High Adverse Effects Research Articles

Specific adverse effects of antiepileptic drugs--A true-to-life monotherapy study.

In patients taking antiepileptic drugs (AEDs) for epilepsy, adverse effects (AEs) often lead to unfavorable quality of life, impaired adherence, and, eventually, discontinuation of pharmacological treatment. In a true-to-life sample of subjects from our academic epilepsy outpatient clinic, we aimed to identify predictors for overall high AE burden and for specific AEs focusing on patients on monotherapy. All patients ≥16years of age with epilepsy for ≥12months were routinely asked to complete the Liverpool Adverse Event Profile (LAEP) just before their appointment. Demographic, epilepsy, and treatment variables were derived from our comprehensive outpatient database. Out of 841 patients, 438 (61% female, mean age: 44.7±17.1years) on monotherapy were included in this study. Levetiracetam (n=151), lamotrigine (n=167), valproic acid (n=73), or controlled-release carbamazepine (n=47) were the most commonly used antiepileptic drugs (AEDs). Independent predictors for general high AE burden (LAEP score≥45) were duration of epilepsy, lack of 12-month seizure freedom, and partial epilepsy, but none of the four individual AEDs. The most frequent LAEP-defined specific AEs were sleepiness, difficulty concentrating, tiredness, and memory problems. The three most frequent independent predictors for each of the 19 AEs were lack of 12-month seizure freedom (13/19 AEs), individual AED (7/19 AEs), and partial epilepsy (6/19 AEs). Levetiracetam was independently associated with anger/aggression, nervousness/agitation, upset stomach, depression, and sleep disturbance; lamotrigine with nervousness/agitation, upset stomach, and difficulty concentrating; and valproic acid with upset stomach and shaky hands. Individual AEDs independently predicted some specific AEs, but not overall high AE burden. Our findings may help to characterize patients with epilepsy who are at high risk for specific AEs. Dose reduction or change to another AED may reduce LAEP score and potential nonadherence.

Colloidal stability and ecotoxicity of multiwalled carbon nanotubes: Influence of select organic matters.

In the last few years, the release of multiwalled carbon nanotubes (MWCNTs) into the environment has raised serious concerns regarding their fate and potential impacts. Aquatic organisms constitute an important pathway for their entrance and transfer throughout the food web, and the current demand for standardization of methodologies to analyze the interactions of MWCNTs with them requires aquatic media that represent natural systems. However, the inherent hydrophobicity of MWCNTs and the substances present in natural waters may greatly affect their stability and bioavailability. The present study analyzes the influence of the most referenced synthetic and natural organic matters (Sigma-Aldrich humic acid and Suwannee River natural organic matter) in the agglomeration kinetics and ecotoxicity of MWCNTs, with the aim of determining their suitability to fulfill the current standardization requirements. Natural organic matter provides increased colloidal stability to the MWCNTs' dispersions, which results in higher adverse effects on the key invertebrate organism Daphnia magna. Furthermore, the results obtained with this type of organic matter allow for observation of the important role of the outer diameter and content impurities of MWCNTs in their stability and ecotoxicity on daphnids. Sigma-Aldrich humic acid appeared to alter the response of the organisms to carbon nanotubes compared with that observed in the presence of natural organic matter.

Dulanermin with rituximab in patients with relapsed indolent B-cell lymphoma: an open-label phase 1b/2 randomised study

Dulanermin-a non-polyhistidine-tagged soluble recombinant human apoptosis ligand 2 (Apo2L) or tumour-necrosis-factor-related apoptosis-inducing-ligand (TRAIL)-has pro-apoptotic activity in a range of cancers and synergistic preclinical activity with rituximab against lymphoma in vivo. We aimed to assess the safety, pharmacokinetics, and efficacy of dulanermin and rituximab in patients with relapsed indolent B-cell non-Hodgkin lymphoma. We did an open-label phase 1b/2 randomised study. Four study centres in the USA enrolled patients into phase 1b, and 27 study centres in the USA, Italy, Australia, France, Czech Republic, New Zealand, and Poland enrolled patients into phase 2. In phase 1b, patients (age ≥18 years) with indolent B-cell non-Hodgkin lymphoma with stable disease or better lasting at least 6 months after the most recent rituximab-containing regimen were included. In phase 2, patients (age ≥18 years) with follicular lymphoma grades 1-3a were included. In phase 1b, patients received 4 mg/kg or 8 mg/kg intravenous dulanermin on days 1-5 of up to four 21-day cycles and intravenous rituximab 375 mg/m(2) weekly for up to eight doses. In phase 2, patients were randomly assigned (1:1:1) centrally by an interactive voice response system to dulanermin (8 mg/kg for a maximum of four 21-day cycles), rituximab (375 mg/m(2) weekly for up to eight doses), or both in combination, stratified by baseline follicular lymphoma International Prognostic Index (0-3 vs 4-5) and geographic site (USA vs non-USA). The primary endpoints of the phase 1b study were the safety, tolerability, and pharmacokinetics of dulanermin with rituximab. The primary endpoint of phase 2 was the proportion of patients who achieved an objective response. All patients who received any dose of study drug were included in safety analyses. Efficacy analyses were per protocol. Treatment was open label; all patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, NCT00400764. Between June 6, 2006, and Feb 15, 2007, 12 patients were enrolled in phase 1b, and between April 4, 2007, and April 20, 2009, 60 patients were enrolled in phase 2, of whom 59 were included in safety analyses and 58 in efficacy analyses. No dose-limiting toxic effects were noted in phase 1b. The most common grade 1-2 adverse events in phase 1b were fatigue (nine; 75%), rash (five; 42%), and chills, decreased appetite, diarrhoea, and nausea (four each; 33%). 19 grade 3 or higher adverse effects were noted in five (42%) patients, with 14 occurring in one patient. After treatment with 8 mg/kg of dulanermin, in six patients the mean serum peak concentration was 80 μg/mL, dropping below the minimum detectable concentration (2 ng/mL) within 24 h after the dose. The mean steady state peak and trough concentrations of rituximab were 461 μg/mL (SD 97.5) and 303 μg/mL (92.8), respectively. In phase 2, eight (14%) of 59 patients experienced 12 grade 3 or higher adverse events. In phase 2, objective responses were noted in 14 of 22 (63.6%, 95% CI 41.8-81.3) patients treated with rituximab only, 16 of 25 (64.0%, 43.1-81.5) treated with dulanermin and rituximab, and one of 11 (9.1%, 0.5-39.0) treated with dulanermin only. The study was terminated early, on May 5, 2010, because of an absence of efficacy in the combination group. The addition of dulanermin to rituximab in patients with indolent B-cell non-Hodgkin lymphoma was tolerable but did not lead to increased objective responses. This combination is not being developed further in non-Hodgkin lymphoma. Genentech and Amgen.

ALUMINUM AND ZINC OXIDES NANOPARTICLES AS A NEW METHODS FOR CONTROLLING THE RED FLOUR BEETLES, Tribolium castaneum (HERBEST) COMPARED TO MALATHION INSECTICIDE.

Among the red flour beetles, Tribolium castaneum (Herbest) is a cosmopolitan and serious pest of cereal grains and their products. Undoubtedly, the excessive use of pesticides and chemical compounds led to a lot of diseases to humans, animals and the environment, in addition to high costs. In the present study two nanoparticles, Aluminum oxide (Al2O3) and Zinc oxide (ZnO) were used as stored product insect protectants compared to malathion as standard reference. Results obtained cleared showed that malathion had the highest adverse effect on the all parameters studied of T. castaneum adults viz, mortality , offspring and weight loss percentage. Data obtained indicated that the increasing of concentration and exposure period caused increasing in mortality (%) and decreasing in weight loss (%).Also results accentuated that the two nanoparticles (Al2O3 and ZnO) significantly inhibited the number of progeny and weight loss (%) and the concentration of 2 g/kg wheat grain had the highest effect based on the LC50 values ZnO was had the most effect compared to Al2O3 nanoparticles. Finally, although malation was the premier, the present study suggest to use Al2O3 and ZnO nanoparticles in integrated pest management programs as alternative to chemical insecticides where they are considered safe for humans if compared with synthetic insecticide.

Aripiprazole versus other atypical antipsychotics for schizophrenia.

Aripiprazole versus other atypical antipsychotics for schizophrenia.

Effects of ionization on the toxicity of silver nanoparticles to Japanese medaka (Oryzias latipes) embryos

Increase in the use of manufactured nanomaterials (NMs) has led to concerns about the environmental impacts. Especially, hazard of metal-based NMs is more severe due to ions released from surface by water quality parameters and physicochemical properties after entering into the water environment. However, little is known about the effects of ionization on the toxicity of metal-based NMs in the water environment. To address this question, we prepared the suspensions of silver nanoparticles (AgNP) at 25 μg L−1 containing different concentrations of Ag+ (5, 10, 20, 45, and 75% Ag+ to total Ag), and evaluated their toxicity to Japanese medaka (Oryzias latipes) embryos. Higher Ag+ ratios in the AgNP suspension, suggesting the lower number of particles, led to the higher adverse effects on embryos and sac-fries. In addition, histopathology analysis revealed that AgNPs penetrated through chorion of eggs and skin membrane, and were distributed into the tissues. The results imply that the ionization could decrease the toxicity of metal-based NMs in the water environment.

Retreatment with pemetrexed-based chemotherapy in advanced nonsquamous NSCLC patients.

e19061^ Background: Retreatment of pemetrexed based chemotherapy (PBC) has been reported in MPM previously, but it is not investigated in non-squamous NSCLC (NS-NSCLC). Methods: We retrospectively enrolled 26 advanced NS-NSCLC patients who had received retreatment of PBC when their response to initial PBC were PR or SD. Chemotherapy regimens administered as retreatment were single pemetrexed (500 mg/m2every 3 weeks) or pemetrexed with a platinum. Response was evaluated according to RECIST. Toxicity was evaluated according to NCI-CTC version 3.0. PFS and OS were computed by Kaplan-Meier. Statistical analyses were performed with SPSS13.0. Results: In retreatment, most adverse effects (AE) were tolerable but doublet regimen was associated with higher AE including bone marrow depression and fatigue. In patients who received retreatment of PBC, objective response rate (ORR) and disease control rate (DCR) was 12% (3/26) and 73% (19/26) respectively. Patient with PFS≥10 months in initial PBC therapy would have a longer PFS in retreatment comparing with those PFS <10 months (6.0 vs 3.1 month, p = 0.004); patients with therapy-free interval (TFI) ≥6 months after initial PBC therapy also have a longer PFS in retreatment comparing with those interval <6 months (7.0 vs 3.0 month, p = 0.001). The OS also tend to be longer but not reach statistic significance. The response of first round PBC therapy (PR vs. SD) was not a factor affecting the PFS in retreatment. Conclusions: Patients with PFS over 10 months or TFI over 6 months after first round of PBC could benefit from retreatment of PBC.

Effects of Azadirachtin, Cypermethrin, Methoxyfenozide and Pyridalil on Functional Response of Habrobracon Hebetor Say (HYM.: Braconidae)

Habrobracon hebetor Say is one of the most important natural enemies of the Helicoverpa armigera Hubner (Lep.: Noctuidae). In this study, the sublethal effects of LC 30 concentration of azadirachtin, cypermethrin, methoxyfenozide and pyridalil on the func- tional response of H. hebetor to different densities of 5th instars larvae of Ephestia kuehniella Zeller were evaluated. Young females were exposed to LC 30 of the insecticides for an appropriate time of exposure. Then, six randomly selected alive females were transferred individually to plastic Petri dishes (10 cm in diameter) and supplied with the following densities: 2, 4, 8, 16, 32 and 64 of 5th instars of E. kuehniella for 24 h. Eight replicates were considered for each insecticide treatment and the control. The results revealed a type II functional response in the control, and all of the insecticide treatments. This study showed that the control and the cypermethrin treatment had the shortest (0.4143 h) and longest (0.624 h) handling time, respectively. The highest (0.0035 per hour) and lowest (0.0029 per hour) attack rate was observed in pyridalil and cypermethrin treatments, respectively. Based on values of handling time, cypermethrin had the highest adverse effect on host-finding in H. hebetor.

The effect of bacterial contamination of semen on sperm chromatin integrity and standard semen parameters in men from infertile couples

A considerable proportion of male factor infertility cases are associated with inflammatory processes. The most common sexually transmissible agents causing sexually transmitted diseases in industrial countries are Chlamydia trachomatis, genital Ureaplasma and Mycoplasma spp. This study was undertaken to investigate whether these bacterial contaminants in semen affect sperm quality parameters and particularly DNA integrity (detected by sperm chromatin structure assay) in males from infertile couples (n = 293). The results showed that semen contaminations with the investigated bacterial species were not associated with sperm DNA fragmentation. However, contaminations with Mycoplasma spp. and C. trachomatis were associated with decreased sperm concentrations. Total sperm numbers in contaminated semen samples tended to be decreased, but not significantly. Mycoplasma had the highest adverse effect on sperm quality (concentration, motility, morphology and DNA condensation). Antibiotic therapy of the selected 47 men was successful in 55%, but semen quality parameters did not improve at least up to 3 months after the therapy. The presence of pathogenic bacteria in semen is primarily associated with low sperm production. Our data showed that Mycoplasma spp. contamination of semen had the highest adverse effect on sperm quality. Sperm chromatin integrity assessed by the presence of DNA breaks was not disturbed.

Clinical Assessment of Topiramate Therapy in Patients With Migrainous Vertigo

To assess the efficacy of topiramate in reducing both the frequency and the severity of vertigo and headache attacks in patients with migrainous vertigo and to compare 50 and 100 mg/day doses of the drug. Thirty patients diagnosed as definite migrainous vertigo were recruited in the study. Vertigo and headache frequency was determined as the monthly number of attacks whereas severity was determined by visual analog scales measured in millimeters from 0 to 100. Patients were randomized to either 50 or 100 mg/day topiramate for 6 months. Vertigo and headache frequency and severity were evaluated at the end of the study period. Number of mothly vertigo attacks decreased significantly in the overall group after treatment (median from 5.5 to 1; P < .01). The same was true for monthly headache attacks (median from 4 to 1; P < .01). A statically significant improvement in vertigo severity was noted (median from 80 to 20 mm; P < .01). Headache severity showed significant improvement as well (median from 60 to 30 mm; P < .01). No statistically significant difference between high- and low-dose groups was present regarding efficacy (P > .05). Four patients in the high-dose group discontinued treatment at the end of the first month because of adverse effects. In the overall group, topiramate was found to be effective in reducing the frequency and the severity of vertigo and headache attacks. Both doses of the drug were equally efficacious. The 50 mg/day dose seems to be appropriate as higher adverse effects were noted when 100 mg/day was used.

Eliciting users' views of ECT in two mental health trusts with a user-designed questionnaire

Background: Users' views of the process of ECT have not been systematically assessed in prospective studies.Aims: (i) To determine the ability of a questionnaire to quantify user satisfaction with ECT; (ii) to elicit users' views of the treatment process; and (iii) to compare findings across two mental health trusts.Method: A self-report questionnaire was designed by a mental health service user group and sent to all patients completing a course of bilateral ECT during the study period. Scored items covered preparation for treatment, information giving, consent and adverse effects. Non-scored items included questions on compulsion, previous ECT and intention to accept future treatment. Open-ended comments were invited and analysed qualitatively.Results: The response rate was 41%. Users having ECT for the first time and those reporting they would ‘never have ECT again’ had lower care satisfaction scores and higher adverse effect scores than those who had had ECT before and those who were prepared to have ECT again. Mean care satisfaction scores differed significantly between the two trusts but reported levels of adverse effects were similar, and high, in both.Conclusions: Prospective research with a user-designed scale may elicit more critical responses than clinician-designed scales used in previous studies.Declarations of Interest: None

Management of Metastatic Renal Cell Carcinoma

Renal cell carcinoma is the most lethal malignancy of all the urologic malignancies. Outcome of those with metastatic disease is dismal with less than 50 surviving beyond 1 year. Several therapeutic strategies have been tried to improve the survival of these patients. Conventional chemotherapy regimens single or in combination failed to improve the response rates. Demonstration of immunogenicity in metastatic renal cell carcinoma gave birth to the concept of immunomodulation as potential treatment strategy in this setting. Though the response rates were better than chemotherapy but occurrence of higher adverse effects limits their use. Exploiting the immune response against tumour with the help of non myeloablative transplant, monoclonal antibody therapy and tumour vaccines have shown promising results in phase I / II trials. Newer chemotherapeutic agents like gemcitabine, capecitabine and novel agents like retinoids are being used in phase II trials. Radiotherapy does not have much role to play in metastatic setting except for palliation of painful bone lesions. This review focuses on the various treatment options available for metastatic renal cell carcinoma.

The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series.

To review all cases of septic shock treated with vasopressin to determine the effects on hemodynamic and renal function and to document any adverse effects. A 14-bed mixed medical-surgical ICU of St. Paul's Hospital, a 450-bed tertiary referral hospital affiliated with the University of British Columbia. All ICU patients who received vasopressin for treatment of severe septic shock between August 5, 1997, and March 21, 1999. We identified 50 patients: age 60 (+/-14); APACHE II score 27 (+/-7). Baseline data (T0) was compared to data at T4, T24 and T48 (4, 24 and 48 h) on infusion. Mean arterial pressure (MAP) increased by 18% from T0 to T4 and remained stable at T24 (p=0.006) and T48 (p=0.008). Systolic pulmonary artery pressure (PAP) was unchanged at 45+/-13 mmHg. Mean cardiac index (CI) decreased by 11% at T4 (p=0.03). Urine output increased 79% at T4 (p=0.005) and further increases were not significant at T24 and T48. Mean pressor dosage decreased by 33% at T4 (p=0.001), by 53% at T24 (p=0.002) and by 48% at T48 (p=0.01). Hospital mortality was 85%. There were six cardiac arrests; all but one occurred at a vasopressin dose of 0.05 U/min or more. In this group of patients with severe septic shock, vasopressin infusion increased MAP and urine output and decreased catecholamine requirements. Doses higher than 0.04 U/min were not associated with increased effectiveness and may have been associated with higher adverse effects.