptom scales, frequency of panic attacks, agoraphobia, general anxiety, depression, social functioning, quality of life and patient satisfaction, measured by various scales as defined in individual studies. We used GRADE to assess the quality of the evidence for each outcome MAIN RESULTS: Forty-one unique RCTs including 9377 participants overall, of whom we included 8252 in the 49 placebo-controlled arms of interest (antidepressant as monotherapy and placebo alone) in this review. The majority of studies were of moderate to low quality due to inconsistency, imprecision and unclear risk of selection and performance bias.We found low-quality evidence that revealed a benefit for antidepressants as a group in comparison with placebo in terms of efficacy measured as failure to respond (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.66 to 0.79; participants = 6500; studies = 30). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 6 to 9): that means seven people would need to be treated with antidepressants in order for one to benefit. We observed the same finding when classes of antidepressants were compared with placebo.Moderate-quality evidence suggested a benefit for antidepressants compared to placebo when looking at number of dropouts due to any cause (RR 0.88, 95% CI 0.81 to 0.97; participants = 7850; studies = 30). The magnitude of effect corresponds to a NNTB of 27 (95% CI 17 to 105); treating 27 people will result in one person fewer dropping out. Considering antidepressant classes, TCAs showed a benefit over placebo, while for SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs) we observed no difference.When looking at dropouts due to adverse effects, which can be considered as a measure of tolerability, we found moderate-quality evidence showing that antidepressants as a whole are less well tolerated than placebo. In particular, TCAs and SSRIs produced more dropouts due to adverse effects in comparison with placebo, while the confidence interval for SNRI, noradrenergic reuptake inhibitors (NRI) and other antidepressants were wide and included the possibility of no difference. The identified studies comprehensively address the objectives of the present review.Based on these results, antidepressants may be more effective than placebo in treating panic disorder. Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit. Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts, but a less favourable profile in terms of dropout due to adverse effects. However, the tolerability profile varied between different classes of antidepressants.The choice of whether antidepressants should be prescribed in clinical practice cannot be made on the basis of this review.Limitations in results include funding of some studies by pharmaceutical companies, and only assessing short-term outcomes.Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.

Metabolism-Activated Multitargeting (MAMUT): An Innovative Multitargeting Approach to Drug Design and Development.

PubMed

Mátyus, Péter; Chai, Christina L L

2016-06-20

Multitargeting is a valuable concept in drug design for the development of effective drugs for the treatment of multifactorial diseases. This concept has most frequently been realized by incorporating two or more pharmacophores into a single hybrid molecule. Many such hybrids, due to the increased molecular size, exhibit unfavorable physicochemical properties leading to adverse effects and/or an inappropriate ADME (absorption, distribution, metabolism, and excretion) profile. To avoid this limitation and achieve additional therapeutic benefits, here we describe a novel multitargeting strategy based on the synergistic effects of a parent drug and its active metabolite(s). The concept of metabolism-activated multitargeting (MAMUT) is illustrated using a number of examples. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Switching and combining strategies of antidepressant medications].

PubMed

Charpeaud, Thomas; Moliere, Fanny; Bubrovszky, Maxime; Haesebaert, Frédéric; Allaïli, Najib; Bation, Rémy; Nieto, Isabel; Richieri, Raphaëlle; Saba, Ghassen; Bellivier, Frank; Bennabi, Djamila; Holtzmann, Jérôme; Camus, Vincent; Courtet, Philippe; Courvoisier, Pierre; d'Amato, Thierry; Doumy, Olivier; Garnier, Marion; Bougerol, Thierry; Lançon, Christophe; Haffen, Emmanuel; Leboyer, Marion; Llorca, Pierre-Michel; Vaiva, Guillaume; El-Hage, Wissam; Aouizerate, Bruno

2016-03-01

Switching antidepressant medication may be helpful in depressed patients having no benefit from the initial antidepressant treatment. Before considering switching strategy, the initial antidepressant treatment should produce no therapeutic effect after at least 4 weeks of administration at adequate dosage. Choosing an antidepressant of pharmacologically distinct profile fails to consistently demonstrate a significant superiority in terms of effectiveness over the switching to another antidepressant within the same pharmacological class. Augmenting SSRI/SNRIs with mirtazapine/mianserin has become the most recommended strategy of antidepressant combinations. Augmenting SSRI with tricyclic drugs is now a less recommended strategy of antidepressant combinations given the increased risk for the occurrence of pharmacokinetic drug-drug interactions and adverse effects. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Comparing new anticoagulants.

PubMed

Wooten, James M

2012-12-01

For years, the pharmaceutical industry has been trying to find a safe and effective drug to replace warfarin. Although warfarin is an effective anticoagulant, its pharmacology, adverse effects, and risk profiles dictate that patients taking this medication must be monitored judiciously. The US Food and Drug Administration has approved two drugs for commercial use, dabigatran and rivaroxaban, that will compete directly with warfarin for use in specific indications. Because of direct marketing to patients, physicians are being asked to comment on these new medications. This brief review illustrates the data available for the two new drugs when compared to warfarin for the specified indications. For some patients, these drugs may be highly beneficial and offer an excellent alternative to warfarin. For others, warfarin may still be the preferred drug.

Perampanel. Just another anticonvulsant for partial epilepsy: no progress.

PubMed

2014-07-01

Nearly a dozen antiepileptic drugs have been shown to prevent attacks in patients with partial epilepsy, whether used alone, or in combination when successive single-agent well-conducted treatments have failed. Perampanel (Fycompa, Eisai) an AMPA glutamate receptor antagonist, has been granted marketing authorisation in the European Union and United States, for use in combination with other antiepileptic drugs in patients aged 12 years or older with partial epilepsy. Perampanel has not been compared with other antiepileptic drugs in clinical trials. Its evaluation is based on three comparative, double-blind, placebo-controlled trials, in which perampanel was added to other antiepileptic drugs considered to be inadequately effective. In these trials, after 19 weeks of treatment, its efficacy was only modest: the response rate was at best only about 20% higher than with placebo. Indirect comparison, albeit inherently unreliable, suggests that perampanel is no better than other antiepileptic drugs. Perampanel has frequent and often dose-dependent adverse effects; they mainly include irritability, aggression, impaired alertness and coordination, and weight gain. Cardiac disorders were observed during a long-term trial of perampanel. This possible adverse effect requires further study. Perampanel led to stunted growth in experimental animals. It is not known whether adolescents are also at risk. Perampanel does not appear to be a potent inducer or inhibitor of the cytochrome P450 enzyme system, but its drug interaction profile requires further evaluation. In animal studies, perampanel exposure resulted in increased perinatal mortality. In practice, there is no evidence that perampanel represents a therapeutic advance for patients with partial epilepsy. In addition to its known adverse effects, there are concerns over possible long-term cardiac toxicity and a deleterious effect on growth. Other acceptable solutions, based on better-known drugs, should be discussed with epileptic patients.

Safety and effectiveness of tadalafil in patients with pulmonary arterial hypertension: Japanese post-marketing surveillance data.

PubMed

Yamazaki, Hiroyoshi; Kobayashi, Noriko; Taketsuna, Masanori; Tajima, Koyuki; Murakami, Masahiro

2017-05-01

To evaluate the long-term safety and effectiveness of tadalafil in patients with pulmonary arterial hypertension (PAH) in real-world clinical practice. This prospective, multicenter, noninterventional, post-marketing surveillance included patients with PAH who were observed for up to 2 years after initiation of tadalafil. Safety was assessed by analyzing the frequency of adverse drug reactions (ADRs), discontinuations due to adverse events (AEs), and serious adverse drug reactions (SADRs). Effectiveness measurements included the assessment of the change in World Health Organization (WHO) functional classification of PAH, 6-minute walk test, cardiac catheterization, and echocardiography. Among 1676 patients analyzed for safety, the overall incidence of ADRs was 31.2%. The common ADRs (≥1.0%) were headache (7.0%), diarrhea (1.9%), platelet count decreased (1.8%), anemia, epistaxis, and nausea (1.6% each), flushing (1.3%), hepatic function abnormal (1.1%), hot flush, and myalgia (1.0% each). The common SADRs (≥0.3%) were cardiac failure (0.7%), interstitial lung disease, worsening of PAH, and platelet count decreased (0.3% each). Among 1556 patients analyzed for effectiveness, the percentages of patients with improvement of WHO functional class at 3 months, 1 year, and 2 years after the initiation of tadalafil, and last observation were 17.1%, 24.8%, 28.9%, and 22.5%, respectively. At all observation points (except pulmonary regurgitation pressure gradient at end diastole at 3 months), the mean 6-minute walk distance, cardiac catheterization, and echocardiogram measurements showed statistically significant improvement. This surveillance demonstrated that tadalafil has favorable safety and effectiveness profiles for long-term use in patients with PAH in Japan.

Zhibitai and low-dose atorvastatin reduce blood lipids and inflammation in patients with coronary artery disease.

PubMed

Zhao, Yuhong; Peng, Ran; Zhao, Wang; Liu, Qiong; Guo, Yuan; Zhao, Shuiping; Xu, Danyan

2017-02-01

Atorvastatin decreases blood lipids but is associated with side effects. Zhibitai is a traditional Chinese medicine used to treat blood lipid disorders. The objective of this study is to evaluate the lipid-lowering effect, antiinflammatory effect, and adverse events of zhibitai combined to atorvastatin in patients with coronary heart diseases (CHDs). Patients with CHD (n = 150) were randomized to: zhibitai 480 mg + atorvastatin 10 mg (ZA10 group), atorvastatin 20 mg (A20 group), and atorvastatin 40 mg (A40 group). Lipid profile, cardiotrophin-1 (CT-1), and C-reactive protein (CRP) were measured after 4 and 8 weeks of treatment. Self-reported side effects, liver function, kidney function, and creatine kinase levels were monitored. After 8 weeks, triglycerides, total cholesterol (TC), LDL-cholesterol (LDL-C), and apolipoprotein B100 (ApoB100) levels were decreased in the ZA10 group (-64%, -37%, -46%, and -54%, respectively, compared with baseline), and these changes were similar to those of the A40 group (P > 0.05). CT-1 and high sensitivity-C reactive protein (hs-CRP) levels were significantly decreased in the ZA10 group after 4 and 8 weeks (4 weeks: -73% and 96%; 8 weeks: -89% and -98%; all P < 0.01), without differences among the 3 groups (P > 0.05). After 8 weeks of treatment, adverse events (abdominal distention, nausea, vomiting, and hunger) were found in 4, 5, and 7 patients in the ZA10, A20, and A40 groups, respectively. ZA10 significantly reduced triglycerides, TC, LDL-C, ApoB, CT-1, and hs-CRP levels in patients with CHD, similar to the effects of A40 and A20, but ZA10 lead to fewer adverse events.

Comparison of oral oxycodone and naproxen in soft tissue injury pain control: a double-blind randomized clinical trial.

PubMed

Fathi, Marzieh; Zare, Mohammad Amin; Bahmani, Hamid Reza; Zehtabchi, Shahriar

2015-09-01

This randomized clinical trial compares the efficacy and safety of oral oxycodone (an oral opioid) with naproxen (a nonsteroidal anti-inflammatory drug) in acute pain control in patients with soft tissue injury. It also evaluates the need for additional doses of analgesics in the first 24 hours of discharge from emergency department (ED). Adult (>18 years old) patients with soft tissue injuries were enrolled in a teaching urban ED. Subjects were randomly allocated to receive a single dose of oral oxycodone (5 mg) or oral naproxen (250 mg). Pain scores and drugs' adverse effects were assessed before, 30 minutes, and 60 minutes after medication. efficacy in pain control (reduction in pain scale >2 points) and safety (rate of side effects). The need for additional pain medication after discharge was assessed by follow-up phone call 24 hours after discharge. A total of 150 patients were enrolled. Pain scores were similar in oxycodone vs naproxen groups before (6.21 ± 0.9 in vs 6.0 ± 1.0), 30 minutes (4.5 ± 1.4 vs 4.4 ± 1.2), and 60 minutes (2.5 ± 1.3 in vs 2.6 ± 1.3) after medication, respectively. Twelve (16.0%) patients in oral oxycodone group and 5 (6.6%) patients in naproxen group needed more analgesics in first 24 hours after ED discharge. Adverse effects were more common in oxycodone group (statistically significant difference). The most common adverse effects in oxycodone group were nausea, (13.3%); vomiting, (8.0%); dizziness, (5.3%); drowsiness, 3 (4.0%); and pruritis, (2.7%). Oral oxycodone is as effective as naproxen in soft tissue injury pain control but has a less favorable safety profile. Copyright © 2015 Elsevier Inc. All rights reserved.

Pranlukast: a review of its use in the management of asthma.

PubMed

Keam, Susan J; Lyseng-Williamson, Katherine A; Goa, Karen L

2003-01-01

Pranlukast (Onon, Azlaire), is an orally administered, selective, competitive antagonist of the cysteinyl leukotrienes (LT) C(4), LTD(4) and LTE(4). It is indicated for the prophylactic treatment of chronic bronchial asthma in paediatric and adult patients. The efficacy of pranlukast 225mg twice daily in adults with mild to moderate asthma was demonstrated in double-blind, placebo- or azelastine-controlled studies of 4 or 8 weeks' duration. The drug at this dosage was superior to both comparators in improving mean attack scores and morning and/or evening peak expiratory flow rates, and decreasing the use of rescue bronchodilators (p < 0.05). In limited clinical studies, pranlukast 225mg twice daily appeared to be as effective as montelukast 10mg once daily and zafirlukast 40mg twice daily in adults with mild to moderate asthma. Tachyphylaxis was absent when the drug was administered for up to 4 years. In patients requiring high-dose inhaled corticosteroid therapy, pranlukast 225 mg twice daily plus a halved dosage of inhaled corticosteroid was as effective as the original dosage of inhaled corticosteroid. Pranlukast was also effective in patients with mild to severe asthma in a clinical practice setting. In a double-blind trial, greater improvements in most outcome measures were observed with pranlukast than with oxatomide in children and adolescents with asthma. In clinical trials, pranlukast was well tolerated in adult and paediatric patients with asthma, with an adverse event profile similar to that of placebo. Gastrointestinal events and hepatic function abnormalities were the most commonly reported adverse events. No clinically significant differences in adverse event profiles between pranlukast, zafirlukast or montelukast were shown in limited comparisons. Although Churg-Strauss syndrome has been noted in pranlukast recipients, a direct causal relationship is unlikely. Pranlukast is a well tolerated and effective preventative treatment in adult and paediatric patients with persistent asthma of all severities. In some patients, pranlukast may be beneficial when added to low-dose inhaled corticosteroids; it may also be a viable alternative to increasing inhaled corticosteroid dosages. The efficacy of pranlukast relative to placebo has been confirmed; its efficacy relative to other therapy awaits further investigation. Nonetheless, pranlukast is a useful therapeutic option (with as-required short-acting beta(2)-agonists), either as preventative monotherapy for the treatment of mild persistent asthma or in conjunction with inhaled corticosteroids in the management of moderate or severe persistent asthma.

An update and review of antiretroviral therapy.

PubMed

Piacenti, Frank J

2006-08-01

The human immunodeficiency virus (HIV) was discovered in 1982, but treatment strategies were not introduced until 5 years later. Early regimens consisted of one or two drugs and often led to treatment failure. Since the advent in 1995 of highly active antiretroviral therapy (HAART), which consists of at least three agents, a dramatic improvement has been seen in the number of patients attaining undetectable viral loads, improved CD4 counts, and improved survival. However, early HAART often consisted of drugs with complex dosing schedules, strict food requirements, treatment-limiting adverse effects, and the need to take 16-20 pills/day. These treatment barriers often led to patient nonadherence, with subsequent treatment failure and development of resistant strains. The CD4 count and viral load are the most important surrogate markers used to determine if treatment is indicated. Current guidelines suggest starting treatment in patients who are symptomatic with an acquired immunodeficiency syndrome-defining illness regardless of CD4 count or viral load, as well as in asymptomatic patients with a CD4 count of 350 cells/mm(3) or below. In patients with CD4 counts above 350 cells/mm(3) and viral loads above 100,000 copies/ml, some clinicians prefer to defer treatment, whereas others will consider starting therapy; treatment is deferred in patients with CD4 counts above 350 cells/mm(3) and viral load s below 100,000 copies/ml. If therapy is started, the selection of appropriate agents is based on comorbidities (liver disease, depression, cardiovascular disease), pregnancy status, adherence potential (dosage regimen, pill burden, dosing frequency), food restrictions (dosing with regard to meals), adverse drug effects, and potential drug-drug interactions. Within the last 8 years, newer antiretroviral agents have focused on ways to improve adherence, such as convenient dosing (fewer pills), pharmacokinetic and formulation changes to reduce dosing frequency or pill burden, and coformulated dosage forms that contain two or three drugs in one convenient pill. Other improvements include increased potency of newer agents, agents sensitive to a highly resistant virus, improved adverse-effect profile (e.g., less gastrointestinal effects, improved lipid profiles), as well as protease inhibitor boosting with ritonavir, which takes advantage of the potent cytochrome P450 inhibitory action of ritonavir. This review focuses on the concepts of antiretroviral therapy, barriers to successful antiretroviral treatment, developments to limit treatment barriers, and new drug entities for the treatment of HIV.

The use of electroconvulsive therapy in the elderly: a study from the psychiatric unit of a north Indian teaching hospital.

PubMed

Jain, Gaurav; Kumar, Vineet; Chakrabarti, Subho; Grover, Sandeep

2008-06-01

There are very little data on elderly patients receiving electroconvulsive therapy (ECT) in India. This study was a preliminary attempt at characterizing the clinical and demographic profile of elderly subjects (>or=60 years) who received ECT in the psychiatric department of a teaching hospital in north India. A retrospective case-note review was carried out to identify patients 60 years or older who had received ECT over an 8-year period at the Postgraduate Institute of Medical Education and Research, Chandigarh, India. Several details about their demographic and clinical profile, indications for ECT, response patterns, and adverse effects were extracted. Over the 8 years, 373 patients received ECT, of which 56 (15%) were 60 years or older. Complete records were available for only 50 of these patients. The majority (96%) had depression. The index depressive episode for which ECT was used was severe in 91.6% of the subjects, and 68% had not responded to adequate psychotropic treatment before ECT. Comorbid medical illnesses were present in 66% of cases and were associated with significantly higher risk of cognitive side effects. However, side effects were usually mild; there were no serious untoward events caused by ECT. About 80% to 90% showed some response to treatment. Those who had received inadequate antidepressant treatment before ECT were significantly more likely to respond to ECT. Elderly with depression constitute a substantial proportion of those receiving ECT in India. Use of ECT in this population seemed to be mainly restricted to those who were very severely ill and poorly responsive to medications. Electroconvulsive therapy seemed to be a safe and effective treatment in such situations. However, particular care may be required in the subgroup with comorbid physical problems that may be more vulnerable to cognitive adverse effects.

Effects of cocoa products/dark chocolate on serum lipids: a meta-analysis.

PubMed

Tokede, O A; Gaziano, J M; Djoussé, L

2011-08-01

Cocoa products, which are rich sources of flavonoids, have been shown to reduce blood pressure and the risk of cardiovascular disease. Dark chocolate contains saturated fat and is a source of dietary calories; consequently, it is important to determine whether consumption of dark chocolate adversely affects the blood lipid profile. The objective was to examine the effects of dark chocolate/cocoa product consumption on the lipid profile using published trials. A detailed literature search was conducted via MEDLINE (from 1966 to May 2010), CENTRAL and ClinicalTrials.gov for randomized controlled clinical trials assessing the effects of flavanol-rich cocoa products or dark chocolate on lipid profile. The primary effect measure was the difference in means of the final measurements between the intervention and control groups. In all, 10 clinical trials consisting of 320 participants were included in the analysis. Treatment duration ranged from 2 to 12 weeks. Intervention with dark chocolate/cocoa products significantly reduced serum low-density lipoprotein (LDL) and total cholesterol (TC) levels (differences in means (95% CI) were -5.90 mg/dl (-10.47, -1.32 mg/dl) and -6.23 mg/dl (-11.60, -0.85 mg/dl), respectively). No statistically significant effects were observed for high-density lipoprotein (HDL) (difference in means (95% CI): -0.76 mg/dl (-3.02 to 1.51 mg/dl)) and triglyceride (TG) (-5.06 mg/dl (-13.45 to 3.32 mg/dl)). These data are consistent with beneficial effects of dark chocolate/cocoa products on total and LDL cholesterol and no major effects on HDL and TG in short-term intervention trials.

Prospective, randomized and controlled trial on magnesium sulfate administration during laparoscopic gastrectomy: effects on surgical space conditions and recovery profiles.

PubMed

Ryu, J H; Koo, B W; Kim, B G; Oh, A Y; Kim, H H; Park, D J; Lee, C M; Kim, S T; Do, S H

2016-11-01

The degree of neuromuscular blockade is one of the important factors that determine the condition of surgical space during laparoscopic surgery. Magnesium sulfate potentiates the actions of neuromuscular blocking agent, and we hypothesized that intraoperative magnesium sulfate infusion may improve surgical space condition during laparoscopic surgery. Eighty-four patients undergoing elective laparoscopic gastrectomy were randomized to receive isotonic saline (group C) or magnesium sulfate (group M, loading dose with 50 mg/kg over 10 min and then 15 mg/kg/h by continuous infusion) to maintain the moderate neuromuscular blockade using rocuronium. Two experienced surgeons scored the quality of surgical space condition using a 5-point surgical rating scale (SRS). The secondary outcomes included recovery profiles, postoperative pain and adverse events. The SRS in group M was higher than that of group C. The proportion of patients with a SRS of 5 (optimal) was 2.7 % in the group C and 40.5 % in the group M (P < 0.0001) although a lower amount of rocuronium was required in group M than group C [24.2 (6.5) mg/h for group M vs. 27.5 (6) mg/h for group C; P = 0.017]. Pain after operation site was less severe in group M than in group C at postoperative 24 h (P = 0.009). Recovery profiles and adverse events were similar between the two groups. Intraoperative administration of magnesium sulfate improved the quality of surgical space conditions and decreased neuromuscular blocking agent requirement and postoperative pain in patients undergoing laparoscopic gastrectomy.

Nonclinical Profile of BLZ-100, a Tumor-Targeting Fluorescent Imaging Agent.

PubMed

Parrish-Novak, Julia; Byrnes-Blake, Kelly; Lalayeva, Narine; Burleson, Stefanie; Fidel, Janean; Gilmore, Rhonda; Gayheart-Walsten, Pamela; Bricker, Gregory A; Crumb, William J; Tarlo, K S; Hansen, Stacey; Wiss, Valorie; Malta, Errol; Dernell, William S; Olson, James M; Miller, Dennis M

BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and nonhuman primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated, and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP. The single-dose no-observed-adverse-effect-levels (NOAELs) were 7 mg (28 mg/kg) in rats and 60 mg (20 mg/kg) in NHP, corresponding to peak concentration values of 89 400 and 436 000 ng/mL and area-under-the-curve exposure values of 130 000 and 1 240 000 h·ng/mL, respectively. Based on a human imaging dose of 3 mg, dose safety margins are >100 for rat and monkey. BLZ-100 produced hypersensitivity reactions in canine imaging studies (lethargy, pruritus, swollen muzzle, etc). The severity of the reactions was not dose related. In a follow-up study in dogs, plasma histamine concentrations were increased 5 to 60 minutes after BLZ-100 injection; this coincided with signs of hypersensitivity, supporting the conclusion that the reactions were histamine based. Hypersensitivity reactions were not observed in other species or in BLZ-100 human clinical studies conducted to date. The combined imaging, safety pharmacology, PK, and toxicology studies contributed to an extensive initial nonclinical profile for BLZ-100, supporting first-in-human clinical trials.

Use of high-throughput and in vivo data to support read ...

EPA Pesticide Factsheets

Disrupting normal function of mitochondria can culminate in a variety of organ-level toxicities. A number of mechanisms - such as uncoupling of oxidative phosphorylation and inhibition of the electron transport chain - have been implicated in mitochondrial toxicity. The presence of mitochondrial toxicity has led to a number of drugs being withdrawn from the market highlighting the need to identify potential mitochondrial toxicants within the environment. High-throughput screening (HTS) assays provide a means of rapidly gathering toxicity data for a large number of chemicals; however, information as to the associated in vivo effect is typically unknown. The Adverse Outcome Pathway (AOP) concept provides a valuable scaffold onto which mechanistic data from different levels of biological organisation can be arranged.Information pertaining to mitochondrial toxicity from the U.S. EPA’s ToxCast program were integrated with rodent in vivo data from U.S. EPA’s ToxRefDB to connect the high throughput ToxCast assay results with potential adverse outcome data. Previously developed structural alerts were utilized to profile the chemicals with both in vitro mitochondrial toxicity and in vivo rodent data. Structural similarity guided by the toxicity profile as measured in the ToxCast assay battery was then used to group those chemicals which either were not tested in a mitochondrial toxicity assay or were not considered a “hit” and read-across was performed. Subsequen

Management of disease-modifying treatments in neurological autoimmune diseases of the central nervous system.

PubMed

Salmen, A; Gold, R; Chan, A

2014-05-01

The therapeutic armamentarium for autoimmune diseases of the central nervous system, specifically multiple sclerosis and neuromyelitis optica, is steadily increasing, with a large spectrum of immunomodulatory and immunosuppressive agents targeting different mechanisms of the immune system. However, increasingly efficacious treatment options also entail higher potential for severe adverse drug reactions. Especially in cases failing first-line treatment, thorough evaluation of the risk-benefit profile of treatment alternatives is necessary. This argues for the need of algorithms to identify patients more likely to benefit from a specific treatment. Moreover, paradigms to stratify the risk for severe adverse drug reactions need to be established. In addition to clinical/paraclinical measures, biomarkers may aid in individualized risk-benefit assessment. A recent example is the routine testing for anti-John Cunningham virus antibodies in natalizumab-treated multiple sclerosis patients to assess the risk for the development of progressive multi-focal leucoencephalopathy. Refined algorithms for individualized risk assessment may also facilitate early initiation of induction treatment schemes in patient groups with high disease activity rather than classical escalation concepts. In this review, we will discuss approaches for individiualized risk-benefit assessment both for newly introduced agents as well as medications with established side-effect profiles. In addition to clinical parameters, we will also focus on biomarkers that may assist in patient selection. © 2013 British Society for Immunology.

Hepatitis C virus adversely affects quality of life.

PubMed

Cillo, Umberto; Amodio, Piero; Ronco, Claudio; Soni, Sachin S; Zanus, Giacomo; Minazzato, Lina; Salari, Annalisa; Neri, Daniele; Bombonato, Giancarlo; Schiff, Sami; Bianco, Tonino

2011-01-01

Chronic liver disease secondary to hepatitis C virus (HCV) infection is a common clinical problem. HCV is likely to adversely affect the quality of life (QoL) of the patient. This effect is said to be disproportionate to the severity of the disease. The aim of our study was to evaluate QoL in HCV-positive patients focusing both on health status and subjective satisfaction. Twenty-four patients with combined HCV and alcoholic liver disease (ETOH-HCV) were enrolled in the study. We adopted two generic tools: SF-36 (a health status questionnaire) and SAT-P (a satisfaction profile) for psychological assessment of the patients. SF-36 and SAT-P scores of ETOH-HCV patients were compared with scores of 23 patients with alcoholic liver disease (ETOH). The scores obtained from the study groups were also compared with the reference scores of the healthy Italian population. Both the groups were comparable with respect to age, histological and clinical severity of liver disease (as assessed by MELD and Child Pugh scores). Patients with ETOH-HCV scored less in the vitality and role emotional status domains of the SF-36 scores and the psychological function, social function and free time domains of the satisfaction profile. These results show a significant impact of HCV infection on health status and subjective satisfaction. Copyright © 2011 S. Karger AG, Basel.

DNA methylation profiles of elderly individuals subjected to indentured childhood labor and trauma.

PubMed

Marinova, Zoya; Maercker, Andreas; Küffer, Andreas; Robinson, Mark D; Wojdacz, Tomasz K; Walitza, Susanne; Grünblatt, Edna; Burri, Andrea

2017-02-27

Childhood trauma is associated with increased vulnerability to mental and somatic disorders later in life. Epigenetic modifications such as DNA methylation are one potential mechanism through which such long-lasting impairments/consequences can be explained. The aim of the present study was to investigate whether childhood trauma is associated with long-term DNA methylation alterations in old age. We assessed genome-wide DNA methylation profiles in a cohort of former indentured child laborers ("Verdingkinder") who suffered severe childhood adversities (N = 30; M age = 75.9 years), and compared them to control group with similar demographic characteristics (N = 15, M age = 72.8 years). DNA was isolated from epithelial buccal cells and hybridized to the Illumina Infinium 450 k DNA methylation array, which provides coverage of 485,000 methylation sites. After accounting for batch effects, age, gender and multiple testing, 71 differentially methylated CpG positions were identified between the two groups. They were annotated among others to genes involved in neuronal projections and neuronal development. Some of the identified genes with differential methylation (DLG associated protein 2, mechanistic target of rapamycin) have previously been associated with traumatic stress. The results indicate specific epigenetic alterations in elderly individuals who were subjected to childhood adversities. Psychiatric and somatic comorbidities as well as differences in buccal epithelial cells proportion may contribute to the observed epigenetic differences.

Psychosis during pregnancy: treatment considerations.

PubMed

Pinkofsky, H B

1997-09-01

The onset of psychosis during pregnancy presents several difficult management decisions and a careful risk-benefit analysis is required. Withholding antipsychotic treatment may produce more risks than benefits. Studies on neuroleptic teratogenicity are contradictory. Most of the commonly used neuroleptics exhibit a pregnancy risk of category C. Neuroleptic use during pregnancy may be associated with adverse effects in the pre- and postnatal period. These concerns include compromising uterine blood flow, post-partum neonatal sedation, and extrapyramidal signs expressed in the neonate. Each neuroleptic exhibits a unique pharmacokinetic profile. The antipsychotic properties and side effects considered most significant include sedation, half-life, hypotension, and apparent hydrophilicity. In this case study a decision to select molindone was based on these parameters.

Ordered roughness effects on NACA 0026 airfoil

NASA Astrophysics Data System (ADS)

Harun, Z.; Abbas, A. A.; Dheyaa, R. Mohammed; Ghazali, M. I.

2016-10-01

The effects of highly-ordered rough surface - riblets, applied onto the surface of a NACA 0026 airfoil, are investigated experimentally using wind tunnel. The riblets are arranged in directionally converging - diverging pattern with dimensions of height, h = 1 mm, pitch or spacing, s = 1 mm, yaw angle α = 0o and 10o The airfoil with external geometry of 500 mm span, 600 mm chord and 156 mm thickness has been built using mostly woods and aluminium. Turbulence quantities are collected using hotwire anemometry. Hotwire measurements show that flows past converging and diverging pattern inherit similar patterns in the near-wall region for both mean velocity and turbulence intensities profiles. The mean velocity profiles in logarithmic regions for both flows past converging and diverging riblet pattern are lower than that with yaw angle α = 0o. Converging riblets cause the boundary layer to thicken and the flow with yaw angle α = 0o produces the thinnest boundary layer. Both the converging and diverging riblets cause pronounced outer peaks in the turbulence intensities profiles. Most importantly, flows past converging and diverging pattern experience 30% skin friction reductions. Higher order statistics show that riblet surfaces produce similar effects due to adverse pressure gradient. It is concluded that a small strip of different ordered roughness features applied at a leading edge of an airfoil can change the turbulence characteristics dramatically.

The adverse health effects of synthetic cannabinoids with emphasis on psychosis-like effects.

PubMed

van Amsterdam, Jan; Brunt, Tibor; van den Brink, Wim

2015-03-01

Cannabis use is associated with an increased risk of psychosis in vulnerable individuals. Cannabis containing high levels of the partial cannabinoid receptor subtype 1 (CB1) agonist tetrahydrocannabinol (THC) is associated with the induction of psychosis in susceptible subjects and with the development of schizophrenia, whereas the use of cannabis variants with relatively high levels of cannabidiol (CBD) is associated with fewer psychotic experiences. Synthetic cannabinoid receptor agonists (SCRAs) are full agonists and often more potent than THC. Moreover, in contrast to natural cannabis, SCRAs preparations contain no CBD so that these drugs may have a higher psychosis-inducing potential than cannabis. This paper reviews the general toxicity profile and the adverse effects of SCRAs with special emphasis on their psychosis-inducing risk. The review shows that, compared with the use of natural cannabis, the use of SCRAs may cause more frequent and more severe unwanted negative effects, especially in younger, inexperienced users. Psychosis and psychosis-like conditions seem to occur relatively often following the use of SCRAs, presumably due to their high potency and the absence of CBD in the preparations. Studies on the relative risk of SCRAs compared with natural cannabis to induce or evoke psychosis are urgently needed. © The Author(s) 2015.

Ophthalmic preservatives: focus on polyquaternium-1.

PubMed

Rolando, Maurizio; Crider, Julie Y; Kahook, Malik Y

2011-11-01

Ophthalmic preservatives, such as polyquaternium-1 (PQ-1), are critical for the inhibition of growth of microbial contaminants in multi-dose bottles of topical medications. These antimicrobial agents must have a high efficacy against pathogenic organisms, while maintaining a favorable tolerability and safety profile. This review focuses on the ophthalmic preservative PQ-1. For comparison purposes, the most commonly used preservative, benzalkonium chloride (BAK), is also discussed. This survey focuses primarily on data collected during the past 10 years. Effective drug delivery requires more than just an active ingredient that achieves its desired biological effect on end-target tissues. In addition, drugs must be stable in the containers that they are stored in, and must possess minimal undesired local and systemic side effects that can cause patients to decrease their adherence. In addressing these concerns, specifically in topical ophthalmic drops, one must take into account the active ingredients, vehicle components and preservatives. Medications with fewer adverse effects may lead to enhanced adherence to therapy; therefore, the induction of such adverse outcomes must be considered by physicians when treating patients with chronic ocular disease. Although BAK will continue to be used in ophthalmic medications, due to its familiarity and compatibility with a broad range of topical ocular formulations, PQ-1 is certainly a viable alternative in the preservative formulary armamentarium.

Comparison of gene expression changes induced by biguanides in db/db mice liver.

PubMed

Heishi, Masayuki; Hayashi, Koji; Ichihara, Junji; Ishikawa, Hironori; Kawamura, Takao; Kanaoka, Masaharu; Taiji, Mutsuo; Kimura, Toru

2008-08-01

Large-scale clinical studies have shown that the biguanide drug metformin, widely used for type 2 diabetes, to be very safe. By contrast, another biguanide, phenformin, has been withdrawn from major markets because of a high incidence of serious adverse effects. The difference in mode of action between the two biguanides remains unclear. To gain insight into the different modes of action of the two drugs, we performed global gene expression profiling using the livers of obese diabetic db/db mice after a single administration of phenformin or metformin at levels sufficient to cause a significant reduction in blood glucose level. Metformin induced modest expression changes, including G6pc in the liver as previously reported. By contrast, phenformin caused changes in expression level of many additional genes. We used a knowledge-based bioinformatic analysis to study the effects of phenformin. Differentially expressed genes identified in this study constitute a large gene network, which may be related to cell death, inflammation or wound response. Our results suggest that the two biguanides show a similar hypoglycemic effect in db/db mice, but phenformin induces a greater stress on the liver even a short time after a single administration. These findings provide a novel insight into the cause of the relatively high occurrence of serious adverse effect after phenformin treatment.

Epilepsy and adverse quality of life in surgically resected meningioma.

PubMed

Tanti, M J; Marson, A G; Jenkinson, M D

2017-09-01

Meningiomas are common intracranial tumors, and despite surgery or therapy with anti-epileptic drugs (AEDs), many patients suffer from seizures. Epilepsy has a significant impact on quality of life (QoL) in non-tumor populations, but the impact of epilepsy on QoL in patients with meningioma is unknown. Our aim was to evaluate the impact of epilepsy on QoL in patients that have undergone resection of a benign meningioma. We recruited meningioma patients without epilepsy (n=109), meningioma patients with epilepsy (n=56), and epilepsy patients without meningioma (n=64). QoL was measured with the Short Form 36 version 2 (SF-36), the Functional Assessment of Cancer Therapy (FACT-BR), and the Liverpool Adverse Events Profile (LAEP). Regression analyses identified significant determinants of QoL. Patients with meningioma and epilepsy had poorer QoL scores than meningioma patients without epilepsy in all measures. In FACT-BR, this difference was significant. Multiple regression analyses demonstrated that current AED use had a greater impact on QoL scores than recent seizures. Other variables associated with impaired QoL included depression, unemployment, and meningioma attributed symptoms. Epilepsy has a negative impact on quality of life in patients with benign meningioma. AED use is correlated with impaired QoL and raised LAEP scores, suggesting that AEDs and adverse effects may have led to impaired QoL in our meningioma patients with epilepsy. The severity of epilepsy in our meningioma population was comparatively mild; therefore, a more conservative approach to AED therapy may be indicated in an attempt to minimize adverse effects. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies.

PubMed

Kunwar, Sandeep; Chang, Susan M; Prados, Michael D; Berger, Mitchel S; Sampson, John H; Croteau, David; Sherman, Jeffrey W; Grahn, Amy Y; Shu, Vince S; Dul, Jeanne L; Husain, Syed R; Joshi, Bharat H; Pedain, Christoph; Puri, Raj K

2006-04-15

Convection-enhanced delivery (CED) is an increasingly used novel local/regional delivery method targeted directly to tissue. It relies on a continuous pressure gradient for distribution of therapeutic agents into the interstitial space, with administration of the infusate over a few days. Cintredekin besudotox (also known as IL13- PE38QQR) is a recombinant chimeric cytotoxin consisting of interleukin-13 and a truncated exotoxin produced by the Pseudomonas aeruginosa bacterium, which targets malignant glioma cells. Cintredekin besudotox was administered via intraparenchymal CED after resection of supratentorial recurrent malignant glioma. The safety and toxicity profile was reviewed for 53 patients in whom infusion catheters had been placed; 51 of them received CED of the study drug. Adverse events were categorized based on time of onset in relation to CED, and the causal relationship with catheter placement or delivery of cintredekin besudotox. Catheters were placed in 53 patients, although only 51 of them received cintredekin besudotox. Most adverse events related to catheter placement or the study drug originated from the central nervous system. Three symptomatic windows were defined: the first one was between surgical procedure and CED; the second was during CED and up to 1 week after its completion; and the third window was 2 to 10 weeks after treatment. Those windows generally reflected adverse events related to surgical procedures, mass effect from infusate, and drug effect on tumor-infiltrated and normal brain parenchyma, respectively. The symptomatic windows identified in this study apply to any CED clinical trials, particularly those in which chimeric cytotoxins are used, and will help to determine the most likely underlying pathophysiological process causing symptoms. This information, in turn, will help to prevent adverse events or minimize their severity. Those events also have implications for dose escalation and outcome measures.

Does physical activity during pregnancy adversely influence markers of the metabolic syndrome in adult offspring? A prospective study over two decades.

PubMed

Danielsen, Inge; Granström, Charlotta; Rytter, Dorte; Hammer Bech, Bodil; Brink Henriksen, Tine; Vaag, Allan Arthur; Olsen, Sjurdur Frodi

2013-08-01

It is unknown whether physical activity during pregnancy (PA) has long-term impact on the metabolic profile of the offspring. We investigated associations of PA with markers of the metabolic syndrome (MS) in 20y old offspring. Longitudinal study where 965 pregnant women during 1988-1989 had four dimensions of PA assessed by questionnaires in gestation week 30: PA at work; leisure time PA, daily amount of walking-biking and sport participation. The following MS markers were assessed in the offspring (n=439): body mass index (BMI), waist circumference, blood pressure, homeostasis model assessment insulin resistance as well as fasting plasma glucose, triglycerides, cholesterol (high-density lipoprotein (HDL), low-density lipoprotein and total cholesterol), insulin and leptin levels. Walking-biking PA in pregnancy is associated with unchanged or subtle, adverse changes of distinct MS markers among offspring including lower levels of HDL cholesterol (ratio 0.95 (95% CI 0.92 to 0.98) per 1 h increment in walking-biking), a higher diastolic blood pressure (difference 1.12 (95% CI 0.03 to 2.20) mm Hg/1 h increment) and a higher BMI (ratio 1.03 (95% CI 1.01 to 1.05) per 1 h increment). In separate analyses in males, these associations persisted and additional adverse associations were found for triglycerides, systolic blood pressure, waist circumference and leptin. No associations were detected with other measures of PA. The study did not substantiate any protective effects of PA in pregnancy. In contrast, data suggested that high amounts of daily walking-biking in pregnancy may have adverse effects on levels of HDL cholesterol, diastolic blood pressure and BMI in young adult offspring.

Investigation of blown boundary layers with an improved wall jet system

NASA Technical Reports Server (NTRS)

Saripalli, K. R.; Simpson, R. L.

1980-01-01

Measurements were made in a two dimensional incompressible wall jet submerged under a thick upstream boundary layer with a zero pressure gradient and an adverse pressure gradient. The measurements included mean velocity and Reynolds stresses profiles, skin friction, and turbulence spectra. The measurements were confined to practical ratios (less than 2) of the jet velocity to the free stream velocity. The wall jet used in the experiments had an asymmetric velocity profile with a relatively higher concentration of momentum away from the wall. An asymmetric jet velocity profile has distinct advantages over a uniform jet velocity profile, especially in the control of separation. Predictions were made using Irwin's (1974) method for blown boundary layers. The predictions clearly show the difference in flow development between an asymmetric jet velocity profile and a uniform jet velocity profile.

Active flow control for a blunt trailing edge profiled body

NASA Astrophysics Data System (ADS)

Naghib Lahouti, Arash

Flow in the wake of nominally two-dimensional bluff bodies is dominated by vortex shedding, beyond a very small threshold Reynolds number. Vortex shedding poses challenges in the design of structures, due to its adverse effects such as cyclic aerodynamic loads and fatigue. The wake vortices are often accompanied by large- and small-scale secondary instabilities, which manifest as dislocations in the primary wake vortices, and/or pairs of counter-rotating streamwise vortices, depending on the dominant instability mode(s), which in turn depends on the profile geometry and Reynolds number. The secondary instabilities interact with the wake vortices through several mechanisms. Therefore, manipulation of the secondary instabilities can be used as a means to alter the wake vortices, in order to reduce their adverse effects. In the present study, flow in the wake of a blunt trailing edge profiled body, composed of an elliptical leading edge and a rectangular trailing edge, has been studied at Reynolds numbers ranging from Re(d) = 500 to 2150 where d is thickness of the body, to identify the secondary instabilities. Various tools, including numerical simulations, Laser Induced Fluorescence (LIF), and Particle Image Velocimetry (PIV) have been used for this study. Proper Orthogonal Decomposition (POD) has been applied to analyze the velocity field data. The results indicate the existence of small-scale instabilities with a spanwise wavelength of 2.0d to 2.5d in the near wake. The mechanism of the instability is similar to the Mode-A instability of a circular cylinder; however, it displays features that are specific to the blunt trailing edge profiled body. An active three-dimensional flow control mechanism based on the small-scale instabilities has been designed and evaluated. The mechanism comprises a series of trailing edge injection ports, with a spanwise spacing equal to the wavelength of the small-scale instabilities. Following preliminary evaluation of the control mechanism through numerical simulations, and experimental study of the effect of injection flow rate, extensive PIV experiments have been conducted to investigate the effectiveness of the flow control mechanism, and its effects on the wake flow structure, at Reynolds numbers ranging from Re(d ) = 700 to 1980. Measurements have been carried out at multiple spanwise locations, to establish a comprehensive image of the effect of the flow control mechanism on parameters such as drag force, wake width, and formation length. POD analysis and frequency spectrums are used to describe the process by which the mechanism affects the wake parameters and drag force. The results indicate that the flow control mechanism is able to reduce drag force by 10%. It is also shown that the best effectiveness in terms of suppression of the drag component resulting from velocity fluctuations is achieved when the flow control actuation wavelength closely matches the wavelength of the small-scale instabilities. KEYWORDS: Blunt Trailing Edge Profiled Body, Vortex Shedding, Wake Instability, Streamwise Vortex, Flow Control, Drag Reduction, Particle Image Velocimetry (PIV), Laser Induced Fluorescence (LIF), Flow Visualization, Numerical Simulation

Rheology, fatty acid profile and storage characteristics of cookies as influenced by flax seed (Linum usitatissimum).

PubMed

Rajiv, Jyotsna; Indrani, Dasappa; Prabhasankar, Pichan; Rao, G Venkateswara

2012-10-01

Flaxseed is a versatile functional ingredient owing to its unique nutrient profile. Studies on the effect of substitution of roasted and ground flaxseed (RGF) at 5, 10, 15 and 20% level on the wheat flour dough properties showed that amylograph peak viscosity, farinograph dough stability, extensograph resistance to extension and extensibility values decreased with the increase in the substitution of RGF from 0-20%. The cookie baking test showed a marginal decrease in spread ratio but beyond substitution of 15% RGF the texture and flavour of the cookies was adversely affected. The data on storage characteristics of control and cookies with 15% RGF showed no significant change with respect to acidity of extracted fat and peroxide values due to storage of cookies upto 90 days in metallised polyester pouches at ambient conditions. The gas chromatographic analysis of fatty acid profile indicated that the control cookies contained negligible linolenic acid and the flaxseed cookies contained 4.75 to 5.31% of linolenic acid which showed a marginal decrease over storage. Hence flaxseed could be used as a source of omega-3-fatty acid.

Proteomic Analysis of Whole Human Saliva Detects Enhanced Expression of Interleukin-1 Receptor Antagonist, Thioredoxin and Lipocalin-1 in Cigarette Smokers Compared to Non-Smokers

PubMed Central

Jessie, Kala; Pang, Wei Wei; Haji, Zubaidah; Rahim, Abdul; Hashim, Onn Haji

2010-01-01

A gel-based proteomics approach was used to screen for proteins of differential abundance between the saliva of smokers and those who had never smoked. Subjecting precipitated proteins from whole human saliva of healthy non-smokers to two-dimensional electrophoresis (2-DE) generated typical profiles comprising more than 50 proteins. While 35 of the proteins were previously established by other researchers, an additional 22 proteins were detected in the 2-DE saliva protein profiles generated in the present study. When the 2-DE profiles were compared to those obtained from subjects considered to be heavy cigarette smokers, three saliva proteins, including interleukin-1 receptor antagonist, thioredoxin and lipocalin-1, showed significant enhanced expression. The distribution patterns of lipocalin-1 isoforms were also different between cigarette smokers and non-smokers. The three saliva proteins have good potential to be used as biomarkers for the adverse effects of smoking and the risk for inflammatory and chronic diseases that are associated with it. PMID:21151451

Antihistamines modulate the integrin signaling pathway in h9c2 rat cardiomyocytes: Possible association with cardiotoxicity.

PubMed

Yun, J S; Kim, S Y

2015-08-01

The identification of biomarkers for toxicity prediction is crucial for drug development and safety evaluation. The selective and specific biomarkers for antihistamines-induced cardiotoxicity is not well identified yet. In order to evaluate the mechanism of the life-threatening effects caused by antihistamines, we used DNA microarrays to analyze genomic profiles in H9C2 rat cardiomyocytes that were treated with antihistamines. The gene expression profiles from drug-treated cells revealed changes in the integrin signaling pathway, suggesting that cardiac arrhythmias induced by antihistamine treatment may be mediated by changes in integrin-mediated signaling. It has been reported that integrin plays a role in QT prolongation that may induce cardiac arrhythmia. These results indicate that the integrin-mediated signaling pathway induced by antihistamines is involved in various biological mechanisms that lead to cardiac QT prolongation. Therefore, we suggest that genomic profiling of antihistamine-treated cardiomyocytes has the potential to reveal the mechanism of adverse drug reactions, and this signal pathway is applicable to prediction of in vitro cardiotoxicity induced by antihistamines as a biomarker candidate. © The Author(s) 2014.

Monitoring and Management of Toxicities of Novel B Cell Signaling Agents.

PubMed

Rhodes, Joanna; Mato, Anthony; Sharman, Jeff P

2018-04-11

B cell signaling agents, including ibrutinib, idelalisib, and the BCL-2 inhibitor venetoclax have become an integral part of therapy for patients with non-Hodgkin's lymphomas. The toxicity profiles of these medications is distinct from chemoimmunotherapy. Here, we will review the mechanism of action of these drugs, their efficacy, and toxicity management. Ibrutinib use is associated with increased risk of atrial fibrillation and bleeding which can be managed using dose interruptions and modifications. Patients on idelalisib require close clinical and frequent laboratory monitoring, particularly of liver function tests to ensure there are no serious adverse events. Monitoring for infections is important in patients on both idelalisib and ibrutinib. Venetoclax requires close clinical and laboratory monitoring to prevent significant tumor lysis. Targeted B cell receptor therapies each have unique side effect profiles which require careful clinical monitoring. As we continue to use these therapies, optimal management strategies will continue to be elucidated.

Development of Impurity Profiling Methods Using Modern Analytical Techniques.

PubMed

Ramachandra, Bondigalla

2017-01-02

This review gives a brief introduction about the process- and product-related impurities and emphasizes on the development of novel analytical methods for their determination. It describes the application of modern analytical techniques, particularly the ultra-performance liquid chromatography (UPLC), liquid chromatography-mass spectrometry (LC-MS), high-resolution mass spectrometry (HRMS), gas chromatography-mass spectrometry (GC-MS) and high-performance thin layer chromatography (HPTLC). In addition to that, the application of nuclear magnetic resonance (NMR) spectroscopy was also discussed for the characterization of impurities and degradation products. The significance of the quality, efficacy and safety of drug substances/products, including the source of impurities, kinds of impurities, adverse effects by the presence of impurities, quality control of impurities, necessity for the development of impurity profiling methods, identification of impurities and regulatory aspects has been discussed. Other important aspects that have been discussed are forced degradation studies and the development of stability indicating assay methods.

Adverse weather impacts on arable cropping systems

NASA Astrophysics Data System (ADS)

Gobin, Anne

2016-04-01

Damages due to extreme or adverse weather strongly depend on crop type, crop stage, soil conditions and management. The impact is largest during the sensitive periods of the farming calendar, and requires a modelling approach to capture the interactions between the crop, its environment and the occurrence of the meteorological event. The hypothesis is that extreme and adverse weather events can be quantified and subsequently incorporated in current crop models. Since crop development is driven by thermal time and photoperiod, a regional crop model was used to examine the likely frequency, magnitude and impacts of frost, drought, heat stress and waterlogging in relation to the cropping season and crop sensitive stages. Risk profiles and associated return levels were obtained by fitting generalized extreme value distributions to block maxima for air humidity, water balance and temperature variables. The risk profiles were subsequently confronted with yields and yield losses for the major arable crops in Belgium, notably winter wheat, winter barley, winter oilseed rape, sugar beet, potato and maize at the field (farm records) to regional scale (statistics). The average daily vapour pressure deficit (VPD) and reference evapotranspiration (ET0) during the growing season is significantly lower (p < 0.001) and has a higher variability before 1988 than after 1988. Distribution patterns of VPD and ET0 have relevant impacts on crop yields. The response to rising temperatures depends on the crop's capability to condition its microenvironment. Crops short of water close their stomata, lose their evaporative cooling potential and ultimately become susceptible to heat stress. Effects of heat stress therefore have to be combined with moisture availability such as the precipitation deficit or the soil water balance. Risks of combined heat and moisture deficit stress appear during the summer. These risks are subsequently related to crop damage. The methodology of defining meteorological risks and subsequently relating the risk to the cropping calendar will be demonstrated for major arable crops in Belgium. Physically based crop models assist in understanding the links between adverse weather events, sensitive crop stages and crop damage. Financial support was obtained from Belspo under research contract SD/RI/03A.

Modified Atkins diet vs classic ketogenic formula in intractable epilepsy.

PubMed

El-Rashidy, O F; Nassar, M F; Abdel-Hamid, I A; Shatla, R H; Abdel-Hamid, M H; Gabr, S S; Mohamed, S G; El-Sayed, W S; Shaaban, S Y

2013-12-01

The study was designed to evaluate the efficacy, safety, and tolerability of the ketogenic diet (KD) whether classic 4:1 formula or the modified Atkins diet (MAD) in intractable childhood epilepsy. Anthropometric measurements and serum lipid profile were measured upon enrollment and after 3 and 6 months in 40 patients with symptomatic intractable epilepsy. Fifteen were given MAD diet, ten were kept on classic 4:1 ketogenic liquid formula, and the rest were allowed to eat as desired. The liquid ketogenic formula group showed significantly higher body mass index compared with those who did not receive KD after 6 months. The lipid profile of KD patients was within normal limits for age and sex during the study period. The rate of change of frequency and severity of seizures showed best improvement in ketogenic liquid formula patients followed by the MAD group than the patients on anti-epileptic medications alone. The KD whether classic 4:1 or MAD is a tolerable, safe, and effective adjuvant therapy for intractable symptomatic childhood epilepsy with limited adverse effects on the growth parameters and accepted changes in the lipid profile. The liquid ketogenic formula patients showed better growth pattern and significantly more seizure control. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Treatment of hay fever.

PubMed Central

Wood, S F

1989-01-01

The range of treatments for hay fever available to the general practitioner has changed considerably in recent years. New antihistamines have addressed the problem of sedation and moved towards one daily dose; nasally applied corticosteroids avoid the need for systemic steroid therapy and its potential adverse effect; and regulatory decisions have set a trend away from immunotherapy in general practice. However, knowledge about the mechanism of action of immunotherapy is increasing and new developments with improved safety profiles include allergen polymers, allergoids, oral immunotherapy and nasal immunotherapy. Choice of treatment depends, as always, on the individual circumstances of the patient and his or her disease. PMID:2556545

Lactating Mother and Psychotropic Drugs

PubMed Central

Tripathi, B. M.; Majumder, Pradipta

2010-01-01

Usage of psychotropics during pregnancy and lactation has always been a topic of debate and controversy. The debate stems from the potential adverse effects on the growing fetus or infants due to the transfer of psychotropic drugs through placenta or breast milk of mothers receiving them; and the problem of discontinuing psychotropics in lactating mother considering chances of relapse. However, most of the psychotropics are found to be relatively safe when used cautiously during the lactation phase. This article describes available data on the use of psychotropics in lactating mothers, in particular, in relation to the safety profile of infants. PMID:21327172

Efficacy of butylscopolamine for the treatment of catheter-related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study.

PubMed

Ryu, J H; Hwang, J W; Lee, J W; Seo, J H; Park, H P; Oh, A Y; Jeon, Y T; Do, S H

2013-12-01

Catheter-related bladder discomfort (CRBD) secondary to intraoperative catheterization of urinary bladder is one of the most distressing symptoms during recovery from anaesthesia. Butylscopolamine, a peripheral antimuscarinic agent, is effective for relieving the pain, which is because of smooth muscle contraction. The aim of this study was to assess the efficacy and safety profiles of butylscopolamine in treating CRBD after urological surgeries. Adult male patients undergoing urological surgery requiring urinary bladder catheterization intraoperatively were enrolled. Induction and maintenance of anaesthesia were standardized. Patients were randomized into two groups after complaining of CRBD in the post-anaesthesia care unit. The control group (n=29) received normal saline and the butylscopolamine group (n=28) was administered butylscopolamine 20 mg i.v. The severity of CRBD, postoperative pain, and adverse effects were assessed at baseline, 20 min, 1, 2, and 6 h after administration of the study drug. The severity of CRBD observed in the butylscopolamine group was significantly lower than that of the control group at 1, 2, and 6 h after administration of the study drug [59 (12), 50 (16), 40 (21) in the control group vs 41 (22), 32 (25), 23 (18) in the butylscopolamine group, P<0.01]. Rescue analgesics were required less in the butylscopolamine group than in the control group (P=0.001). Adverse events were comparable between the two groups. Butylscopolamine 20 mg administered i.v. after complaining CRBD during recovery reduced both the severity of CRBD and the need for rescue analgesics without adverse effects in patients undergoing urologic surgeries.

Motor outcome and electrode location in deep brain stimulation in Parkinson's disease.

PubMed

Koivu, Maija; Huotarinen, Antti; Scheperjans, Filip; Laakso, Aki; Kivisaari, Riku; Pekkonen, Eero

2018-05-30

To evaluate the efficacy and adverse effects of subthalamic deep brain stimulation (STN-DBS) in patients with advanced Parkinson's disease (PD) and the possible correlation between electrode location and clinical outcome. We retrospectively reviewed 87 PD-related STN-DBS operations at Helsinki University Hospital (HUH) from 2007 to 2014. The changes of Unified Parkinson's Disease Rating Scale (UPDRS) part III score, Hoehn & Yahr stage, antiparkinson medication, and adverse effects were studied. We estimated the active electrode location in three different coordinate systems: direct visual analysis of MRI correlated to brain atlas, location in relation to the nucleus borders and location in relation to the midcommisural point. At 6 months after operation, both levodopa equivalent doses (LEDs; 35%, Wilcoxon signed-rank test = 0.000) and UPDRS part III scores significantly decreased (38%, Wilcoxon signed-rank test = 0.000). Four patients (5%) suffered from moderate DBS-related dysarthria. The generator and electrodes had to be removed in one patient due to infection (1%). Electrode coordinates in the three coordinate systems correlated well with each other. On the left side, more ventral location of the active contact was associated with greater LED decrease. STN-DBS improves motor function and enables the reduction in antiparkinson medication with an acceptable adverse effect profile. More ventral location of the active contact may allow stronger LED reduction. Further research on the correlation between contact location, clinical outcome, and LED reduction is warranted. © 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

Neuropsychological Effects of Neuromodulation Techniques for Treatment-Resistant Depression: A Review

PubMed Central

Moreines, Jared L.; McClintock, Shawn M.; Holtzheimer, Paul E.

2010-01-01

Electroconvulsive therapy (ECT) and ablative neurosurgical procedures are established interventions for treatment-resistant depression (TRD), but their use may be limited in part by neuropsychological adverse effects. Additional neuromodulation strategies are being developed that aim to match or exceed the efficacy of ECT/ablative surgery with a better neurocognitive side effect profile. In this review, we briefly discuss the neurocognitive effects of ECT and ablative neurosurgical procedures, then synthesize the available neurocognitive information for emerging neuromodulation therapies including repetitive transcranial magnetic stimulation, magnetic seizure therapy, transcranial direct current stimulation, vagus nerve stimulation, and deep brain stimulation. The available evidence suggests these procedures may be more cognitively benign relative to ECT or ablative neurosurgical procedures, though further research is clearly needed to fully evaluate the neurocognitive effects, both positive and negative, of these novel neuromodulation interventions. PMID:21255751

A prospective, active haemovigilance study with combined cohort analysis of 19 175 transfusions of platelet components prepared with amotosalen–UVA photochemical treatment

PubMed Central

Knutson, F; Osselaer, J; Pierelli, L; Lozano, M; Cid, J; Tardivel, R; Garraud, O; Hervig, T; Domanovic, D; Cukjati, M; Gudmundson, S; Hjalmarsdottir, I B; Castrillo, A; Gonzalez, R; Brihante, D; Santos, M; Schlenke, P; Elliott, A; Lin, J-S; Tappe, D; Stassinopoulos, A; Green, J; Corash, L

2015-01-01

Background and Objectives A photochemical treatment process (PCT) utilizing amotosalen and UVA light (INTERCEPT™ Blood System) has been developed for inactivation of viruses, bacteria, parasites and leucocytes that can contaminate blood components intended for transfusion. The objective of this study was to further characterize the safety profile of INTERCEPT-treated platelet components (PCT-PLT) administered across a broad patient population. Materials and Methods This open-label, observational haemovigilance programme of PCT-PLT transfusions was conducted in 21 centres in 11 countries. All transfusions were monitored for adverse events within 24 h post-transfusion and for serious adverse events (SAEs) up to 7 days post-transfusion. All adverse events were assessed for severity (Grade 0–4), and causal relationship to PCT-PLT transfusion. Results Over the course of 7 years in the study centres, 4067 patients received 19 175 PCT-PLT transfusions. Adverse events were infrequent, and most were of Grade 1 severity. On a per-transfusion basis, 123 (0·6%) were classified an acute transfusion reaction (ATR) defined as an adverse event related to the transfusion. Among these ATRs, the most common were chills (77, 0·4%) and urticaria (41, 0·2%). Fourteen SAEs were reported, of which 2 were attributed to platelet transfusion (<0·1%). No case of transfusion-related acute lung injury, transfusion-associated graft-versus-host disease, transfusion-transmitted infection or death was attributed to the transfusion of PCT-PLT. Conclusion This longitudinal haemovigilance safety programme to monitor PCT-PLT transfusions demonstrated a low rate of ATRs, and a safety profile consistent with that previously reported for conventional platelet components. PMID:25981525

Safety and tolerability of atomoxetine in treatment of attention deficit hyperactivity disorder in adult patients: an integrated analysis of 15 clinical trials.

PubMed

Camporeale, Angelo; Porsdal, Vibeke; De Bruyckere, Katrien; Tanaka, Yoko; Upadhyaya, Himanshu; Deix, Claudia; Deberdt, Walter

2015-01-01

The safety profile of atomoxetine in the treatment of attention deficit hyperactivity disorder has been studied in many clinical trials. We performed an integrated safety analysis of 15 clinical trials in adults with attention deficit hyperactivity disorder. The analysis pooled patient data into three groups: acute placebo-controlled trials; long-term placebo-controlled trials; all trials. In total, 4829 adults (18-77 years, median: 36 years) were exposed to atomoxetine. Statistically significantly more atomoxetine-treated than placebo-treated patients experienced treatment-emergent adverse events (81.3% vs. 68.3% acute; 90.6% vs. 76.8% long term) and discontinued due to adverse events (8.9% vs. 4.0% acute; 17.9% vs. 6.3% long term). No statistically significant differences were observed in the proportion of patients experiencing serious adverse events. No previously unknown adverse events were identified. The most common adverse events included nausea, dry mouth, decreased appetite, insomnia and erectile dysfunction. Mean increases in heart rate (+5.2 beats per min) and blood pressure (systolic +2 mmHg, diastolic +1.9 mmHg) were modest. The proportion of patients experiencing clinically significant increases in blood pressure and heart rate at any time was statistically significantly higher with atomoxetine (systolic blood pressure 13-17%, diastolic blood pressure 37-40%, heart rate 42-43%) compared to placebo (systolic blood pressure 8-13%, diastolic blood pressure 29-34%, heart rate 21-26%). There was no increased risk of suicidal ideation or behaviour. Our findings confirm atomoxetine's known safety profile. From a safety perspective, atomoxetine is a useful treatment option for adults with attention deficit hyperactivity disorder. © The Author(s) 2014.

Influence of linear profile modification and loading conditions on the dynamic tooth load and stress of high contact ratio gears

NASA Technical Reports Server (NTRS)

Lee, Chinwai; Lin, Hsiang Hsi; Oswald, Fred B.; Townsend, Dennis P.

1990-01-01

A computer simulation for the dynamic response of high-contact-ratio spur gear transmissions is presented. High contact ratio gears have the potential to produce lower dynamic tooth loads and minimum root stress but they can be sensitive to tooth profile errors. The analysis presented examines various profile modifications under realistic loading conditions. The effect of these modifications on the dynamic load (force) between mating gear teeth and the dynamic root stress is presented. Since the contact stress is dependent on the dynamic load, minimizing dynamic loads will also minimize contact stresses. It is shown that the combination of profile modification and the applied load (torque) carried by a gear system has a significant influence on gear dynamics. The ideal modification at one value of applied load will not be the best solution for a different load. High-contact-ratio gears were found to require less modification than standard low-contact-ratio gears. High-contact-ratio gears are more adversely affected by excess modification than by under modification. In addition, the optimal profile modification required to minimize the dynamic load (hence the contact stress) on a gear tooth differs from the optimal modification required to minimize the dynamic root (bending) stress. Computer simulation can help find the design tradeoffs to determine the best profile modification to satisfy the conflicting constraints of minimizing both the load and root stress in gears which must operate over a range of applied loads.

Atenolol Versus Propranolol for Treatment of Infantile Hemangiomas During the Proliferative Phase: A Retrospective Noninferiority Study.

PubMed

Bayart, Cheryl B; Tamburro, Joan E; Vidimos, Allison T; Wang, Lu; Golden, Alex B

2017-07-01

The nonselective beta-blocker propranolol is the current criterion standard for treatment of infantile hemangiomas (IHs) and the first therapy that the U.S. Food and Drug Administration has approved for the condition, but concern about adverse effects, such as bronchospasm, hypoglycemia, and sleep disturbances, has sparked interest in the use of alternative agents such as the selective β1 antagonist atenolol. Our aim was to compare the efficacy and adverse effect profiles of atenolol with those of propranolol in the treatment of IHs in a retrospective noninferiority trial. Twenty-seven children with IHs treated with atenolol according to the Cleveland Clinic foundation's standardized clinical assessment and management plan (SCAMP) met inclusion criteria and were compared with a matched group of 53 children with IHs treated with propranolol. Three reviewers assessed response to therapy using a modified version of the previously validated Hemangioma Activity Score (HAS). The mean change in HAS was -2.94 ± 1.20 for patients treated with atenolol and -2.96 ± 1.42 for those treated with propranolol. There was no statistically significant difference in pre- and posttreatment modified HAS scores between the two groups (p = 0.60). There was no significant difference in the overall rate of adverse effects (p = 0.10), although 11% of patients treated with propranolol experienced reactive airway symptoms, whereas this was not seen in any of the patients treated with atenolol. Our study supports previous findings that atenolol is at least as effective as propranolol for treatment of IHs and poses less risk of bronchospasm. Our SCAMP proposes guidelines for dosing and monitoring parameters. © 2017 Wiley Periodicals, Inc.

Safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension: a sub-group analysis based on Japan post-marketing surveillance.

PubMed

Yamazaki, Hiroyoshi; Kobayashi, Noriko; Taketsuna, Masanori; Tajima, Koyuki; Suzuki, Nahoko; Murakami, Masahiro

2017-12-01

To evaluate the long-term safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension (PAH) in real-world clinical practice. This is an observational surveillance of PAH patients receiving tadalafil in the contracted sites. A sub-group analysis was performed of 391 pediatric PAH patients (<18 years) who were included from 1,704 total patients in this surveillance. Safety was assessed from the frequency of adverse drug reactions (ADRs), discontinuations due to adverse events (AEs), and serious adverse drug reactions (SADRs). Effectiveness measurements included change in World Health Organization (WHO) functional classification of PAH, cardiac catheterization (pulmonary arterial pressure: PAP), and echocardiography (tricuspid regurgitation pressure gradient: TRPG). Survival rate was also measured. The mean patient age was 5.7 ± 5.34 years. Associated PAH (APAH) and idiopathic PAH (IPAH) accounted for 76.0% and 17.6%, respectively, of the PAH patients. Patients were followed for up to 2 years. Among 391 patients analyzed for safety, the overall incidence rate of ADRs was 16.6%. The common ADRs (≥ 1%) were headache (2.8%), hepatic function abnormal, platelet count decreased (1.3% each), and epistaxis, (1.0%). Eleven patients (2.8%) reported 16 SADRs. Three patients died secondary to SADRs. For the effectiveness analysis, the incidence of WHO functional class improvement at 3 months, 1 year, and 2 years after the initiation of tadalafil and last observation in pediatric patients were 16.5%, 19.7%, and 16.3%, respectively. Both PAP and TRPG showed a statistically significant reduction at last observation. This manuscript reveals the use of tadalafil in the real-world pediatric population with an acceptable safety profile in Japan.

Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review.

PubMed

Mushtaq, Adeela; Kapoor, Vikas; Latif, Azka; Iftikhar, Ahmad; Zahid, Umar; McBride, Ali; Abraham, Ivo; Riaz, Irbaz Bin; Anwer, Faiz

2018-05-01

Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (n = 5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ≥3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20-27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20-56 and 20-70 mg/m2 dose of CFZ vs standard 20-27 mg/m2 dose in NDMM and RRMM. Copyright © 2018 Elsevier B.V. All rights reserved.

Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop.

PubMed

Aigner, Achim; Buesen, Roland; Gant, Tim; Gooderham, Nigel; Greim, Helmut; Hackermüller, Jörg; Hubesch, Bruno; Laffont, Madeleine; Marczylo, Emma; Meister, Gunter; Petrick, Jay S; Rasoulpour, Reza J; Sauer, Ursula G; Schmidt, Kerstin; Seitz, Hervé; Slack, Frank; Sukata, Tokuo; van der Vies, Saskia M; Verhaert, Jan; Witwer, Kenneth W; Poole, Alan

2016-12-01

The European Centre for the Ecotoxicology and Toxicology of Chemicals (ECETOC) organised a workshop to discuss the state-of-the-art research on noncoding RNAs (ncRNAs) as biomarkers in regulatory toxicology and as analytical and therapeutic agents. There was agreement that ncRNA expression profiling data requires careful evaluation to determine the utility of specific ncRNAs as biomarkers. To advance the use of ncRNA in regulatory toxicology, the following research priorities were identified: (1) Conduct comprehensive literature reviews to identify possibly suitable ncRNAs and areas of toxicology where ncRNA expression profiling could address prevailing scientific deficiencies. (2) Develop consensus on how to conduct ncRNA expression profiling in a toxicological context. (3) Conduct experimental projects, including, e.g., rat (90-day) oral toxicity studies, to evaluate the toxicological relevance of the expression profiles of selected ncRNAs. Thereby, physiological ncRNA expression profiles should be established, including the biological variability of healthy individuals. To substantiate the relevance of key ncRNAs for cell homeostasis or pathogenesis, molecular events should be dose-dependently linked with substance-induced apical effects. Applying a holistic approach, knowledge on ncRNAs, 'omics and epigenetics technologies should be integrated into adverse outcome pathways to improve the understanding of the functional roles of ncRNAs within a regulatory context. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Screening the Emission Sources of Volatile Organic Compounds (VOCs) in China Based on Multi-effect Evaluation

NASA Astrophysics Data System (ADS)

Niu, H., Jr.

2015-12-01

Volatile organic compounds (VOCs) in the atmosphere have adverse impacts via three main pathways: photochemical ozone formation, secondary organic aerosol production, and direct toxicity to humans. Few studies have integrated these effects to prioritize control measures for VOCs sources. In this study, we developed a multi-effect evaluation methodology based on updated emission inventories and source profiles, which was combined with ozone formation potential (OFP), secondary organic aerosol potential (SOAP), and VOC toxicity data to identify important emission sources and key species. We derived species-specific emission inventories for 152 sources. The OFPs, SOAPs, and toxicity of each source were determined, and the contribution and share of each source to each of these adverse effects was calculated. Weightings were given to the three adverse effects by expert scoring, and the integrated impact was determined. Using 2012 as the base year, solvent usage and industrial process were found to be the most important anthropogenic sources, accounting for 24.2 and 23.1% of the integrated environmental effect, respectively. This was followed by biomass burning, transportation, and fossil fuel combustion, all of which had a similar contribution ranging from 16.7 to 18.6%. The top five industrial sources, including plastic products, rubber products, chemical fiber products, the chemical industry, and oil refining, accounted for nearly 70.0% of industrial emissions. In China, emissions reductions are required for styrene, toluene, ethylene, benzene, and m/p-xylene. The 10 most abundant chemical species contributed 76.5% of the integrated impact. Beijing, Chongqing, Shanghai, Jiangsu, and Guangdong were the five leading provinces when considering the integrated effects. Besides, the chemical mass balance model (CMB) was used to verify the VOCs inventories of 47 cities in China, so as to optimize our evaluation results. We suggest that multi-effect evaluation is necessary to identify the need for abatement at the source type and substance levels.

Maternal treatment with a high dose of CpG ODN during gestation alters fetal craniofacial and distal limb development in C57BL/6 mice.

PubMed

Prater, M Renee; Johnson, Victor J; Germolec, Dori R; Luster, Michael I; Holladay, Steven D

2006-01-16

Synthetic oligodeoxynucleotides (ODN) containing CpG motifs, characteristic of bacterial DNA, are currently being evaluated as vaccine adjuvants for inducing protective immunity. Recently, there is increasing pressure to vaccinate pregnant women against maternally transmitted diseases including AIDS and tetanus, as well as against potential bio-weapons such as anthrax. CpG vaccines are effective because they trigger transient increases in T(H)1 cytokine production. Recent literature suggests, however, that a shift toward a T(H)1 cytokine profile during pregnancy may increase the risk of fetal morphologic defects. On this basis, we hypothesized that exposure to CpG motifs during pregnancy could result in T(H)1 inflammation leading to adverse effects on fetal development. To address this hypothesis, pregnant C57BL/6 mice were injected with CpG ODN (0-300 microg/dam) and maternal and fetal outcomes were determined. Injection of dams with the highest dose of CpG ODN resulted in markedly increased fetal resorptions and craniofacial/limb defects, while lower doses had little, if any effects. Histological examination of placentas revealed cellular necrosis with mixed inflammation and calcification in the spongiotrophoblast layer and dysregulation of labyrinthine vascular development. Concomitant elevations in maternal serum cytokine levels were observed including interleukin (IL)-2, IL-10 and IL-12. Treatment with 300 microg of non-CpG ODN did not cause any adverse effects. The 300 microg dose of CpG ODN used in the present study is 30-fold higher than the highest dose that has been administered to humans during clinical trials. These results suggest that the induction of T(H)1 cytokines during pregnancy by CpG motifs may potentially increase the risk of fetal loss and morphologic defects in mice, at least at high doses, and support the need for further investigation of teratogenesis that may result from exposure to vaccine adjuvants designed to produce T(H)1 cytokine profile shifts.

Fascia iliaca compartment nerve block versus systemic pain control for acute femur fractures in the pediatric emergency department.

PubMed

Neubrand, Tara L; Roswell, Kelley; Deakyne, Sara; Kocher, Kendra; Wathen, Joseph

2014-07-01

To compare management of acute femur fractures in children who received a fascia iliaca compartment nerve block (FICNB) to those who received systemic intravenously administered analgesics in the pediatric emergency department. The comparison evaluated frequency of use, effectiveness, and associated adverse event profiles. Study population was derived from a retrospective chart review of pediatric patients sustaining acute femur fractures between 2005 and 2009. Cases (received FICNB) were compared with controls (only systemic analgesia) in terms of effectiveness and adverse event. Outcomes included total doses of systemic medications received and comparison of preintervention and postintervention pain scores. Two hundred fifty-nine charts were reviewed: 158 who received FICNB versus 101 who did not. The median dose of systemic medications was 1 dose lower in the FICNB group compared with the systemic medications group. This remained significant after controlling for age and preintervention pain scores (P = 0.02). Median postintervention pain scores in the FICNB group were 1.5 points lower than those in the systemic medications group. This remained significant while controlling for preintervention pain scores and age (P < 0.01). There was no difference in the total adverse events between the FICNB and the control group in either the unadjusted or adjusted analyses (P = 0.08). The FICNB group had 2 seizure episodes, one of which had associated subarachnoid hemorrhage. No patient in either group experienced bradycardia, arrhythmia, visual disturbance, abnormal hearing, mouth numbness, motor tremors, pain or bleeding at injection site, or prolonged nerve block. We report on the largest number of FICNBs administered in a pediatric emergency department for acute femur fractures. Effectiveness, as measured by pain scores and total doses of systemic analgesia, was improved in the FICNB group versus the control. There was no difference in adverse events between the groups.

Maternal adversities during pregnancy and cord blood oxytocin receptor (OXTR) DNA methylation.

PubMed

Unternaehrer, Eva; Bolten, Margarete; Nast, Irina; Staehli, Simon; Meyer, Andrea H; Dempster, Emma; Hellhammer, Dirk H; Lieb, Roselind; Meinlschmidt, Gunther

2016-09-01

The aim of this study was to investigate whether maternal adversities and cortisol levels during pregnancy predict cord blood DNA methylation of the oxytocin receptor (OXTR). We collected cord blood of 39 babies born to mothers participating in a cross-sectional study (N = 100) conducted in Basel, Switzerland (2007-10). Mothers completed the Inventory of Life Events (second trimester: T2), the Edinburgh Postnatal Depression Scale (EPDS, third trimester: T3), the Trier Inventory of Chronic Stress (TICS-K, 1-3 weeks postpartum) and provided saliva samples (T2, T3) for maternal cortisol profiles, as computed by the area under the curve with respect to ground (AUCg) or increase (AUCi) for the cortisol awakening response (CAR) and for diurnal cortisol profiles (DAY). OXTR DNA methylation was quantified using Sequenom EpiTYPER. The number of stressful life events (P = 0.032), EPDS score (P = 0.007) and cortisol AUCgs at T2 (CAR: P = 0.020; DAY: P = 0.024) were negatively associated with OXTR DNA methylation. Our findings suggest that distinct prenatal adversities predict decreased DNA methylation in a gene that is relevant for childbirth, maternal behavior and wellbeing of mother and offspring. If a reduced OXTR methylation increases OXTR expression, our findings could suggest an epigenetic adaptation to an adverse early environment. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Effect of methanol extract of Trigonella foenum-graecum L. seeds on anxiety, sedation and motor coordination.

PubMed

Assad, Tahira; Khan, Rafeeq Alam

2017-04-01

Currently available anxiolytics cause numerous adverse effects and show craving and tolerance during long term treatment. Currently traditional medicines have been re-evaluated widely through work on various plant species. Numerous plants in traditional system show pharmacological activity with unlimited prospective for therapeutic use. Hence we planned to evaluate the effect of methanol extract of T. foenum-graecum L. seeds on anxiety, sedation and motor coordination in mice at different doses following 15 days of oral feeding. Effect on anxiety was assessed by Hole board test and Light and Dark transition models.Phenobarbitone induced sleeping time and Rota rod test were performed to assess effect on sedation and motor coordination. In Hole board test, T. foenum-graecum L. seeds decreased the number of head dips in mice at all the three doses. In Light and Dark transition model, T. foenum-graecum L. seeds increased the period spent in the light box and the number of moves among the two compartments at 100 and 200 mg/kg as compared to control animals. In phenobarbitone induced sleeping time, T. foenum-graecum L. seeds did not reveal any sedative effect. In Rota rod test, extract exhibited significant skeletal muscle relaxant effect at 200 mg/kg (at 90 min) as compared to the control animals. Results of our study shows significant antianxiety effects of T. foenum-graecum L. seeds and may also recommend improved adverse effect profile as compared to diazepam.

Determining clinical benefits of drug-eluting coronary stents according to the population risk profile: a meta-regression from 31 randomized trials.

PubMed

Moreno, Raul; Martin-Reyes, Roberto; Jimenez-Valero, Santiago; Sanchez-Recalde, Angel; Galeote, Guillermo; Calvo, Luis; Plaza, Ignacio; Lopez-Sendon, Jose-Luis

2011-04-01

The use of drug-eluting stents (DES) in unfavourable patients has been associated with higher rates of clinical complications and stent thrombosis, and because of that concerns about the use of DES in high-risk settings have been raised. This study sought to demonstrate that the clinical benefit of DES increases as the risk profile of the patients increases. A meta-regression analysis from 31 randomized trials that compared DES and bare-metal stents, including overall 12,035 patients, was performed. The relationship between the clinical benefit of using DES (number of patients to treat [NNT] to prevent one episode of target lesion revascularization [TLR]), and the risk profile of the population (rate of TLR in patients allocated to bare-metal stents) in each trial was evaluated. The clinical benefit of DES increased as the risk profile of each study population increased: NNT for TLR=31.1-1.2 (TLR for bare-metal stents); p<0.001. The use of DES was safe regardless of the risk profile of each study population, since the effect of DES in mortality, myocardial infarction, and stent thrombosis, was not adversely affected by the risk profile of each study population (95% confidence interval for β value 0.09 to 0.11, -0.12 to 0.19, and -0.03 to-0.15 for mortality, myocardial infarction, and stent thrombosis, respectively). The clinical benefit of DES increases as the risk profile of the patients increases, without affecting safety. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: Relevance for human safety

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ryan, Patricia C., E-mail: ryanp@medimmune.com; Sleeman, Matthew A.; Rebelatto, Marlon

Mavrilimumab (CAM-3001) is an investigational human IgG4 monoclonal antibody (MAb) targeting GM-CSF receptor alpha which is currently being developed for the treatment of RA. GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. To support clinical development, the nonclinical safety of mavrilimumab was evaluated in several studies with cynomolgus monkeys as the pharmacologically relevant species. Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26 weeks. Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters othermore » than microscopic findings in lung. In several studies, minimal accumulation of foamy alveolar macrophages was observed. This finding was only seen in studies of at least 11 weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥ 30 mg/kg/week), in a 26-week repeat-IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse. The dose- and time-related accumulation of foamy macrophages in lung following exposure to mavrilimumab observed in several NHP studies was expected based upon the known role of GM-CSFRα signaling in the function of alveolar macrophages. Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In clinical studies in RA patients, mavrilimumab has demonstrated good clinical activity with adequate safety to support further clinical development. A Phase 2b study of mavrilimumab in subjects with RA is in progress. - Highlights: • Mavrilimumab is a MAB targeting GM-CSFRα being developed for RA therapy. • Mavrilimumab has an acceptable safety profile in cynomolgus monkeys. • Lung changes observed reflect role of GM-CSF in alveolar macrophage function. • High safety margins support continued clinical development of mavrilimumab.« less

Use of the false discovery rate for evaluating clinical safety data.

PubMed

Mehrotra, Devan V; Heyse, Joseph F

2004-06-01

Clinical adverse experience (AE) data are routinely evaluated using between group P values for every AE encountered within each of several body systems. If the P values are reported and interpreted without multiplicity considerations, there is a potential for an excess of false positive findings. Procedures based on confidence interval estimates of treatment effects have the same potential for false positive findings as P value methods. Excess false positive findings can needlessly complicate the safety profile of a safe drug or vaccine. Accordingly, we propose a novel method for addressing multiplicity in the evaluation of adverse experience data arising in clinical trial settings. The method involves a two-step application of adjusted P values based on the Benjamini and Hochberg false discovery rate (FDR). Data from three moderate to large vaccine trials are used to illustrate our proposed 'Double FDR' approach, and to reinforce the potential impact of failing to account for multiplicity. This work was in collaboration with the late Professor John W. Tukey who coined the term 'Double FDR'.

Post-marketing surveillance of live-attenuated Japanese encephalitis vaccine safety in China.

PubMed

Wang, Yali; Dong, Duo; Cheng, Gang; Zuo, Shuyan; Liu, Dawei; Du, Xiaoxi

2014-10-07

Japanese encephalitis (JE) is the most severe form of viral encephalitis in Asia and no specific treatment is available. Vaccination provides an effective intervention to prevent JE. In this paper, surveillance data for adverse events following immunization (AEFI) related to SA-14-14-2 live-attenuated Japanese encephalitis vaccine (Chengdu Institute of Biological Products) was presented. This information has been routinely generated by the Chinese national surveillance system for the period 2009-2012. There were 6024 AEFI cases (estimated reported rate 96.55 per million doses). Most common symptoms of adverse events were fever, redness, induration and skin rash. There were 70 serious AEFI cases (1.12 per million doses), including 9 cases of meningoencephalitis and 4 cases of death. The post-marketing surveillance data add the evidence that the Chengdu institute live attenutated vaccine has a reasonable safety profile. The relationship between encephalitis and SA-14-14-2 vaccination should be further studied. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of the in vitro cytogenotoxicity profile of antipsychotic drug haloperidol using human peripheral blood lymphocytes.

PubMed

Gajski, Goran; Gerić, Marko; Garaj-Vrhovac, Vera

2014-07-01

Haloperidol (HLP) is a potent antipsychotic drug that is commonly used for the treatments of schizophrenia and bipolar disorders but has a tendency to cause adverse effects. In the present study, the cyto/genotoxic potential of clinically relevant concentrations of HLP was evaluated in human peripheral blood lymphocytes (HPBLs) as sensitive biomarkers of exposure. HLP was administered as HLP hydrochloride in the final concentrations of 5, 10 and 20 ng/ml for 4 and 24 h period. Cytotoxicity was determined using differential staining of HPBLs with acridine orange and ethidium bromide while chromosomal aberrations, micronucleus and comet assays were applied to estimate the chromosomal and DNA damage after the treatment. The results of the present study indicate that HLP is capable of inducing cyto/genotoxicity in tested cells. Present study has also confirmed the need for further cytogenetic research and regular patient monitoring to minimize the risk of any possible adverse events. Copyright © 2014 Elsevier B.V. All rights reserved.

[Assessment of SUSARs. Clinical evaluation of single cases in terms of regulatory requirements].

PubMed

Wroblewski, H; Schmickler, M

2005-04-01

In the course of implementing the European directives on pharmaceutical law, focus is set on suspected unexpected serious adverse reactions (SUSARs). SUSARs are essential for expedited reporting to authorities and ethics committees. During on-line monitoring of the study, the investigator documents all adverse events. Serious adverse events are forwarded to the sponsor in due time. The sponsor identifies SUSARs for expedited reporting. Clinical causality assessment between the investigational product and the adverse event is substantial in this process. This requires a balanced clinical assessment of all case relevant aspects and information available reflecting the complexity of the specific case, which cannot be covered by algorithms in general. In the setting of on-line monitoring, SUSARs ensure the safety of the patient and the study. In addition, SUSARs are relevant for generation of the safety profile of the substance.

Post-donation telephonic interview of blood donors providing an insight into delayed adverse reactions: First attempt in India.

PubMed

Tiwari, Aseem K; Aggarwal, Geet; Dara, Ravi C; Arora, Dinesh; Srivastava, Khushboo; Raina, Vimarsh

2017-04-01

Blood donor experiences both immediate adverse reactions (IAR) and delayed adverse reactions (DAR). With limited published data available on the incidence of DAR, a study was conducted to estimate incidence and profile of DAR through telephonic interview. Study was conducted over a 45-day period for consecutive volunteer whole blood donations at tertiary care hospital. Donors were divided into first-time, repeat and regular and were monitored for IAR. They were given written copy of post-donation advice. Donors were contacted telephonically three weeks post-donation and enquired about general wellbeing and specific DAR in accordance with a standard n international (International Society of Blood Transfusion) standard format. Donors participated in the study of which 1.6% donors experienced an IAR. Much larger number reported DAR (10.3% vs.1.6% p<0.0001). Further, DAR was presented as a variegated profile with bruise, painful arms and fatigue being the commonest. DARs were more common in females than males (25% vs. 10.3%, p<0.02). Localized DAR like bruise and painful arms were more common in younger donors (age <50 years) whereas systemic DAR like fatigue was common in older donors (>50 years). First time (12.3%) and repeat donors (13.5%) had similar frequency of DAR but were lower among regular donors (6.7%). DARs are more common than IAR and are of different profile. Post-donation interview has provided an insight into donor experiences and can be used as a valuable tool in donor hemovigilance. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gender differences in first onset Schizophrenia spectrum psychoses.

PubMed

Talonen, Sanni; Väänänen, Juha; Kaltiala-Heino, Riittakerttu

2017-02-01

Mental health profiles differ between boys and girls from puberty onwards. It is not known whether differences also extend to symptom presentation in schizophrenia spectrum disorders. It may be that girls and boys are not treated entirely equally by the professionals. To study gender differences in symptom profiles, family adversities, pathway to care, and characteristics of inpatient treatment at the first episode of diagnosed schizophrenia spectrum disorder (F20-29) among adolescents aged 13-17. A retrospective chart review of all (n = 106) consecutive adolescents diagnosed for the first time with schizophrenia spectrum disorder (F20-29) in a specified catchment area. Girls and boys were compared with regard to sociodemographics, pathways to care, living arrangements, symptom profiles, and treatment received. During the study period more adolescent girls (n = 70, 66%) than boys (n = 36, 34%) were diagnosed with schizophrenia spectrum (F20-29) psychoses, most commonly F29. Girls were moreover younger (mean age = 15.46) than boys (mean age = 16.62) at admission. Girls more often displayed mood symptoms and boys aggressive behaviours, alcohol abuse problems, and isolation. Family adversities recorded as current stressors were more numerous among girls. Girls were more likely to be referred to specialized after-care than boys. The gender differences observed in symptoms presentation are reminiscent of differences encountered in the general adolescent population. Prior to transition to psychosis, girls and boys are equally in contact with psychiatric services due to other (possibly prodromal) symptoms/disorders. Family adversities may be more stressful for girls vulnerable to psychosis than to boys.

Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials

PubMed Central

MacConell, Leigh; Brown, Carl; Gurney, Kate; Han, Jenny

2012-01-01

Background Exenatide twice daily is a first-in-class glucagon-like peptide receptor agonist approved for the treatment of type 2 diabetes. The objective of this analysis was to evaluate the safety profile of exenatide twice daily and to compare its profile with that of a pooled comparator (placebo and insulin) in patients with type 2 diabetes. Methods Data from 19 completed, randomized, controlled clinical trials of exenatide twice daily (5 μg and 10 μg) were pooled and analyzed; the pooled data included 5594 intent-to-treat patients who were followed for 12–52 weeks. Incidence rates, exposure-adjusted incidence rates, and 95% confidence intervals around risk differences between groups were calculated. Results Baseline demographics and exposure time were comparable between groups (exenatide, N = 3261; pooled comparator, N = 2333; mean exposure time 166–171 days). Transient, mild- to-moderate nausea was the most frequent adverse event with exenatide (36.9% versus 8.3% in the pooled comparator). The incidence of hypoglycemia (minor or major) with concomitant sulfonylurea (exenatide 26.5%, pooled comparator 20.7%) was higher than that without sulfonylurea (exenatide 3.1%, pooled comparator 2.7%) in all groups. Serious adverse events, discontinuations due to serious adverse events, and deaths were reported with similar frequency in the exenatide and pooled comparator groups. Composite exposure-adjusted incidence rates were not statistically different between groups for pancreatitis, renal impairment, or major adverse cardiac events; there was a difference in incidence rates for benign thyroid neoplasm (0.3% versus 0%). Conclusion Overall, this analysis, representing over 1500 patient-years of exposure, demonstrated that exenatide twice daily was safe and generally well tolerated in patients with type 2 diabetes. The incidence of most adverse events, including serious adverse events, was similar in both exenatide-treated and comparator-treated patients. The most distinct differences between groups were in gastrointestinal-related adverse events, which is consistent with other therapies within the glucagon-like peptide class. PMID:22375098

Failure or success of search strategies to identify adverse effects of medical devices: a feasibility study using a systematic review.

PubMed

Golder, Su; Wright, Kath; Rodgers, Mark

2014-10-13

Research has indicated that adverse effects terms are increasingly prevalent in the title, abstract or indexing terms of articles that contain adverse drug effects data in MEDLINE and Embase. However, it is unknown whether adverse effects terms are present in the database records of articles that contain adverse effects data of medical devices, and thus, to what extent the development of an adverse effects search filter for medical devices may be feasible. A case study systematic review of a medical device was selected. The included studies from a systematic review of the safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) for spinal fusion were used in the analysis. For each included study, the corresponding database record on MEDLINE and Embase was assessed to measure the presence or absence of adverse effects terms in the title, abstract or indexing. The performance of each potential adverse effects search term was also measured and compared. There were 82 publications (49 studies) included in the systematic review with 51 of these indexed on MEDLINE and 55 on Embase. Ninety-four percent (48/51) of the records on MEDLINE and 95% (52/55) of the records on Embase contained at least one adverse effects related search term. The wide variety of adverse effects terms included in the title, abstract or indexing of bibliographic records, and the lack of any individual high-performing search terms suggests that a combination of terms in different fields is required to identify adverse effects of medical devices. In addition, the most successful search terms differed from the most successful terms for identifying adverse drug effects. The search filters currently available for adverse drug effects are not necessarily useful for searching adverse effects data of medical devices. The presence of adverse effects terms in the bibliographic records of articles on medical devices, however, indicates that combinations of adverse effects search terms may be useful in search strategies in MEDLINE and Embase. The results, therefore, suggest that not only a search filter for the adverse effects of medical devices is feasible, but also that it should be a research priority.

Are adverse effects incorporated in economic models? An initial review of current practice.

PubMed

Craig, D; McDaid, C; Fonseca, T; Stock, C; Duffy, S; Woolacott, N

2009-12-01

To identify methodological research on the incorporation of adverse effects in economic models and to review current practice. Major electronic databases (Cochrane Methodology Register, Health Economic Evaluations Database, NHS Economic Evaluation Database, EconLit, EMBASE, Health Management Information Consortium, IDEAS, MEDLINE and Science Citation Index) were searched from inception to September 2007. Health technology assessment (HTA) reports commissioned by the National Institute for Health Research (NIHR) HTA programme and published between 2004 and 2007 were also reviewed. The reviews of methodological research on the inclusion of adverse effects in decision models and of current practice were carried out according to standard methods. Data were summarised in a narrative synthesis. Of the 719 potentially relevant references in the methodological research review, five met the inclusion criteria; however, they contained little information of direct relevance to the incorporation of adverse effects in models. Of the 194 HTA monographs published from 2004 to 2007, 80 were reviewed, covering a range of research and therapeutic areas. In total, 85% of the reports included adverse effects in the clinical effectiveness review and 54% of the decision models included adverse effects in the model; 49% included adverse effects in the clinical review and model. The link between adverse effects in the clinical review and model was generally weak; only 3/80 (< 4%) used the results of a meta-analysis from the systematic review of clinical effectiveness and none used only data from the review without further manipulation. Of the models including adverse effects, 67% used a clinical adverse effects parameter, 79% used a cost of adverse effects parameter, 86% used one of these and 60% used both. Most models (83%) used utilities, but only two (2.5%) used solely utilities to incorporate adverse effects and were explicit that the utility captured relevant adverse effects; 53% of those models that included utilities derived them from patients on treatment and could therefore be interpreted as capturing adverse effects. In total, 30% of the models that included adverse effects used withdrawals related to drug toxicity and therefore might be interpreted as using withdrawals to capture adverse effects, but this was explicitly stated in only three reports. Of the 37 models that did not include adverse effects, 18 provided justification for this omission, most commonly lack of data; 19 appeared to make no explicit consideration of adverse effects in the model. There is an implicit assumption within modelling guidance that adverse effects are very important but there is a lack of clarity regarding how they should be dealt with and considered in modelling. In many cases a lack of clear reporting in the HTAs made it extremely difficult to ascertain what had actually been carried out in consideration of adverse effects. The main recommendation is for much clearer and explicit reporting of adverse effects, or their exclusion, in decision models and for explicit recognition in future guidelines that 'all relevant outcomes' should include some consideration of adverse events.

CHARACTERIZATION OF RELATIVE SENSITIVITY OF AMPHIBIANS TO ULTRAVIOLET RADIATION

EPA Science Inventory

Different studies have demonstrated that solar ultraviolet (UV) radiation can adversely affect survival and development of embryonic and larval amphibians. However, because of among-laboratory variations in exposure profiles (artificial vs. natural sunlight; natural sunlight at d...

CHARACTERIZATION OF RELATIVE SENSITIVITY OF AMPHIBIANS TO ULTRA VIOLET RADIATION

EPA Science Inventory

Different studies have demonstrated that solar ultraviolet (UV) radiation can adversely affect survival and development of embryonic and larval amphibians. However, because of among-laboratory variations in exposure profiles (artificial vs. natural sunlight; natural sunlight at d...

The effects of nitroglycerin during cardiopulmonary resuscitation.

PubMed

Stefaniotou, Antonia; Varvarousi, Giolanda; Varvarousis, Dimitrios P; Xanthos, Theodoros

2014-07-05

The outcome for both in-hospital and out-of hospital cardiac arrest remains dismal. Vasopressors are used to increase coronary perfusion pressure and thus facilitate return of spontaneous circulation during cardiopulmonary resuscitation. However, they are associated with a number of potential adverse effects and may decrease endocardial and cerebral organ blood flow. Nitroglycerin has a favourable haemodynamic profile which promotes forward blood flow. Several studies suggest that combined use of nitroglycerin with vasopressors during resuscitation, is associated with increased rates of resuscitation and improved post-resuscitation outcome. This article reviews the effects of nitroglycerin during cardiopulmonary resuscitation and postresuscitation period, as well as the beneficial outcomes of a combination regimen consisting of a vasopressor and a vasodilator, such as nitroglycerin. Copyright © 2014 Elsevier B.V. All rights reserved.

A Review on the Traditional Chinese Medicinal Herbs and Formulae with Hypolipidemic Effect

PubMed Central

Sham, Tung-Ting; Chan, Chi-On; Wang, You-Hua; Yang, Jian-Mei; Mok, Daniel Kam-Wah; Chan, Shun-Wan

2014-01-01

Hyperlipidemia, characterized by the abnormal blood lipid profiles, is one of the dominant factors of many chronic diseases such as diabetes, obesity, and cardiovascular diseases (CVD). For the low cost, effectiveness, and fewer side effects, the popularity of using traditional Chinese medicine (TCM) to handle hyperlipidemia is increasing and its role in health care has been recognized by the public at large. Despite the importance of TCM herbs and formulations, there is no comprehensive review summarizing their scientific findings on handling hyperlipidemia. This review summarizes the recent experimental and clinical results of nine representative single Chinese herbs and seven classic TCM formulae that could improve lipid profiles so as to help understand and compare their underlying mechanisms. Most of single herbs and formulae demonstrated the improvement of hyperlipidemic conditions with multiple and diverse mechanisms of actions similar to conventional Western drugs in spite of their mild side effects. Due to increasing popularity of TCM, more extensive, well-designed preclinical and clinical trials on the potential synergistic and adverse side effects of herb-drug interactions as well as their mechanisms are warranted. Hyperlipidemic patients should be warned about the potential risks of herb-drug interactions, particularly those taking anticoagulants and antiplatelet drugs. PMID:25110708

High fructose consumption in pregnancy alters the perinatal environment without increasing metabolic disease in the offspring.

PubMed

Lineker, Christopher; Kerr, Paul M; Nguyen, Patricia; Bloor, Ian; Astbury, Stuart; Patel, Nikhil; Budge, Helen; Hemmings, Denise G; Plane, Frances; Symonds, Michael E; Bell, Rhonda C

2016-10-01

Maternal carbohydrate intake is one important determinant of fetal body composition, but whether increased exposure to individual sugars has long-term adverse effects on the offspring is not well established. Therefore, we examined the effect of fructose feeding on the mother, placenta, fetus and her offspring up to 6 months of life when they had been weaned onto a standard rodent diet and not exposed to additional fructose. Dams fed fructose were fatter, had raised plasma insulin and triglycerides from mid-gestation and higher glucose near term. Maternal resistance arteries showed changes in function that could negatively affect regulation of blood pressure and tissue perfusion in the mother and development of the fetus. Fructose feeding had no effect on placental weight or fetal metabolic profiles, but placental gene expression for the glucose transporter GLUT1 was reduced, whereas the abundance of sodium-dependent neutral amino acid transporter-2 was raised. Offspring born to fructose-fed and control dams were similar at birth and had similar post-weaning growth rates, and neither fat mass nor metabolic profiles were affected. In conclusion, raised fructose consumption during reproduction results in pronounced maternal metabolic and vascular effects, but no major detrimental metabolic effects were observed in offspring up to 6 months of age.

Adverse effects of aromatherapy: a systematic review of case reports and case series.

PubMed

Posadzki, Paul; Alotaibi, Amani; Ernst, Edzard

2012-01-01

This systematic review was aimed at critically evaluating the evidence regarding the adverse effects associated with aromatherapy. Five electronic databases were searched to identify all relevant case reports and case series. Forty two primary reports met our inclusion criteria. In total, 71 patients experienced adverse effects of aromatherapy. Adverse effects ranged from mild to severe and included one fatality. The most common adverse effect was dermatitis. Lavender, peppermint, tea tree oil and ylang-ylang were the most common essential oils responsible for adverse effects. Aromatherapy has the potential to cause adverse effects some of which are serious. Their frequency remains unknown. Lack of sufficiently convincing evidence regarding the effectiveness of aromatherapy combined with its potential to cause adverse effects questions the usefulness of this modality in any condition.

[Curcumine (Turmeric - Curcuma longa) as a Supportive Phytotherapeutic Treatment in Oncology].

PubMed

Frassová, Z; Rudá-Kučerová, J

2017-01-01

Turmeric (Curcuma longa) is mainly known as a constituent of curry spice. The main active ingredient, responsible for most of its biological effects, is the polyphenol curcumin. This review aims to provide a comprehensive overview of studies evaluating the benefits of therapeutic curcumin use in oncology. Preclinical studies provide information on the mechanism of action and potential toxicity of curcumin. Clinical studies have so far focused mainly on safety, pharmacokinetics, and determination of the optimal dose of curcumin. However, there are a growing number of trials evaluating the anti-tumor and oncopreventive effects of curcumin and its effect in alleviating the adverse effects of chemotherapeutics and radiotherapy. So far, the results have been optimistic and should encourage further research. The main problem associated with curcumin treatment is its low oral bioavailability, which means it must administrated at high doses to be effective. Therefore, curcumin is more appropriate as a local treatment for areas such as the intestine, mucous membrane, or the skin, where there is no need for a strong systemic effect. Curcumin has a good safety profile when used up to several grams. Curcumin can also be used as a food supplement for people at increased risk of oncological disease, such as heavy smokers or those with pre-cancerous lesions. Due to its good safety profile, curcumin can be recommended to oncological patients who request a natural treatment.Key words: phytotherapy - drug-herb interactions - cancer - adverse effects - curcumine - turmeric - Curcuma longaSubmitted: 20. 7. 2017Accepted: 25. 9. 2017 This publication was written at Masaryk University as part of the project "Behavioural psychopharmacology and pharmacokinetics in preclinical drug research", number MUNI/A/1132/2017 with the support of the Specific University Research Grant, as provided by the Ministry of Education, Youth and Sports of the Czech Republic in the year 2018. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles

PubMed Central

Smith, Claire; Hu, Leijun; Coutant, David E.; Whitehurst, Kelly; Phipps, Krista; McNearney, Terry Ann; Yang, Xiao; Ackermann, Bradley; Pottanat, Thomas; Landschulz, William

2017-01-01

Abstract Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator‐blind, parallel‐group, multiple‐ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose‐dependent blockade of the EP4 receptor. Compared with placebo, 24‐h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070. PMID:28857461

Protective effect of Withania somnifera roots extract on hematoserological profiles against lead nitrate-induced toxicity in mice.

PubMed

Sharma, Veena; Sharma, Sadhana; Pracheta

2012-12-01

The in vivo protective role of hydro-methanolic root extract of Withania somnifera (WS) was evaluated in alleviating lead nitrate (LN)-induced toxicity in male Swiss albino mice by measuring hematoserological profiles. The lead-treated (20 mg/kg body wt, p.o.) albino mice (25-30 g) concurrently received the root extract (200 and 500 mg/kg body wt, p.o.) once daily for the duration of six weeks. Animals exposed to LN showed significant (P < 0.001) decline in haemoglobin content, red blood cell count, white blood cell count, packed cell volume and insignificant decrease in mean corpuscular haemoglobin and mean corpuscular haemoglobin content, while mean corpuscular volume and platelet count were increased. A significant elevation (P < 0.001) in serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, alkaline phosphatase, acid phosphatase and total cholesterol were also observed, when compared with control mice. Thus, the study demonstrated that the concurrent daily administration of root extract of WS protected the adverse effects of LN intoxication in mice.

Environmental profile and milk production of Friesian-Zebu crosses in Nigerian Guinea Savanna

NASA Astrophysics Data System (ADS)

Igono, M. O.; Aliu, Y. O.

1982-06-01

A 10-year meteorologic data have been collated to enable delienation of the environmental profile of the Nigerian Guinea Savanna zone. Three distinct seasons are defined: a hot-dry season which lasts from March to April; a hot-humid season (May to October); and the harmattan season (November to February). The effects of these seasons on milk production by half and three-quarter Friesian-Zebu crosses were evaluated during the first 100 days of lactation over a 2-year period. There were no significant differences in milk yield between the genotypes, but at heat intensities above 27‡C, the half cross gave more milk than the three-quarter cross. It is thus recommended that the half Friesian-Zebu cross be selected for milk production in the Nigerian Guinea Savanna and that suitable husbandry and managerial adjustments such as provision of adequate clean water, shelter, good quality and silage and night grazing should be evolved to ameliorate the adverse effects of thermal stress and nutritional deficiency during the drier and hotter months of the year.

Low-profile heliostat design for solar central receiver systems

NASA Technical Reports Server (NTRS)

Fourakis, E.; Severson, A. M.

1977-01-01

Heliostat designs intended to reduce costs and the effect of adverse wind loads on the devices were developed. Included was the low-profile heliostat consisting of a stiff frame with sectional focusing reflectors coupled together to turn as a unit. The entire frame is arranged to turn angularly about a center point. The ability of the heliostat to rotate about both the vertical and horizontal axes permits a central computer control system to continuously aim the sun's reflection onto a selected target. An engineering model of the basic device was built and is being tested. Control and mirror parameters, such as roughness and need for fine aiming, are being studied. The fabrication of these prototypes is in process. The model was also designed to test mirror focusing techniques, heliostat geometry, mechanical functioning, and tracking control. The model can be easily relocated to test mirror imaging on a tower from various directions. In addition to steering and aiming studies, the tests include the effects of temperature changes, wind gusting and weathering. The results of economic studies on this heliostat are also presented.

Adverse metabolic risk profiles in Greenlandic Inuit children compared to Danish children.

PubMed

Munch-Andersen, T; Sorensen, K; Andersen, L B; Aachmann-Andersen, N J; Aksglaede, L; Juul, A; Helge, J W

2013-06-01

During recent decades, the prevalence of metabolic morbidity has increased rapidly in adult Greenlandic Inuit. To what extent this is also reflected in the juvenile Inuit population is unknown. The objective was, therefore, in the comparison with Danish children, to evaluate metabolic profiles in Greenlandic Inuit children from the capital in the southern and from the northern most villages 187 Inuit and 132 Danish children were examined with anthropometrics, pubertal staging, fasting blood samples, and a maximal aerobic test. Both Inuit children living in Nuuk and the northern villages had significantly higher glucose, total cholesterol, apolipoprotein A1 levels, and diastolic blood pressure compared with Danish children after adjustment for differences in adiposity and aerobic fitness levels. The Inuit children living in Nuuk had significantly higher BMI, body fat %, HbA1 c, and significantly lower aerobic fitness and ApoA1 levels than northern living Inuit children. Greenlandic Inuit children had adverse metabolic health profile compared to the Danish children, the differences where more pronounced in Inuit children living in Nuuk. The tendencies toward higher prevalence of diabetes and metabolic morbidity in the adult Greenlandic Inuit population may also be present in the Inuit children population. Copyright © 2013 The Obesity Society.

Early molecular correlates of adverse events following yellow fever vaccination

PubMed Central

Chan, Candice Y.Y.; Chan, Kuan Rong; Chua, Camillus J.H.; nur Hazirah, Sharifah; Ghosh, Sujoy; Ooi, Eng Eong; Low, Jenny G.

2017-01-01

The innate immune response shapes the development of adaptive immunity following infections and vaccination. However, it can also induce symptoms such as fever and myalgia, leading to the possibility that the molecular basis of immunogenicity and reactogenicity of vaccination are inseparably linked. To test this possibility, we used the yellow fever live-attenuated vaccine (YFLAV) as a model to study the molecular correlates of reactogenicity or adverse events (AEs). We analyzed the outcome of 68 adults who completed a YFLAV clinical trial, of which 43 (63.2%) reported systemic AEs. Through whole-genome profiling of blood collected before and after YFLAV dosing, we observed that activation of innate immune genes at day 1, but not day 3 after vaccination, was directly correlated with AEs. These findings contrast with the gene expression profile at day 3 that we and others have previously shown to be correlated with immunogenicity. We conclude that although the innate immune response is a double-edged sword, its expression that induces AEs is temporally distinct from that which engenders robust immunity. The use of genomic profiling thus provides molecular insights into the biology of AEs that potentially forms a basis for the development of safer vaccines. PMID:28978802

The Phosphate Binder Ferric Citrate and Mineral Metabolism and Inflammatory Markers in Maintenance Dialysis Patients: Results From Prespecified Analyses of a Randomized Clinical Trial

PubMed Central

Van Buren, Peter N.; Lewis, Julia B.; Dwyer, Jamie P.; Greene, Tom; Middleton, John; Sika, Mohammed; Umanath, Kausik; Abraham, Josephine D.; Arfeen, Shahabul S.; Bowline, Isai G.; Chernin, Gil; Fadem, Stephen Z.; Goral, Simin; Koury, Mark; Sinsakul, Marvin V.; Weiner, Daniel E.

2016-01-01

Background Phosphate binders are the cornerstone of hyperphosphatemia management in dialysis patients. Ferric citrate is an iron-based oral phosphate binder that effectively lowers serum phosphorus levels. Study Design 52-week, open-label, phase 3, randomized, controlled trial for safety-profile assessment. Setting & Participants Maintenance dialysis patients with serum phosphorus levels ≥6.0 mg/dL after washout of prior phosphate binders. Intervention 2:1 randomization to ferric citrate or active control (sevelamer carbonate and/or calcium acetate). Outcomes Changes in mineral bone disease, protein-energy wasting/inflammation, and occurrence of adverse events after 1 year. Measurements Serum calcium, intact parathyroid hormone, phosphorus, aluminum, white blood cell count, percentage of lymphocytes, serum urea nitrogen, and bicarbonate. Results There were 292 participants randomly assigned to ferric citrate, and 149, to active control. Groups were well matched. For mean changes from baseline, phosphorus levels decreased similarly in the ferric citrate and active control groups (−2.04 ± 1.99 [SD] vs −2.18 ± 2.25 mg/dL, respectively; P = 0.9); serum calcium levels increased similarly in the ferric citrate and active control groups (0.22 ± 0.90 vs 0.31 ± 0.95 mg/dL; P = 0.2). Hypercalcemia occurred in 4 participants receiving calcium acetate. Parathyroid hormone levels decreased similarly in the ferric citrate and active control groups (−167.1 ± 399.8 vs −152.7 ± 392.1 pg/mL; P = 0.8). Serum albumin, bicarbonate, serum urea nitrogen, white blood cell count and percentage of lymphocytes, and aluminum values were similar between ferric citrate and active control. Total and low-density lipoprotein cholesterol levels were lower in participants receiving sevelamer than those receiving ferric citrate and calcium acetate. Fewer participants randomly assigned to ferric citrate had serious adverse events compared with active control. Limitations Open-label study, few peritoneal dialysis patients. Conclusions Ferric citrate was associated with similar phosphorus control compared to active control, with similar effects on markers of bone and mineral metabolism in dialysis patients. There was no evidence of protein-energy wasting/inflammation or aluminum toxicity, and fewer participants randomly assigned to ferric citrate had serious adverse events. Ferric citrate is an effective phosphate binder with a safety profile comparable to sevelamer and calcium acetate. PMID:25958079

The US Food and Drug Administration's perspective on the new antidepressant vortioxetine.

PubMed

Zhang, Jing; Mathis, Mitchell V; Sellers, Jenn W; Kordzakhia, George; Jackson, Andre J; Dow, Antonia; Yang, Peiling; Fossom, Linda; Zhu, Hao; Patel, Hiren; Unger, Ellis F; Temple, Robert J

2015-01-01

This article summarizes the US Food and Drug Administration's (FDA's) review of the New Drug Application for vortioxetine, especially the clinical efficacy and safety data. It emphasizes the issues that were important to the FDA's approval decision, particularly the difference in the effective dose in domestic and foreign studies, and notes several new labeling features, specifically, description of time course of treatment response and detailed sexual dysfunction evaluation. The data sources were the original raw data sets for all clinical trials included in the development program for vortioxetine, as well as the sponsor's original analyses of these data. Data were available from 51 human trials involving vortioxetine, and included a total of 7,666 healthy volunteers and patients with a diagnosis of major depressive disorder (MDD) or generalized anxiety disorder who were exposed to at least 1 dose of vortioxetine for a total of 2,743 patient-years. Vortioxetine was effective in treating MDD in the United States at a dose of 20 mg/d. The recommended starting dose is 10 mg once daily without regard to food, with increase to 20 mg/d if the 10 mg/d dose is tolerated. For patients who do not tolerate 20 mg/d, 10 mg/d can be used and 5-mg/d dose can be considered. Vortioxetine can be discontinued abruptly, but it is recommended that doses of 15 mg/d or 20 mg/d be reduced to 10 mg/d for 1 week prior to full discontinuation to avoid potential withdrawal symptoms. Although the non-US maintenance study showed that maintenance doses of 5 to 10 mg/d were effective, a clinical judgment needs to be made to decide the maintenance dose in the United States. The applicant has agreed to conduct a US maintenance dose-response study covering the US-approved dose range. Vortioxetine's adverse event profile is similar to that of other selective serotonin reuptake inhibitors (SSRIs). Nausea is the most common adverse event and is dose dependent. No dose adjustment is needed based on age, gender, or the presence of renal or mild to moderate hepatic impairment. The maximum recommended dose is 10 mg/d in known cytochrome P450 2D6 poor metabolizers. Vortioxetine is a new treatment for MDD, and its adverse event profile is similar to that of other SSRIs. © Copyright 2015 Physicians Postgraduate Press, Inc.

Adverse event reports following yellow fever vaccination, 2007-13.

PubMed

Lindsey, Nicole P; Rabe, Ingrid B; Miller, Elaine R; Fischer, Marc; Staples, J Erin

2016-05-01

Yellow fever (YF) vaccines have been available since the 1930s and are generally considered safe and effective. However, rare reports of serious adverse events (SAE) following vaccination have prompted the Advisory Committee for Immunization Practices to periodically expand the list of conditions considered contraindications and precautions to vaccination. We describe adverse events following YF vaccination reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) from 2007 through 2013 and calculate age- and sex-specific reporting rates of all SAE, anaphylaxis, YF vaccine-associated neurologic disease (YEL-AND) and YF vaccine-associated viscerotropic disease (YEL-AVD). There were 938 adverse events following YF vaccination reported to VAERS from 2007 through 2013. Of these, 84 (9%) were classified as SAEs for a rate of 3.8 per 100 000 doses distributed. Reporting rates of SAEs increased with increasing age with a rate of 6.5 per 100 000 in persons aged 60-69 years and 10.3 for ≥70 years. The reporting rate for anaphylaxis was 1.3 per 100 000 doses distributed and was highest in persons ≤18 years (2.7 per 100 000). Reporting rates of YEL-AND and YEL-AVD were 0.8 and 0.3 per 100 000 doses distributed, respectively; both rates increased with increasing age. These findings reinforce the generally acceptable safety profile of YF vaccine, but highlight the importance of continued physician and traveller education regarding the risks and benefits of YF vaccination, particularly for older travellers. Published by Oxford University Press on behalf of the International Society of Travel Medicine, 2016. This work is written by US Government employees and is in the public domain in the United States.

Effects of opium consumption on cardiometabolic diseases.

PubMed

Masoudkabir, Farzad; Sarrafzadegan, Nizal; Eisenberg, Mark J

2013-12-01

Opium is the second-most-commonly abused substance (after tobacco) in developing countries of the Middle East region, and in many Asian nations. One of the reasons for the high prevalence of opium abuse in these countries is a traditional belief among Eastern people, even including some medical staff, that opium might have beneficial effects on cardiovascular health and in the control of diabetes mellitus, hypertension, and dyslipidaemia. In this Perspectives article, we summarize the current understanding of the pharmacotoxicology of opium and its specific effects on glycaemic control, blood pressure, lipid profile, and atherosclerosis. On the basis of the available evidence, we believe not only that opium has no ameliorating effect on cardiovascular diseases, but also that the use of this drug might have adverse effects on these conditions. Therefore, people should be educated about the hazardous effects of opium consumption on cardiometabolic diseases.

XEN Gel Implant: a new surgical approach in glaucoma.

PubMed

Chaudhary, Ankita; Salinas, Lauriane; Guidotti, Jacopo; Mermoud, André; Mansouri, Kaweh

2018-01-01

Glaucoma is a leading cause of blindness worldwide. Intraocular pressure (IOP) lowering is the only effective treatment strategy. Traditional glaucoma surgeries are generally considered to be unpredictable and associated with a high rate of complications. This has led to the development of a novel XEN Gel Implant, a type of minimally invasive glaucoma surgery (MIGS), lowering the IOP without extensive surgical dissection. Areas covered: A literature search was undertaken on PubMed using the terms XEN glaucoma, gelatin microstent, and MIGS. All the articles and case reports on XEN Gel Implant and selected articles on MIGS were studied and reviewed. We have discussed the results of most studies on XEN Gel Implant related to its efficacy, safety and success. Expert commentary: The XEN Gel Implant effectively lowers IOP and medication use, with a favorable safety profile. Long-term data on its success and cost-effectiveness are lacking. The studies have shown it to be without any serious adverse events and to have good safety profile encouraging future research on this novel implant. There is a need to correctly identify selection criteria for patients, who would benefit the most from the XEN Gel Implant.

Creatine metabolism and safety profiles after six-week oral guanidinoacetic acid administration in healthy humans.

PubMed

Ostojic, Sergej M; Niess, Barbara; Stojanovic, Marko; Obrenovic, Milos

2013-01-01

Guanidinoacetic acid (GAA) is a natural precursor of creatine, yet the potential use of GAA as a nutritional additive for restoring creatine availability in humans has been limited by unclear efficacy and safety after exogenous GAA administration. The present study evaluated the effects of orally administered GAA on serum and urinary GAA, creatine and creatinine concentration, and on the occurrence of adverse events in healthy humans. Twenty-four healthy volunteers were randomized in a double-blind design to receive either GAA (2.4 grams daily) or placebo (PLA) by oral administration for 6 weeks. www.clinicaltrials.gov, identification number NCT01133899. Serum creatine and creatinine increased significantly from before to after administration in GAA-supplemented participants (P < 0.05). The proportion of participants who reported minor side effects was 58.3% in the GAA group and 45.5% in the placebo group (P = 0.68). A few participants experienced serum creatine levels above 70 µmol/L. Exogenous GAA is metabolized to creatine, resulting in a significant increase of fasting serum creatine after intervention. GAA had an acceptable side-effects profile with a low incidence of biochemical abnormalities.

Creatine Metabolism and Safety Profiles after Six-Week Oral Guanidinoacetic Acid Administration in Healthy Humans

PubMed Central

Ostojic, Sergej M.; Niess, Barbara; Stojanovic, Marko; Obrenovic, Milos

2013-01-01

Objectives; Guanidinoacetic acid (GAA) is a natural precursor of creatine, yet the potential use of GAA as a nutritional additive for restoring creatine availability in humans has been limited by unclear efficacy and safety after exogenous GAA administration. The present study evaluated the effects of orally administered GAA on serum and urinary GAA, creatine and creatinine concentration, and on the occurrence of adverse events in healthy humans. Methods and Results; Twenty-four healthy volunteers were randomized in a double-blind design to receive either GAA (2.4 grams daily) or placebo (PLA) by oral administration for 6 weeks. Clinical trial registration: www.clinicaltrials.gov, identification number NCT01133899. Serum creatine and creatinine increased significantly from before to after administration in GAA-supplemented participants (P < 0.05). The proportion of participants who reported minor side effects was 58.3% in the GAA group and 45.5% in the placebo group (P = 0.68). A few participants experienced serum creatine levels above 70 µmol/L. Conclusion; Exogenous GAA is metabolized to creatine, resulting in a significant increase of fasting serum creatine after intervention. GAA had an acceptable side-effects profile with a low incidence of biochemical abnormalities. PMID:23329885

A review on effects of conjugated linoleic fatty acid (CLA) upon body composition and energetic metabolism.

PubMed

Lehnen, Tatiana Ederich; da Silva, Marcondes Ramos; Camacho, Augusto; Marcadenti, Aline; Lehnen, Alexandre Machado

2015-01-01

Conjugated linoleic acid (CLA) is highly found in fats from ruminants and it appears to favorably modify the body composition and cardiometabolic risk factors. The capacity of CLA to reduce the body fat levels as well as its benefic actions on glycemic profile, atherosclerosis and cancer has already been proved in experimental models. Furthermore, CLA supplementation may modulate the immune function, help re-synthetize of glycogen and potentiate the bone mineralization. CLA supplementation also could increase the lipolysis and reduce the accumulation of fatty acids on the adipose tissue; the putative mechanisms involved may be its action in reducing the lipase lipoprotein activity and to increase the carnitine-palmitoil-transferase-1 (CAT-1) activity, its interaction with PPARγ, and to raise the expression of UCP-1. Although studies made in human have shown some benefits of CLA supplementation as the weight loss, the results are still discordant. Moreover, some have shown adverse effects, such as negative effects on glucose metabolism and lipid profile. The purpose of this article is to review the available data regarding the benefits of CLA on the energetic metabolism and body composition, emphasizing action mechanisms.

Tanezumab in the treatment of chronic musculoskeletal conditions.

PubMed

Jayabalan, Prakash; Schnitzer, Thomas J

2017-02-01

The management of pain associated with chronic musculoskeletal conditions represents a significant challenge for the clinician. There remains a need for novel medications that have a significant analgesic benefit and are also safe and well tolerated. Both pre-clinical and clinical data have provided evidence of the role of nerve growth factor (NGF) in a multitude of pain eliciting conditions. Therefore, the development of monoclonal antibodies to NGF for chronic painful musculoskeletal conditions has generated interest. Areas covered: This manuscript is a review that examines both the pharmacological properties and clinical studies of tanezumab, the most widely studied antibody to NGF, for management of osteoarthritis (OA) and low back pain. In addition, the safety and tolerability profile and development history of tanezumab are also discussed. Expert opinion: Most studies provide strong support for the ability of tanezumab to provide clinically meaningful pain relief in individuals with these conditions, with longer-term studies suggesting durability of effect. The adverse event profile appears favorable, assuming the risk mitigation strategies are effective at reducing the incidence of joint-related side effects. Further data are being collected to define the optimal dose and dosing strategy in both OA and chronic low back pain.

Gene expression profiles in liver of mouse after chronic exposure to drinking water.

PubMed

Wu, Bing; Zhang, Yan; Zhao, Dayong; Zhang, Xuxiang; Kong, Zhiming; Cheng, Shupei

2009-10-01

cDNA micorarray approach was applied to hepatic transcriptional profile analysis in male mouse (Mus musculus, ICR) to assess the potential health effects of drinking water in Nanjing, China. Mice were treated with continuous exposure to drinking water for 90 days. Hepatic gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 arrays, and pathway analysis was carried out by Molecule Annotation System 2.0 and KEGG pathway database. A total of 836 genes were found to be significantly altered (1.5-fold, P < or = 0.05), including 294 up-regulated genes and 542 down-regulated genes. According to biological pathway analysis, drinking water exposure resulted in aberration of gene expression and biological pathways linked to xenobiotic metabolism, signal transduction, cell cycle and oxidative stress response. Further, deregulation of several genes associated with carcinogenesis or tumor progression including Ccnd1, Egfr, Map2k3, Mcm2, Orc2l and Smad2 was observed. Although transcription changes in identified genes are unlikely to be used as a sole indicator of adverse health effects, the results of this study could enhance our understanding of early toxic effects of drinking water exposure and support future studies on drinking water safety.

Dietary caffeine, performance and mood: enhancing and restorative effects after controlling for withdrawal reversal.

PubMed

James, Jack E; Gregg, M Elizabeth; Kane, Marian; Harte, Frances

2005-01-01

This study aimed to determine whether sustained (i.e. dietary) use of caffeine has net effects on performance and mood compared with sustained abstinence, and whether dietary caffeine restores performance and mood adversely affected by sleep restriction. Participants (n = 96) alternated weekly between ingesting placebo and caffeine (1.75 mg/kg) three times daily for 4 consecutive weeks, while either rested or sleep restricted. Performance involved either a single task requiring sustained vigilance or a varied battery of brief psychomotor and cognitive tasks, and mood was assessed using the Profile of Mood States. Caffeine had no significant net enhancing effects for either performance or mood when participants were rested, and produced no net restorative effects when performance and mood were degraded by sleep restriction. Copyright 2005 S. Karger AG, Basel

Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study

PubMed Central

Porter, John; Galanello, Renzo; Saglio, Giuseppe; Neufeld, Ellis J; Vichinsky, Elliott; Cappellini, Maria Domenica; Olivieri, Nancy; Piga, Antonio; Cunningham, Melody J; Soulières, Denis; Gattermann, Norbert; Tchernia, Gilbert; Maertens, Johan; Giardina, Patricia; Kwiatkowski, Janet; Quarta, Giovanni; Jeng, Michael; Forni, Gian Luca; Stadler, Michael; Cario, Holger; Debusscher, Louisette; Porta, Matteo Della; Cazzola, Mario; Greenberg, Peter; Alimena, Giuliana; Rabault, Bertrand; Gathmann, Insa; Ford, John Malcolm; Alberti, Daniele; Rose, Christian

2008-01-01

Objectives/methods This 1-yr prospective phase II trial evaluated the efficacy of deferasirox in regularly transfused patients aged 3–81 yrs with myelodysplastic syndromes (MDS; n = 47), Diamond–Blackfan anaemia (DBA; n = 30), other rare anaemias (n = 22) or β-thalassaemia (n = 85). Dosage was determined by baseline liver iron concentration (LIC). Results In patients with baseline LIC ≥7 mg Fe/g dry weight, deferasirox initiated at 20 or 30 mg/kg/d produced statistically significant decreases in LIC (P < 0.001); these decreases were greatest in MDS and least in DBA. As chelation efficiency and iron excretion did not differ significantly between disease groups, the differences in LIC changes are consistent with mean transfusional iron intake (least in MDS: 0.28 ± 0.14 mg/kg/d; greatest in DBA: 0.4 ± 0.11 mg/kg/d). Overall, LIC changes were dependent on dose (P < 0.001) and transfusional iron intake (P < 0.01), but not statistically different between disease groups. Changes in serum ferritin and LIC were correlated irrespective of disease group (r = 0.59), supporting the potential use of serum ferritin for monitoring deferasirox therapy. Deferasirox had a safety profile compatible with long-term use. There were no disease-specific safety/tolerability effects: the most common adverse events were gastrointestinal disturbances, skin rash and non-progressive serum creatinine increases. Conclusions Deferasirox is effective for reducing iron burden with a defined, clinically manageable safety profile in patients with various transfusion-dependent anaemias. There were no disease-specific adverse events. Once differences in transfusional iron intake are accounted for, dose-dependent changes in LIC or serum ferritin are similar in MDS and other disease groups. PMID:18028431

Ondansetron-induced dystonia, hypoglycemia, and seizures in a child.

PubMed

Patel, Aneet; Mittal, Shweta; Manchanda, Samiksha; Puliyel, Jacob Mammen

2011-01-01

To document ondansetron-induced dystonia, hypoglycemia, and seizures in a child. A 4-year-old boy was admitted with dystonia following an intravenous dose of ondansetron 2 mg (0.13 mg/kg) that he had received for vomiting that day. In the emergency department, he developed generalized tonicclonic seizures lasting for a few minutes. He was administered lorazepam 1.5 mg (0.1 mg/kg) to control the seizures. His blood glucose level was 10 mg/dL; the hypoglycemia responded promptly to intravenous dextrose 10% (7 mL/kg). Serum electrolytes, renal profile, capillary blood gas, and results of a computed tomography scan of the brain were normal. Subsequent blood glucose values were within normal range. On follow-up after 7 days, the child was healthy with no recurrences of the symptoms. A provisional diagnosis of ondansetron-induced acute dystonia with seizures and hypoglycemia was made. Ondansetron is an antiemetic known for its safety profile. There have been a few case reports of extrapyramidal adverse effects and seizures from this drug but none of ondansetron-associated hypoglycemia. 5-Hydroxytryptamine (5-HT(3)) receptors are involved in arginine vasopressin-mediated release of adrenocorticotropin hormone and cortisol in response to stress. Blunting of this stress response by ondansetron, a 5-HT(3) receptor antagonist, could have caused the hypoglycemia in this patient. According to the Naranjo scale, ondansetron was probably the cause of the dystonia and seizures, and possibly the cause of the hypoglycemia. Other potential explanations for hypoglycemia were considered but were thought to be less likely. Dystonia and seizures have been associated with ondansetron in a few case reports. In addition, clinicians need to consider hypoglycemia as a possible adverse effect of ondansetron.

Tofacitinib: A Review in Rheumatoid Arthritis.

PubMed

Dhillon, Sohita

2017-12-01

Tofacitinib (Xeljanz ® ) is a potent, selective JAK inhibitor that preferentially inhibits Janus kinase (JAK) 1 and JAK3. In the EU, oral tofacitinib 5 mg twice daily is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant of, one or more DMARDs. Several clinical studies of ≤ 24 months' duration showed that tofacitinib monotherapy (as first- or second-line treatment) and combination therapy with a conventional synthetic DMARD (csDMARD; as second- or third-line treatment) was effective in reducing signs and symptoms of disease and improving health-related quality of life (HR-QOL), with benefits sustained during long-term therapy (≤ 96 months). Tofacitinib monotherapy inhibited progression of structural damage in methotrexate-naïve patients during ≤ 24 months' treatment, with beneficial effects also seen in patients receiving tofacitinib plus methotrexate as second-line therapy for 12 months. Tofacitinib was generally well tolerated during ≤ 114 months' treatment, with most adverse events of mild or moderate severity. The tolerability profile of tofacitinib was generally similar to that of biological DMARDs (bDMARDs), with infections and infestations the most common adverse events (AEs) in tofacitinib recipients. However, the incidence of herpes zoster (HZ) was higher with tofacitinib than in the general RA population, although infections were clinically manageable. When added to background methotrexate, tofacitinib was noninferior to adalimumab in terms of efficacy, and both combination therapies had generally similar tolerability profiles. Although additional comparative studies are needed to more definitively position tofacitinib relative to bDMARDs and other targeted synthetic DMARDs, current evidence indicates that oral tofacitinib is a useful option for the treatment of patients with RA.

Usefulness of oral loading of oxcarbazepine suspension in selected patients with epilepsy.

PubMed

Kim, Dong Wook; Gu, Namyi; Lee, Howard; Jang, In-Jin; Chu, Kon; Yu, Kyung-Sang; Cho, Joo-Youn; Yoon, Seo Hyun; Na, Hyun Jeong; Lee, Sang Kun

2013-10-01

Oral loading of oxcarbazepine tablet is effective and well tolerated to adequately achieve the therapeutic levels of its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD) in epilepsy patients. The present study was performed to investigate the safety, tolerability, and pharmacokinetic profiles of oral loading of oxcarbazepine suspension in epilepsy patients with a high risk of recurrent seizures. Oxcarbazepine suspension was administered orally at a single loading dose of 30 mg/kg to 38 adult patients with recurrent seizures, who required rapid seizure control or temporarily discontinued antiepileptic drugs for diagnostic or pre-surgical evaluation. Plasma concentrations of oxcarbazepine and MHD were determined, and adverse events were assessed at 2, 4, 6, 8, 10, 12, 14, 16, and 24 hours after oral loading of oxcarbazepine suspension. 30 patients experienced ≥ 1 adverse event during the first 24 hours after oral loading of oxcarbazepine (e.g., dizziness, transient diplopia, nausea or vomiting), most of which occurred within 4 hours after loading, suggesting no temporal association with MHD plasma levels. 35 (92.1%) patients were still compliant with a maintenance dose of oxcarbazepine after discharge from hospital. 34 (89.4%) patients reached the lower therapeutic level of MHD (12 mg/l) at 4 hours after oral loading of oxcarbazepine suspension, which lasted up to 24 hours in most patients. No patient reached the supratherapeutic levels of MHD (> 35 mg/l) during the study. The mean plasma concentration-time curves and pharmacokinetic profiles of oral loading of oxcarbazepine suspension were similar to those of oral loading of oxcarbazepine tablet. Oral loading of oxcarbazepine suspension followed by maintenance dosing is well tolerated and effective in steadily achieving the therapeutic level of MHD in selected patients with epilepsy.

Characterization of Particulate Matter Profiling and Alveolar Deposition from Biomass Burning in Northern Thailand: The 7-SEAS Study

NASA Technical Reports Server (NTRS)

Chuang, Hsiao-Chi; Hsiao, Ta-Chih; Wang, Sheng-Hsiang; Tsay, Si-Chee; Lin, Neng-Huei

2016-01-01

Biomass burning (BB) frequently occurs in SouthEast Asia (SEA), which significantly affects the air quality and could consequently lead to adverse health effects. The aim of this study was to characterize particulate matter (PM) and black carbon (BC) emitted from BB source regions in SEA and their potential of deposition in the alveolar region of human lungs. A 31-day characterization of PM profiling was conducted at the Doi Ang Khang (DAK) meteorology station in northern Thailand in March 2013. Substantial numbers of PM (10147 +/- 5800 # per cubic centimeter) with a geometric mean diameter (GMD) of 114.4 +/- 9.2 nm were found at the study site. The PM of less than 2.5 micron in aerodynamic diameter (PM sub 2.5) hourly-average mass concentration was 78.0 +/- 34.5 per cubic microgram whereas the black carbon (BC) mass concentration was 4.4 +/- 2.6 micrograms per cubic meter. Notably, high concentrations of nanoparticle surface area (100.5 +/- 54.6 square micrometers per cubic centimeter) emitted from biomass burning can be inhaled into the human alveolar region. Significant correlations with fire counts within different ranges around DAK were found for particle number, the surface area concentration of alveolar deposition, and BC. In conclusion, biomass burning is an important PM source in SEA, particularly nanoparticles, which has high potency to be inhaled into the lung environment and interact with alveolar cells, leading to adverse respiratory effects. The fire counts within 100 to 150 km shows the highest Pearson's r for particle number and surface area concentration. It suggests 12 to 24 hr could be a fair time scale for initial aging process of BB aerosols. Importantly, the people lives in this region could have higher risk for PM exposure.

The innate and adaptive immune response induced by alveolar macrophages exposed to ambient particulate matter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miyata, Ryohei; Eeden, Stephan F. van, E-mail: Stephan.vanEeden@hli.ubc.ca

Emerging epidemiological evidence suggests that exposure to particulate matter (PM) air pollution increases the risk of cardiovascular events but the exact mechanism by which PM has adverse effects is still unclear. Alveolar macrophages (AM) play a major role in clearing and processing inhaled PM. This comprehensive review of research findings on immunological interactions between AM and PM provides potential pathophysiological pathways that interconnect PM exposure with adverse cardiovascular effects. Coarse particles (10 {mu}m or less, PM{sub 10}) induce innate immune responses via endotoxin-toll-like receptor (TLR) 4 pathway while fine (2.5 {mu}m or less, PM{sub 2.5}) and ultrafine particles (0.1 {mu}mmore » or less, UFP) induce via reactive oxygen species generation by transition metals and/or polyaromatic hydrocarbons. The innate immune responses are characterized by activation of transcription factors [nuclear factor (NF)-{kappa}B and activator protein-1] and the downstream proinflammatory cytokine [interleukin (IL)-1{beta}, IL-6, and tumor necrosis factor-{alpha}] production. In addition to the conventional opsonin-dependent phagocytosis by AM, PM can also be endocytosed by an opsonin-independent pathway via scavenger receptors. Activation of scavenger receptors negatively regulates the TLR4-NF-{kappa}B pathway. Internalized particles are subsequently subjected to adaptive immunity involving major histocompatibility complex class II (MHC II) expression, recruitment of costimulatory molecules, and the modulation of the T helper (Th) responses. AM show atypical antigen presenting cell maturation in which phagocytic activity decreases while both MHC II and costimulatory molecules remain unaltered. PM drives AM towards a Th1 profile but secondary responses in a Th1- or Th-2 up-regulated milieu drive the response in favor of a Th2 profile.« less

Fatigue during treatment with antiepileptic drugs: A levetiracetam-specific adverse event?

PubMed

Mula, Marco; von Oertzen, Tim J; Cock, Hannah R; Yogarajah, Mahinda; Lozsadi, Dora A; Agrawal, Niruj

2017-07-01

To examine the prevalence and clinical correlates of fatigue as an adverse event (AE) of antiepileptic drug (AED) treatment in patients with epilepsy. Data from 443 adult outpatients with epilepsy assessed with the Adverse Event Profile (AEP) and the Neurological Disorder Depression Inventory for Epilepsy (NDDIE) were analysed. Fatigue is reported by 36.6% of patients as always a problem during AED treatment. Fatigue is more likely to be reported by females (64.8% vs. 35.2%; Chi-Square=16.762; df=3; p=0.001) and during treatment with levetiracetam (42.3% vs. 33.2%; Chi-Square=11.462; df=3; p=0.009). The associations with the female gender and levetiracetam treatment were not mediated by depression, as identified with the NDDIE, and could not be simply explained by the large number of subjects on levetiracetam treatment, as analogous figures resulted from the analysis of a monotherapy subsample (41.7% vs. 30.3%; Chi-Square=11.547; df=3; p=0.009). One third of patients with epilepsy reports fatigue as a significant problem during AED treatment. Fatigue is more likely to be reported by females and seems to be specifically associated with LEV treatment. However, fatigue is not mediated by a negative effect of LEV on mood. Copyright © 2017 Elsevier Inc. All rights reserved.

Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis.

PubMed

Ogura, Takashi; Taniguchi, Hiroyuki; Azuma, Arata; Inoue, Yoshikazu; Kondoh, Yasuhiro; Hasegawa, Yoshinori; Bando, Masashi; Abe, Shinji; Mochizuki, Yoshiro; Chida, Kingo; Klüglich, Matthias; Fujimoto, Tsuyoshi; Okazaki, Kotaro; Tadayasu, Yusuke; Sakamoto, Wataru; Sugiyama, Yukihiko

2015-05-01

A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone. Copyright ©ERS 2015.

Lesinurad for the treatment of hyperuricaemia in people with gout.

PubMed

Robinson, Philip C; Dalbeth, Nicola

2017-12-01

Gout is a common form of inflammatory arthritis caused by deposition of monosodium urate crystals. The central strategy for effective long-term management of gout is serum urate lowering. Current urate-lowering drugs include both xanthine oxidase inhibitors and uricosuric agents. Lesinurad is a URAT1 inhibitor that selectively inhibits urate rebsorption at the proximal renal tubule. Lesinurad 200mg daily in combination with a xanthine oxidase is approved for urate-lowering therapy in patients with gout. Areas covered: The published literature was searched using Pubmed and additional information was obtained from publically available regulatory documents. Pre-clinical data and clinical trials of lesinurad are described. Serum urate-lowering efficacy and effects on other clinical endpoints are discussed. Adverse event data, focusing on renal safety are also presented. Expert opinion: Lesinurad is an effective urate-lowering drug that has a generally acceptable safety profile when used at 200mg daily dosing in combination with a xanthine oxidase inhibitor. The recent approval of fixed dose combination pills of lesinurad with allopurinol is an important step in improving adherence and reducing risk of renal adverse events. It remains to be seen if this therapy will provide additional benefit for gout management above improved use of widely available generic therapies.

Additive gene-environment effects on hippocampal structure in healthy humans.

PubMed

Rabl, Ulrich; Meyer, Bernhard M; Diers, Kersten; Bartova, Lucie; Berger, Andreas; Mandorfer, Dominik; Popovic, Ana; Scharinger, Christian; Huemer, Julia; Kalcher, Klaudius; Pail, Gerald; Haslacher, Helmuth; Perkmann, Thomas; Windischberger, Christian; Brocke, Burkhard; Sitte, Harald H; Pollak, Daniela D; Dreher, Jean-Claude; Kasper, Siegfried; Praschak-Rieder, Nicole; Moser, Ewald; Esterbauer, Harald; Pezawas, Lukas

2014-07-23

Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although genetic and environmental variables affecting hippocampal volume have extensively been studied and related to mental illness, limited evidence is available with respect to G × E interactions on hippocampal volume. The present MRI study investigated interaction effects on hippocampal volume between three well-studied functional genetic variants (COMT Val158Met, BDNF Val66Met, 5-HTTLPR) associated with hippocampal volume and a measure of environmental adversity (life events questionnaire) in a large sample of healthy humans (n = 153). All three variants showed significant interactions with environmental adversity with respect to hippocampal volume. Observed effects were additive by nature and driven by both recent as well as early life events. A consecutive analysis of hippocampal subfields revealed a spatially distinct profile for each genetic variant suggesting a specific role of 5-HTTLPR for the subiculum, BDNF Val66Met for CA4/dentate gyrus, and COMT Val158Met for CA2/3 volume changes. The present study underscores the importance of G × E interactions as determinants of hippocampal volume, which is crucial for the neurobiological understanding of stress-related conditions, such as mood disorders or post-traumatic stress disorder (PTSD). Copyright © 2014 the authors 0270-6474/14/349917-10$15.00/0.

Toxicity and gastric tolerance of essential oils from Cymbopogon citratus, Ocimum gratissimum and Ocimum basilicum in Wistar rats.

PubMed

Fandohan, P; Gnonlonfin, B; Laleye, A; Gbenou, J D; Darboux, R; Moudachirou, M

2008-07-01

Oils of Cymbopogon citratus, Ocimum gratissimum and Ocimum basilicum are widely used for their medicinal properties, and as food flavours and perfumes. Recently in a study in West Africa, these oils have been recommended to combat Fusarium verticillioides and subsequent fumonisin contamination in stored maize, but their toxicological profile was not investigated. The current study was undertaken to provide data on acute and subacute toxicity as well as on gastric tolerance of these oils in rat. For this purpose, the oils were given by gavage to Wistar rats for 14 consecutive days. The animals were observed daily for their general behaviour and survival, and their visceral organs such as stomach and liver were taken after sacrifice for histological analyses. A dose-dependent effect of the tested oils was observed during the study. Applied at doses generally higher than 1500 mg/kg body weight, the oils caused significant functional damages to stomach and liver of rat. Unlike the other oils, administration of O. gratissimum oil did not result in adverse effects in rat liver at the tested doses. The no observed adverse effect level (NOAEL) of the tested oils has been established. The three tested oils can be considered as safe to human when applied on stored maize at recommended concentrations.

A Profile of Pornography Users in Australia: Findings From the Second Australian Study of Health and Relationships.

PubMed

Rissel, Chris; Richters, Juliet; de Visser, Richard O; McKee, Alan; Yeung, Anna; Caruana, Theresa

2017-02-01

There are societal concerns that looking at pornography has adverse consequences among those exposed. However, looking at sexually explicit material could have educative and relationship benefits. This article identifies factors associated with looking at pornography ever or within the past 12 months for men and women in Australia, and the extent to which reporting an "addiction" to pornography is associated with reported bad effects. Data from the Second Australian Study of Health and Relationships (ASHR2) were used: computer-assisted telephone interviews (CASIs) completed by a representative sample of 9,963 men and 10,131 women aged 16 to 69 years from all Australian states and territories, with an overall participation rate of 66%. Most men (84%) and half of the women (54%) had ever looked at pornographic material. Three-quarters of these men (76%) and more than one-third of these women (41%) had looked at pornographic material in the past year. Very few respondents reported that they were addicted to pornography (men 4%, women 1%), and of those who said they were addicted about half also reported that using pornography had had a bad effect on them. Looking at pornographic material appears to be reasonably common in Australia, with adverse effects reported by a small minority.

Effects of the organophosphate insecticides phosmet and chlorpyrifos on trophoblast JEG-3 cell death, proliferation and inflammatory molecule production.

PubMed

Guiñazú, Natalia; Rena, Viviana; Genti-Raimondi, Susana; Rivero, Virginia; Magnarelli, Gladis

2012-04-01

Epidemiological data have associated environmental organophosphate insecticide (OP) exposure during pregnancy with fetal growth deficits. To better understand OP injury that may adversely affect pregnancy, we used the JEG-3 choriocarcinoma cell line, which provide a recognized in vitro model to study placental function. The effects of the OP phosmet (Pm) and chlorpyrifos (Cp) on JEG-3 cells viability, proliferation, cell cycle and inflammatory molecule production were evaluated. Both insecticides affected cellular viability in a concentration- and time-dependent manner, inducing apoptosis and decreasing [(3)H]-thymidine incorporation. However, only Pm reduced DNA synthesis independently of cellular death and decreased the cell percentage at the S-phase. Unlike apoptosis, TNFα production varied with the concentration tested, suggesting that other TNFα independent mechanisms might trigger cell death. No induction of the inflammatory molecule nitric oxide was detected. The mRNA levels of pro-inflammatory IL-6, IL-17 and the anti-inflammatory IL-13 cytokines were differentially modulated. These findings show that Pm and Cp generate a specific toxicity signature, altering cell viability and inducing an inflammatory cytokine profile, suggesting that trophoblasts may represent a possible target for OP adverse effects. Copyright © 2012 Elsevier Ltd. All rights reserved.

Deuterium Tetrabenazine for Tardive Dyskinesia.

PubMed

Cummings, Michael A; Proctor, George J; Stahl, Stephen M

2018-01-01

Tardive dyskinesia remains a significant, potentially stigmatizing or crippling adverse effect for any patient treated with an antipsychotic medication. While second- and third-generation antipsychotics have exhibited lower annual incidence rates for tardive dyskinesia than classic or first-generation agents, 3.9% versus 5.5%, the estimated incidence rate is only modestly lower. When coupled with the fact that second- and third-generation antipsychotic medications have come to be employed in treating a wider range of disorders (e.g., autism spectrum disorders, mood disorders, personality disorders, etc.), it is clear that the population of patients exposed to the risk of tardive dyskinesia has expanded. On April 3, 2017, the U.S. Food and Drug Administration (FDA) approved a deuterated version of tetrabenazine (Xenozine®) for the treatment of the involuntary choreic movements associated with Huntington's disease. More recent data, however, have indicated that deuterium tetrabenazine or deutetrabenazine (Austedo®) is effective in treating tardive dyskinesia. Moreover, like the other derivative of tetrabenazine, valbenazine (Ingrezza®), deutetrabenazine offers less frequent dosing and a better short-term adverse effect profile than that of tetrabenazine. Longer use in a broader range of patients, however, will be required to identify risks and benefits not found in short-term trials, as well as optimal use parameters for treatment of tardive dyskinesia.

Phosphodiesterase 4 inhibitors in chronic obstructive pulmonary disease: a new approach to oral treatment

PubMed Central

Currie, Graeme P; Butler, Claire A; Anderson, Wendy J; Skinner, Chris

2008-01-01

Chronic obstructive pulmonary disease represents a major global health care burden for both primary and secondary care providers and is the most common respiratory condition necessitating hospital admission. Short-acting bronchodilators play a vital role in immediate relief of symptoms, while inhaled long-acting bronchodilators and inhaled corticosteroids are advocated for regular use in individuals with persistent symptoms and exacerbations. Theophylline is a nonspecific phosphodiesterase inhibitor and is usually reserved for patients with ongoing symptoms despite optimum inhaled bronchodilator treatment or when difficulty is encountered with inhaler devices. However, it is often not widely used mainly due to frequency of dose-related adverse effects, numerous drug interactions and narrow therapeutic index. This in turn has lead to the development of more selective phosphodiesterase inhibitors in an attempt to create a drug which patients can use with beneficial effects but without the problems associated with theophylline. Current data do indicate that phosphodiesterase 4 inhibitors confer some benefits in chronic obstructive pulmonary disease when compared to placebo in terms of lung function, quality of life and exacerbations. They are also generally well tolerated. Further studies are required to determine fully their long-term beneficial and adverse effect profiles and ultimately where they might comfortably sit in management algorithms. PMID:18341675

Current trends in antithyroid drug treatment of Graves' disease.

PubMed

Okosieme, Onyebuchi E; Lazarus, John H

2016-10-01

Graves' hyperthyroidism is associated with significant morbidity and mortality risk. The thionamides, methimazole, its pro-drug derivative carbimazole, and propylthiouracil, remain a cornerstone of management. Yet despite decades of use, optimal strategies for maximising treatment response and curtailing adverse effect risk remains uncertain. We reviewed the current literature on the evidence based medical management of Graves' disease. Specifically, we evaluated current approaches to the use of thionamides, adjunctive therapies, and potential novel agents for controlling Graves' hyperthyroidism. Primary medical therapy is successful in less than 50% of cases and so careful selection of patients for medical treatment based on a combination of pathological and pragmatic considerations is essential. Carbimazole or methimazole is the treatment of choice in the non-pregnant population driven by its more favourable pharmacokinetic and adverse effect profile over propylthiouracil. In pregnancy the choice of treatment is less straightforward and an approach that minimises undue fetal exposure to all thionamides should be adopted. Additional data is needed on the value of adjunctive therapies including potassium perchlorate, iodides, glucocorticoids, lithium, and cholestyramine. Novel agents directed against pathogenetic targets including TSH receptor blocking monoclonal antibodies and small molecule antagonists may hold promise for the future.

Advancing drug delivery systems for the treatment of multiple sclerosis.

PubMed

Tabansky, Inna; Messina, Mark D; Bangeranye, Catherine; Goldstein, Jeffrey; Blitz-Shabbir, Karen M; Machado, Suly; Jeganathan, Venkatesh; Wright, Paul; Najjar, Souhel; Cao, Yonghao; Sands, Warren; Keskin, Derin B; Stern, Joel N H

2015-12-01

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. It is characterized by demyelination of neurons and loss of neuronal axons and oligodendrocytes. In MS, auto-reactive T cells and B cells cross the blood-brain barrier (BBB), causing perivenous demyelinating lesions that form multiple discrete inflammatory demyelinated plaques located primarily in the white matter. In chronic MS, cortical demyelination and progressive axonal transections develop. Treatment for MS can be stratified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs aim to decrease circulating immune cells or to prevent these cells from crossing the BBB and reduce the inflammatory response. There are currently 10 DMTs approved for the relapsing forms of MS; these vary with regard to their efficacy, route and frequency of administration, adverse effects, and toxicity profile. Better drug delivery systems are being developed in order to decrease adverse effects, increase drug efficacy, and increase patient compliance through the direct targeting of pathologic cells. Here, we address the uses and benefits of advanced drug delivery systems, including nanoparticles, microparticles, fusion antibodies, and liposomal formulations. By altering the properties of therapeutic particles and enhancing targeting, breakthrough drug delivery technologies potentially applicable to multiple disease treatments may rapidly emerge.

Clinical relevance of cimetidine drug interactions.

PubMed

Shinn, A F

1992-01-01

The excellent efficacy and tolerability profiles of H2-antagonists have established these agents as the leading class of antiulcer drugs. Attention has been focused on drug interactions with H2-antagonists as a means of product differentiation and because many patients are receiving multiple drug therapy. The main mechanism of most drug interactions involving cimetidine appears to be inhibition of the hepatic microsomal enzyme cytochrome P450, an effect which may be related to the different structures of H2-antagonists. Ranitidine appears to have less affinity than cimetidine for this system. There have been many published case reports and studies of drug interactions with cimetidine, but many of these have provided pharmacokinetic data only, with little information concerning the clinical significance of these findings. Nevertheless, the coadministration of cimetidine with drugs that have a narrow therapeutic margin (such as theophylline) may potentially result in clinically significant adverse effects. The monitoring of serum concentrations of drugs coadministered with cimetidine may reduce the risk of adverse events but does not abolish the problem. However, for most patients, concomitant administration of cimetidine with drugs possessing a wide therapeutic margin is unlikely to pose a significant problem.

Safety assessment of nicotinamide riboside, a form of vitamin B3.

PubMed

Conze, D B; Crespo-Barreto, J; Kruger, C L

2016-01-20

Nicotinamide riboside (NR) is a naturally occurring form of vitamin B 3 present in trace amounts in some foods. Like niacin, it has been shown to be a precursor in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). The safety of Niagen™, a synthetic form of NR, was determined using a bacterial reverse mutagenesis assay (Ames), an in vitro chromosome aberration assay, an in vivo micronucleus assay, and acute, 14-day and 90-day rat toxicology studies. NR was not genotoxic. There was no mortality at an oral dose of 5000 mg/kg. Based on the results of a 14-day study, a 90-day study was performed comparing NR at 300, 1000, and 3000 mg/kg/day to an equimolar dose of nicotinamide at 1260 mg/kg/day as a positive control. Results from the study show that NR had a similar toxicity profile to nicotinamide at the highest dose tested. Target organs of toxicity were liver, kidney, ovaries, and testes. The lowest observed adverse effect level for NR was 1000 mg/kg/day, and the no observed adverse effect level was 300 mg/kg/day. © The Author(s) 2016.

Itopride in the treatment of functional dyspepsia in Chinese patients: a prospective, multicentre, post-marketing observational study.

PubMed

Sun, Jing; Yuan, Yao-Zong; Holtmann, Gerald

2011-12-01

Prokinetic agents are commonly used in the symptomatic treatment of functional dyspepsia (FD). Safety or efficacy issues associated with the use of available prokinetics, such as metoclopramide, domperidone, cisapride and mosapride, mean there is a need for an effective and well tolerated prokinetic agent. Itopride is a novel prokinetic agent with a dual mode of action, good safety profile and documented efficacy in placebo-controlled trials. The objective of this study was to assess the effectiveness and safety of itopride in the management of FD. This was a prospective, multicentre, post-marketing observational study carried out in private outpatient clinics throughout China. The study included patients with symptomatic FD aged ≥18 years. Patients were prescribed itopride 50 mg three times daily before meals for 4 weeks, after which there was a 2-week follow-up period during which they did not take itopride. Effectiveness and tolerability data obtained from patients who completed 4 weeks of therapy were analysed. The treatment response rate after 4 weeks was measured by patient global assessment; scores at the end of treatment were compared with baseline scores. Response rate based on symptom scoring was also measured after 4 weeks, with an effective treatment being defined as a symptom improvement of ≥50%. In total, 587 patients with FD were enrolled. The mean ± SD difference in the total symptom score before and after the 4-week treatment period was -5.62 ± 3.27, corresponding to a 69.23 ± 26.53% reduction from baseline (p < 0.001). The treatment response rates in patients who fulfilled Rome I, II and III criteria for FD were 33.68%, 34.71% and 35.50%, respectively, after 1 week of treatment; 52.82%, 54.61% and 56.51%, respectively, after 2 weeks; 66.67%, 67.23% and 68.64%, respectively, after 3 weeks; and 72.82%, 73.54% and 75.15%, respectively, after 4 weeks. Response rates were significantly different at 1 week versus 4 weeks of treatment. Nine patients (1.54%) had adverse events: four were probably related to the study drug, three were possibly related and two were not related. Of the nine patients with adverse events, two discontinued the study drug, two suspended (i.e. temporarily discontinued the drug until the adverse event subsided) the study drug, and five continued the study drug. Seven of the nine patients with adverse events had adverse reactions (defined as adverse events considered causally related to the study drug): two improved, three recovered and two showed no change. No adverse reactions were serious enough to warrant discontinuation of therapy. Itopride was an effective and well tolerated drug in the management of FD in this patient population.

Thermal-structural modeling of polymer Bragg grating waveguides illuminated by a light emitting diode.

PubMed

Joon Kim, Kyoung; Bar-Cohen, Avram; Han, Bongtae

2012-02-20

This study reports both analytical and numerical thermal-structural models of polymer Bragg grating (PBG) waveguides illuminated by a light emitting diode (LED). A polymethyl methacrylate (PMMA) Bragg grating (BG) waveguide is chosen as an analysis vehicle to explore parametric effects of incident optical powers and substrate materials on the thermal-structural behavior of the BG. Analytical models are verified by comparing analytically predicted average excess temperatures, and thermally induced axial strains and stresses with numerical predictions. A parametric study demonstrates that the PMMA substrate induces more adverse effects, such as higher excess temperatures, complex axial temperature profiles, and greater and more complicated thermally induced strains in the BG compared with the Si substrate. © 2012 Optical Society of America

[15-year experience of moxifloxacin in the treatment of patients with bacterial rhinosinusitis].

PubMed

Ovchinnikov, A Y; Edzhe, M A; Miroshnichenko, N A; Hon, E M; Korostelev, S A

2015-01-01

The article summarizes 15 years of experience of the use of moxifloxacin (Avelox) in Russia in patients with acute bacterial rhinosinusitis. Emphasize its high bactericidal activity against a broad spectrum of microorganisms- from basic agents to the atypical and anaerobic microflora. The results of these studies suggest the continued effectiveness of the dosage of 400 mg a short course (7 days) over 15 years of practical use of the drug, which in its clinical efficacy is superior to amoxicillin/clavulanate, cefuroxime axetil and levofloxacin. The safety profile of moxifloxacin, studied at the population level is not associated with an increased risk of adverse effects in compliance with the dosing regimen, taking into account the indications and contraindications.

Assessment of Serum Biomarkers in Rats After Exposure to Pesticides of Different Chemical Classes

EPA Science Inventory

There is increasing emphasis on the use of biomarkers of adverse outcomes in safety assessment and translational research. We evaluated serum biomarkers and targeted metabolite profiles after exposure to pesticides (permethrin, deltamethrin, imidacloprid, carbaryl, triadimefon...

75 FR 39535 - Agency Information Collection Activities; Proposed Collection; Comment Request; Adverse Event...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-09

... Safety Network (MedSun). Additionally, the electronic form will include hospital profile information and... Device-Safety Exchange (DS-X) (formerly called M-Den), which was a moderated site where MedSun members... emerging [[Page 39536

Oscillatory magnetic brain activity is related to dissociative symptoms and childhood adversities - A study in women with multiple trauma.

PubMed

Schalinski, I; Moran, J K; Elbert, T; Reindl, V; Wienbruch, C

2017-08-15

Individuals with trauma-related disorders are complex and heterogeneous; part of this complexity derives from additional psychopathology like dissociation as well as environmental adversities such as traumatic stress, experienced throughout the lifespan. Understanding the neurophysiological abnormalities in Post-traumatic stress disorder (PTSD) requires a simultaneous consideration of these factors. Resting state magnetoencephalography (MEG) recordings were obtained from 41 women with PTSD and comorbid depressive symptoms, and 16 healthy women. Oscillatory brain activity was extracted for five frequency bands and 11 source locations, and analyzed in relation to shutdown dissociation and adversity-related measures. Dissociative symptoms were related to increased delta and lowered beta power. Adversity-related measures modulated theta and alpha oscillatory power (in particular childhood sexual abuse) and differed between patients and controls. Findings are based on women with comorbid depressive symptoms and therefore may not be applicable for men or groups with other clinical profiles. In respect to childhood adversities, we had no reliable source for the early infancy. Trauma-related abnormalities in neural organization vary with both exposure to adversities as well as their potential to evoke ongoing shutdown responses. Copyright © 2017 Elsevier B.V. All rights reserved.

Clustering of adversity in young adults on disability pension due to mental disorders: a latent class analysis.

PubMed

Joensuu, Matti; Mattila-Holappa, Pauliina; Ahola, Kirsi; Ervasti, Jenni; Kivimäki, Mika; Kivekäs, Teija; Koskinen, Aki; Vahtera, Jussi; Virtanen, Marianna

2016-02-01

Mental disorders are the leading cause of work disability among young adults. This study examined whether distinct classes could be identified among young adults on the basis of medical history before receiving a disability pension due to a mental disorder. Medical history was obtained from pension applications and attached medical certificates for 1163 individuals aged 18-34 years who, in 2008, received a disability pension due to a mental disorder. Using latent class analysis, 10 clinical and individual adversities and their associations with sex, age and diagnostic category were examined. Three classes were identified: childhood adversity (prevalence, 33%), comorbidity (23%), and undefined (44%). The childhood adversity class was characterized by adverse events and symptoms reported during childhood and it associated with depressive disorders. The comorbidity class was characterized by comorbid mental disorders, suicide attempts and substance abuse and associated with younger age and bipolar disorder. The undefined class formed no distinct profile; individuals in this class had the lowest number of adversities and it associated with psychotic disorders. The identification of subgroups characterized by childhood circumstances and comorbidity may help planning of prevention and support practices for young adults with mental disorders and risk of work disability.

Minimizing AED adverse effects: improving quality of life in the interictal state in epilepsy care.

PubMed

St Louis, Erik K; Louis, Erik K

2009-06-01

The goals of epilepsy therapy are to achieve seizure freedom while minimizing adverse effects of treatment. However, producing seizure-freedom is often overemphasized, at the expense of inducing adverse effects of treatment. All antiepileptic drugs (AEDs) have the potential to cause dose-related, "neurotoxic" adverse effects (i.e., drowsiness, fatigue, dizziness, blurry vision, and incoordination). Such adverse effects are common, especially when initiating AED therapy and with polytherapy. Dose-related adverse effects may be obviated in most patients by dose reduction of monotherapy, reduction or elimination of polytherapy, or substituting for a better tolerated AED. Additionally, all older and several newer AEDs have idiosyncratic adverse effects which usually require withdrawal in an affected patient, including serious rash (i.e., Stevens-Johnson Syndrome, toxic epidermal necrolysis), hematologic dyscrasias, hepatotoxicity, teratogenesis in women of child bearing potential, bone density loss, neuropathy, and severe gingival hyperplasia. Unfortunately, occurrence of idiosyncratic AED adverse effects cannot be predicted or, in most cases, prevented in susceptible patients. This article reviews a practical approach for the definition and identification of adverse effects of epilepsy therapies, and reviews the literature demonstrating that adverse effects result in detrimental quality of life in epilepsy patients. Strategies for minimizing AED adverse effects by reduction or elimination of AED polytherapy, appropriately employing drug-sparing therapies, and optimally administering AEDs are outlined, including tenets of AED selection, titration, therapeutic AED laboratory monitoring, and avoidance of chronic idiosyncratic adverse effects.

Blood metal levels and third trimester maternal plasma matrix metalloproteinases (MMPs).

PubMed

Au, Felicia; Bielecki, Agnieszka; Blais, Erica; Fisher, Mandy; Cakmak, Sabit; Basak, Ajoy; Gomes, James; Arbuckle, Tye E; Fraser, William D; Vincent, Renaud; Kumarathasan, Prem

2016-09-01

While it is known that in utero exposure to environmental toxicants, namely heavy metals, can adversely affect the neonate, there remains a significant paucity of information on maternal biological changes specific to metal exposures during pregnancy. This study aims at identifying associations between maternal metal exposures and matrix metalloproteinases (MMPs) that are known to be engaged in pregnancy process. Third trimester maternal plasma (n = 1533) from a pregnancy cohort (Maternal-Infant Research on Environmental Chemicals Study, MIREC) were analyzed for MMP-1,-2,-7,-9 and -10 by affinity-based multiplex protein array analyses. Maternal metal concentrations (mercury, cadmium, lead, arsenic and manganese) in 1st and 3rd trimesters exhibited strong correlations (p < 0.05). Multivariate regression models were used to estimate odds ratio (OR) for the association between metal concentrations in quartiles and high (90%) and low (10%) maternal MMP levels. Significant (p < 0.05) metal exposure-related effects were observed with the different MMP isoform responses. MMP profiles were specific to the trimester at which the maternal blood metals were analyzed. Our findings suggest that the profiles of these MMP isoforms vary with the type of metal exposure, blood metal concentrations and the trimester at which metal levels were determined. These new findings on maternal metal-MMP relationships can guide future explorations on toxicity mechanisms relevant to metal exposure-mediated adverse birth outcomes. Copyright © 2016. Published by Elsevier Ltd.

Management of crizotinib therapy for ALK-rearranged non-small cell lung carcinoma: an expert consensus.

PubMed

Cappuzzo, Federico; Moro-Sibilot, Denis; Gautschi, Oliver; Boleti, Ekaterini; Felip, Enriqueta; Groen, Harry J M; Germonpré, Paul; Meldgaard, Peter; Arriola, Edurne; Steele, Nicola; Fox, Jesme; Schnell, Patrick; Engelsberg, Arne; Wolf, Jürgen

2015-02-01

Within 4 years of the discovery of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC), the ALK inhibitor crizotinib gained US and European approval for the treatment of advanced ALK-positive NSCLC. This was due to the striking response data observed with crizotinib in phase I and II trials in patients with ALK-positive NSCLC, as well as the favorable tolerability and safety profile observed. Recently published phase III data established crizotinib as a new standard of care for this NSCLC molecular subset. A consequence of such rapid approval, however, is the limited clinical experience and relative paucity of information concerning optimal therapy management. In this review, we discuss the development of crizotinib and the clinical relevance of its safety profile, examining crizotinib-associated adverse events in detail and making specific management recommendations. Crizotinib-associated adverse events were mostly mild to moderate in severity in clinical studies, and appropriate monitoring and supportive therapies are considered effective in avoiding the need for dose interruption or reduction in most cases. Therapy management of patients following disease progression on crizotinib is also discussed. Based on available clinical data, it is evident that patients may have prolonged benefit from crizotinib after Response Evaluation Criteria in Solid Tumors-defined disease progression, and crizotinib should be continued for as long as the patient derives benefit. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Results of European post-marketing surveillance of bosentan in pulmonary hypertension.

PubMed

Humbert, M; Segal, E S; Kiely, D G; Carlsen, J; Schwierin, B; Hoeper, M M

2007-08-01

After the approval of bosentan for the treatment of pulmonary arterial hypertension (PAH), European authorities required the introduction of a post-marketing surveillance system (PMS) to obtain further data on its safety profile. A novel, prospective, internet-based PMS was designed, which solicited reports on elevated aminotransferases, medical reasons for bosentan discontinuation and other serious adverse events requiring hospitalisation. Data captured included demographics, PAH aetiology, baseline functional status and concomitant PAH-specific medications. Safety signals captured included death, hospitalisation, serious adverse events, unexpected adverse events and elevated aminotransferases. Within 30 months, 4,994 patients were included, representing 79% of patients receiving bosentan in Europe. In total, 4,623 patients were naïve to treatment; of these, 352 had elevated aminotransferases, corresponding to a crude incidence of 7.6% and an annual rate of 10.1%. Bosentan was discontinued due to elevated aminotransferases in 150 (3.2%) bosentan-naïve patients. Safety results were consistent across subgroups and aetiologies. The novel post-marketing surveillance captured targeted safety data ("potential safety signals") from the majority of patients and confirmed that the incidence and severity of elevated aminotransferase levels in clinical practice was similar to that reported in clinical trials. These data complement those from randomised controlled clinical trials and provide important additional information on the safety profile of bosentan.

Efficacy and safety of Vitex agnus-castus extract for treatment of premenstrual syndrome in Japanese patients: a prospective, open-label study.

PubMed

Momoeda, Mikio; Sasaki, Hidetaka; Tagashira, Eiko; Ogishima, Masayuki; Takano, Yuichi; Ochiai, Kazunori

2014-03-01

Herbal medicine containing Vitex agnus-castus (VAC) extract is widely used by women with premenstrual syndrome (PMS) in Europe, however, in Japan, clinical evidence remains to be determined. This study attempted to investigate the efficacy and safety profiles of VAC extract in Japanese patients with PMS. A multi-center, prospective, open-label, single-arm, phase 3 study was performed in Japanese women with PMS and aged 18-44 years. The patients received Prefemin® (Max Zeller Söhne AG, Romanshorn, Switzerland), containing 20 mg of VAC extract, once daily for three menstrual cycles. The efficacy profile was examined based on the intensity of ten PMS symptoms-irritability, depressed mood, anger, headache, bloating, breast fullness, skin disorder, fatigue, drowsiness, and sleeplessness-recorded by patients via a visual analog scale (VAS). In addition, the responder rate was calculated based on the total VAS score defined by the sum of the VAS scores of the first six symptoms mentioned above. Furthermore, physician's global assessment (PGA) scores were recorded. Adverse events including vital signs and laboratory test values were monitored as safety evaluation. Sixty-nine patients received Prefemin®. After the first menstrual cycle, a statistically significant decrease in total VAS score was observed (P<0.001), and the score continued to diminish for the following two cycles. Each of the ten symptom scores decreased significantly in this manner. In addition, the responder rate increased in a time-dependent manner; the rate at the third menstrual cycle was 91.0%, and almost all of the patients were without symptoms or exhibited only mild symptoms based on PGA. Eight patients exhibited non-serious adverse events, one of which was allergic dermatitis whose causal relationship with VAC was not ruled out. VAC extract improved PMS symptoms in Japanese patients, with no substantial adverse events. This is the first study to report the effect of VAC extract in Japanese patients.

Differential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis

PubMed Central

Xie, Jiangan; Codd, Christopher; Mo, Kevin; He, Yongqun

2016-01-01

M. bovis strain Bacillus Calmette–Guérin (BCG) has been the only licensed live attenuated vaccine against tuberculosis (TB) for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs) have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE)-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis), skin (e.g., skin ulceration and cyanosis), and respiratory system (e.g., cough and pneumonia); in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria). With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased) shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG-associated death outcome. PMID:27749923