Comparative pharmacovigilance assessment of mortality with pimavanserin in Parkinson disease-related psychosis.

BACKGROUND: Pimavanserin is approved for treatment of Parkinson disease (PD)-related psychosis, but its use has been associated with an increased risk of death during clinical trials, as well as during postmarketing surveillance. Previous reports on the association between pimavanserin and mortality have not taken into account limitations of data sources nor included comparable populations or comparisons to relevant treatment alternatives. OBJECTIVE: To conduct a comparative pharmacovigilance assessment of pimavanserin vs treatment alternatives and by restricting surveillance data to more representative populations. METHODS: This was a retrospective analysis of adverse event case reports submitted to the FDA's Adverse Event Reporting System (FAERS) from 2016 through 2019 quarter 3 (Q3). FAERS data are collected from the full population, were further restricted to only those with PD, and were based on PD medication use. Reports were assessed for exposure to pimavanserin, clozapine, quetiapine, haloperidol, and other atypical antipsychotics. The outcome of interest was all-cause death. A proportional reporting ratio (PRR) and 95% confidence limits were calculated for each 2 by 2 contingency of outcome (death) and exposure (pimavanserin and others). For each outcome/exposure pair, the baseline population was altered to include the full FAERS sample, only reports with PD, reports with PD treated with levodopa, and reports with PD treated with multiple PD medications. The sample was also stratified by time period before April 2018 and after September 2018 to capture periods of public knowledge and federal response. A lower 95% CI (Lower95CI) ≥ 2 for the PRR was considered as the accepted threshold for a drug safety signal. RESULTS: As of 2019 Q3, there were 2,287 reports of death associated with pimavanserin. Compared within the full FAERS base population, pimavanserin yielded a PRR Lower95CI = 2.08 but was smaller when restricted to comparison among only a base population with PD (Lower95CI = 1.09), PD treated with levodopa (Lower95CI = 1.15), or PD treated with multiple PD medications (Lower95CI = 1.63). Metrics for quetiapine, clozapine, and other atypical antipsychotics were similar in magnitude. Stratification by time showed a possible reporting bias associated with pimavanserin, since no safety signal was detected before April 2018; however, a signal was present thereafter. CONCLUSIONS: Compared in context with treatment alternatives for patients with PD, pimavanserin was not associated with excess reports of death in the FAERS data. This information should be used in shared decision making between physicians and PD patients to balance the risks and benefits of pimavanserin and other treatments for PD psychosis. DISCLOSURES: No outside funding supported this study. The authors report no disclosures or conflicts of interest relevant to this study. Armstrong receives research support from the NIA (P30AG047266, R01AG068128) and the Florida Department of Health (grant 20A08). She is the local principal investigator of a Lewy Body Dementia Association Research Center of Excellence. She also receives compensation from the American Academy of Neurology for work as an evidence-based medicine methodology consultant. She is on the level of evidence editorial board for Neurology and related publications (uncompensated), receives publishing royalties for Parkinson's Disease: Improving Patient Care (Oxford University Press, 2014), and has received an honorarium for presenting for Medscape CME in 2018. Okun serves as a consultant for the Parkinson's Foundation and has received research grants from NIH, Parkinson's Foundation, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. Okun has participated as a site principal investigator and/or co-investigator for several NIH-, foundation-, and industry-sponsored trials over the years but has not received honoraria. Malaty has participated in research funded by the Parkinson Foundation, Tourette Association, Dystonia Coalition, Abbvie, Boston Scientific, Eli Lilly, Neuroderm, Pfizer, Revance, and Teva. She has received travel compensation and/or honoraria from the Tourette Association of America, NeuroChallenge Foundation and NIH/Neurobiology of Disease in Children, Parkinson Foundation, Medscape, International Association of Parkinsonism and Related Disorders, and Cleveland Clinic, and royalties from Robert Rose publishers. The other authors have no disclosures.

Blinded SAPS-PD Assessment After 10 Weeks of Pimavanserin Treatment for Parkinson's Disease Psychosis.

BACKGROUND: Parkinson's disease psychosis (PDP) is a common nonmotor symptom that affects up to 60% of patients. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, is approved for treating hallucinations and delusions associated with PDP. OBJECTIVE: Evaluate the efficacy and tolerability of pimavanserin in an open-label extension (OLE) study. METHODS: Patients completing a pivotal 6-week placebo-controlled trial (Core Study) could enroll in the OLE. All patients pimavanserin 34 mg once daily, blinded to previous treatment allocation. Prespecified blinded assessments at Week 4 were the Scale for the Assessment of Positive Symptoms (SAPS) PD version and SAPS H + D scales, Caregiver Burden Scale (CBS), and Clinical Global Impression (CGI) Improvement and Severity scales. RESULTS: Of 171 who entered the OLE, 148 (87%) completed Week 4. Among patients who received placebo in the Core Study, mean (SD) change from OLE baseline to OLE Week 4 for the SAPS-PD was - 3.4 (6.3); p < 0.0001. Mean change from Core Study baseline to OLE Week 4 for SAPS-PD was similar among prior pimavanserin- and placebo-treated patients (-6.9 vs. -6.3). Improvement was similar with CGI-I, CGI-S, CBS, and SAPS-H + D in patients previously treated with placebo. Adverse events occurred in 92 (53.8%) patients during the 4-week OLE. CONCLUSION: Improvements at OLE Week 4 from pretreatment baseline were similar with placebo and pimavanserin in the Core Study. The beneficial effects observed with pimavanserin in the 6-week Core Study were maintained for 4 weeks in the blinded OLE, supporting the durability of response with pimavanserin 34 mg for PDP over 10 weeks.

Ultrasound assessment of the keratolytic effect of a 50% urea anhydrous paste on psoriasis plaques: a prospective study.

BACKGROUND: The keratolytic effect of urea is well-known, although the majority of the available studies rely on clinical observation only. The aim of this open trial was to evaluate, through clinical and ultrasound assessment, the efficacy and tolerability of a 50% urea anhydrous paste on hyperkeratotic psoriatic plaques. METHODS: Twenty-five patients (12 male, 13 female; age: 35-75 years) with plaque psoriasis characterized by an evident hyperkeratotic component were enrolled. One target lesion was selected in each patient that was instructed to apply the 50% urea anhydrous paste twice a day for up to 3-week study duration. RESULTS: Clinical clearance of hyperkeratosis at day 21 was observed in 23 out of 25 plaques (92%), with nine (36%) and ten (40%) patients already reaching clear status respectively at day 7 and 14. Ultrasound significant reduction of the mean epidermal thickness score was also observed at the same time-points. No side effects were reported and all patients rated the product as excellent in terms of cosmetic acceptability. CONCLUSIONS: The tested product resulted to be an effective keratolytic agent in plaque psoriasis. Strength of our study was the ultrasound assessment, allowing to objectively confirm and correlate the epidermal changes seen at clinical evaluation.

Assessment of efficacy and post-bleaching sensitivity of home bleaching using 10% carbamide peroxide in extended and non-extended bleaching trays.

AIM: This study aimed to compare the effect of extended margin and conventional bleaching trays on tooth bleaching and tooth sensitivity. METHOD AND METHODS: Twenty subjects (18-56 years) were investigated in a split arch design clinical study that was conducted in a general dental practice. Each subject received a custom made bleaching tray and 10% carbamide peroxide gel. The bleaching trays had the borders extended 5 mm beyond the gingival margins on the right side and finished just at the gingival margin on the left side. Shade change and tooth sensitivity were the primary outcomes studied and analysed in this study. The shade of the six upper and lower anterior teeth was assessed using a value-ordered shade guide before, one week and two weeks after treatment. Sensitivity was self-assessed using a visual analogue scale (VAS) at the end of the first and second weeks of the study. RESULTS: At the end of week two, the mean shade change was 5.01 (± 3.37) and 5.10 (± 3.36) for teeth covered by extended and non-extended tray design, respectively. The mean VAS sensitivity scores for teeth covered by extended and non-extended tray design were 0.96 (± 1.39) and 0.66 (± 0.96), respectively. There was no significant statistical difference between the two designs at any assessment point with regard to shade change and sensitivity (p >0.05). CONCLUSIONS: It can be concluded that an extended tray design confers no superior effect in terms of the whitening outcome achieved or in reducing levels of sensitivity. Thus, both tray designs can be used depending on a dentist's personal preference.

Assessment of the release of mercury from silver amalgam alloys exposed to different 10% carbamide peroxide bleaching agents.

This in vitro study assessed the amount of mercury (Hg) released from a silver amalgam alloy following the application of different 10% carbamide peroxide bleaching agents. A total of 30 specimens (2 mm thick x 4 mm in diameter) were stored in deionized water at 37°C for 7 days. Next, the control group (n = 10) remained in the deionized water for 15 days, while the remaining samples were exposed to 1 of 2 bleaching agents (n = 10) for 8 hours daily (total exposure = 120 hours); for the remaining 16 hours, specimens in the test groups were stored in deionized water at 37°C under relative humidity. After this period, the quantity of Hg in the deionized water was assessed (using atomic absorption spectrophotometry) and compared to the amount of Hg at baseline. The results indicate that exposing amalgam alloys to bleaching agents released greater amounts of Hg compared to exposing samples to deionized [corrected] water.

Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects.

UNLABELLED: AIMS To evaluate the pharmacology and tolerability of PF-04457845, an orally available fatty acid amide hydrolase-1 (FAAH1) inhibitor, in healthy subjects. METHODS: Double-blind, randomized, placebo-controlled single and multiple rising dose studies and an open-label, randomized, food effect study were conducted. Plasma and urine PF-04457845 concentrations, plasma fatty acid amide concentrations and FAAH1 activity in human leucocytes were measured. Tolerability, including effects on cognitive function, were assessed. RESULTS: PF-04457845 was rapidly absorbed (median t(max) 0.5-1.2 h). Exposure increased supraproportionally to dose from 0.1 to 10 mg and proportionally between 10 and 40 mg single doses. The pharmacokinetics appeared dose proportional following 14 days once daily dosing between 0.5 and 8 mg. Steady-state was achieved by day 7. Less than 0.1% of the dose was excreted in urine. Food had no effect on PF-04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (>97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF-04457845. Mean fatty acid amide concentrations increased (3.5- to 10-fold) to a plateau and then were maintained following PF-04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF-04457845 on cognitive function. PF-04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated. CONCLUSIONS: PF-04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.

Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 2. Patch test relationship to formaldehyde contact allergy, experimental provocation tests, amount of formaldehyde released, and assessment of risk to consumers allergic to formaldehyde.

This is the second part of an article on formaldehyde-releasers in cosmetics. The patch test relationship between the releasers in cosmetics to formaldehyde contact allergy is reviewed and it is assessed whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose a threat to individuals with contact allergy to formaldehyde. There is a clear relationship between positive patch test reactions to formaldehyde-releasers and formaldehyde contact allergy: 15% of all reactions to 2-bromo-2-nitropropane-1,3-diol and 40-60% of the reactions to the other releasers are caused by a reaction to the formaldehyde in the test material. There is only fragmented data on the amount of free formaldehyde in cosmetics preserved with formaldehyde donors. However, all releasers (with the exception of 2-bromo-2-nitropropane-1,3-diol, for which adequate data are lacking) can, in the right circumstances of concentration and product composition, release >200 p.p.m. formaldehyde, which may result in allergic contact dermatitis. Whether this is actually the case in any particular product cannot be determined from the ingredient labelling. Therefore, we recommend advising patients allergic to formaldehyde to avoid leave-on cosmetics preserved with quaternium-15, diazolidinyl urea, DMDM hydantoin, or imidazolidinyl urea, acknowledging that many would tolerate some products.

Over-the-counter whitening agents: a concise review.

Tooth discoloration is commonly found in the dental clinic and tooth bleaching has been considered the preferred esthetic alternative, being more conservative, safe and with predictable results. Supervised home-use of 10% Carbamide Peroxide (CP) bleaching with custom-trays is the most common bleaching procedure dispensed by dentists to their patients. The good results obtained with this technique stimulated the flourishing of new products and techniques. Over-the-counter (OTC) bleaching products appeared as a low-cost alternative to bleach discolored teeth without dentist supervision. Different OTC products are available in supermarkets, drug stores or on the Internet, including rinses, paint-on brushes, toothpastes, chewing guns, dental floss, and whitening strips. There is lack of clinical evidence regarding the safety and effectiveness of these products, being most of the studies supported by the manufacturers'. Basically, toothpastes, chewing gums, and dental floss are removal agents of superficial stains. Rinses and paint-on brushes with low levels of hydrogen peroxide have some whitening effect, but without clinical relevance. Strips present similar esthetic results and side-effects, compared to bleaching with 10% CP using trays; however, the studies have financial support from the manufacturers and were based on short term evaluations. Legislation varies widely in different countries regarding OTC dental bleaching. Concerns have appeared due to the potential abusive use of these self-medication agents, especially in young patients, with potential harmful results. Dentists should be acquainted with this kind of products to be able to inform their patients. In conclusion, there is a need for independent clinical trials to provide sufficient evidence regarding the use of OTC bleaching products.

Over-the-counter whitening agents: a concise review

Tooth discoloration is commonly found in the dental clinic and tooth bleaching has been considered the preferred esthetic alternative, being more conservative, safe and with predictable results. Supervised home-use of 10 percent Carbamide Peroxide (CP) bleaching with custom-trays is the most common bleaching procedure dispensed by dentists to their patients. The good results obtained with this technique stimulated the flourishing of new products and techniques. Over-the-counter (OTC) bleaching products appeared as a low-cost alternative to bleach discolored teeth without dentist supervision. Different OTC products are available in supermarkets, drug stores or on the Internet, including rinses, paint-on brushes, toothpastes, chewing guns, dental floss, and whitening strips. There is lack of clinical evidence regarding the safety and effectiveness of these products, being most of the studies supported by the manufacturers'. Basically, toothpastes, chewing gums, and dental floss are removal agents of superficial stains. Rinses and paint-on brushes with low levels of hydrogen peroxide have some whitening effect, but without clinical relevance. Strips present similar esthetic results and side-effects, compared to bleaching with 10 percent CP using trays; however, the studies have financial support from the manufacturers and were based on short term evaluations. Legislation varies widely in different countries regarding OTC dental bleaching. Concerns have appeared due to the potential abusive use of these self-medication agents, especially in young patients, with potential harmful results. Dentists should be acquainted with this kind of products to be able to inform their patients. In conclusion, there is a need for independent clinical trials to provide sufficient evidence regarding the use of OTC bleaching products.

Final report of the safety assessment of Urea.

Although Urea is officially described as a buffering agent, humectant, and skin-conditioning agent-humectant for use in cosmetic products, there is a report stating that Urea also is used in cosmetics for its desquamating and antimicrobial action. In 2001, the Food and Drug Administration (FDA) reported that Urea was used in 239 formulations. Concentrations of use for Urea ranged from 0.01% to 10%. Urea is generally recognized as safe by FDA for the following uses: side-seam cements for food contact; an inhibitor or stabilizer in pesticide formulations and formulations applied to animals; internal sizing for paper and paperboard and surface sizing and coating of paper and paper board that contact water-in-oil dairy emulsions, low-moisture fats and oils, moist bakery products, dry solids with surface containing no free fats or oil, and dry solids with the surface of fat or oil; and to facilitate fermentation of wine. Urea is the end product of mammalian protein metabolism and the chief nitrogenous compound of urine. Urea concentrations in muscle, liver, and fetuses of rats increased after a subcutaneous injection of Urea. Urea diffused readily through the placenta and into other maternal and fetal organs. The half-life of Urea injected into rabbits was on the order of several hours, and the reutilization rate was 32.2% to 88.8%. Urea given to rats by a bolus injection or continuous infusion resulted in distribution to the following brain regions: frontal lobe, caudate nucleus, hippocampus, thalamus plus hypothalamus, pons and white matter (corpus callosum). The permeability constant after treatment with Urea of whole skin and the dermis of rabbits was 2.37 +/- 0.13 (x 10(6)) and 1.20 +/- 0.09 (x10(3)) cm/min, respectively. The absorption of Urea across normal and abraded human skin was 9.5% +/- 2.3% and 67.9% +/- 5.6%, respectively. Urea increased the skin penetration of other compounds, including hydrocortisone. No toxicity was observed for Urea at levels as high as 2000 mg/kg in acute oral studies using female rats or mice. No signs of toxicity were observed in male piglets dosed orally with up to 4 g/kg Urea for 5 days. Dogs dosed orally with 5 to 30 g/L Urea for 4 to 10 days had signs of toxicity, including weakness, anorexia, vomiting and retching, diarrhea and a decreased body temperature, which led to a deep torpor or coma. No significant microscopic changes were observed in the skin of male nude mice dermally exposed to 100% Urea for 24 h. No observable effect on fetal development was seen in rats and mice dosed orally with an aqueous solution of Urea (2000 mg/kg) on days 10 and 12 of gestation. The mean number of implants, live fetuses, percent fetal resorptions, mean fetal weight, and percent fetuses malformed were comparable to control group. A detergent containing 15% Urea was injected into pregnant ICR-JCl mice and dams and fetuses had no significant differences when compared to control animals. Urea given orally did not enhance the developmental toxicity of N-nitrosomethylurea. Female Sprague-Dawley rats injected in the uterine horn with 0.05 ml Urea on day 3 (preimplantation) or on day 7 (post implantation) exhibited no maternal mortality or morbidity; a dose-dependent reduction in embryo survival was seen with preimplantation treatment. Urea injected intra-amniotically induces mid-trimester abortions in humans. Urea was not genotoxic in several bacterial and mammalian assays; although in assays where Urea was used at a high concentration, genotoxicity was found, many in in vitro assays. Urea is commonly used in studies of DNA because it causes uncoiling of DNA molecules. Urea was not carcinogenic in Fisher 344 rats or C57B1/6 mice fed diets containing up to 4.5% Urea. Exposure of normal human skin to 60% Urea produced no significant irritation in one study, but 5% Urea was slightly irritating and 20% Urea was irritating in other reports. Burning sensations are the most frequently reported effect of Urea used alone or with other agents in treatment of diseased skin. Overall, there are few reports of sensitization among the many clinical studies that report use of Urea in treatment of diseased skin. The Cosmetic Ingredient Review (CIR) Expert Panel determined the data provided in this report to be sufficient to assess the safety of Urea. The Panel did note that Urea can cause uncoiling of DNA, a property used in many DNA studies, but concluded that this in vitro activity is not linked to any in vivo genotoxic activity. Although noting that formulators should be aware that Urea can increase the percutaneous absorption of other chemicals, the CIR Expert Panel concluded that Urea is safe as used in cosmetic products.

Occupational rhinitis and bronchial asthma due to TBTU and HBTU sensitization.

Exposure to an increasing amount of products in the work environment is leading to new cases of occupational asthma among workers. We report the case of a worker at a pharmaceutical plant who developed occupational rhinitis and bronchial asthma due to HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate sensitization, two chemical products widely used in peptide synthesis and coupling. Skin tests (prick test) with HBTU and TBTU solutions in PBS were positive at a concentration of 1 mg/ml. Skin tests with the same solutions in 10 atopic controls yielded a negative result. Nasal challenge tests with these products were positive with HBTU at a concentration of 0.01 mg/ml and TBTU at a concentration of 1 mg/ml. In both cases PNIF (peak nasal inspiratory flow) decreased by more than 60% and severe sneezing and rhinorrhea were induced. Nasal challenge tests performed on 10 atopic controls with TBTU and HBTU at a concentration of 1 mg/ml were negative. We conclude that the patient presents occupational rhinitis and bronchial asthma due to TBTU and HBTU; the operational mechanism is probably immunological IgE-mediated given the positive prick tests and nasal challenge with these products.

The safety-in-use of 10% carbamide peroxide (Opalescence) for bleaching teeth under the supervision of a dentist.

Fears that the dentist-supervised use of a product that contains carbamide peroxide and that emits hydrogen peroxide may not be safe from the viewpoints of toxicity and cancer risk were engendered by unrealistic animal tests. These fears prompted the UK Government Departments of Trade and Industry (DTI) and of Health (DOH) to try to prohibit the marketing of Opalescence (manufactured by Ultradent Inc.). Faced with the fact that Opalescence had already been awarded a CE mark under the EC Medical Devices Directive, the DTI and DOH attempted to bring about its prohibition by reclassifying Opalescence as falling under the EC Cosmetics Directive, according to which the marketing of products containing more than 0.1% hydrogen peroxide is not permitted.

[Experimental assessment of coal and rock dust absorbing hazardous substances released from synthetic resins]. / Eksperimental'naia otsenka sorbtsii ugol'noi i porodnoi pyl'iu vrednykh veshchestv, vydeliaiushchikhsia iz sinteticheskikh smol.

The experimental study evaluated the factors (temperature, mass of n polymer, time of sorption et al.) influencing coal and rock dust sorption of carbamide-formaldehyde, penopolyurethane monomers. The atmosphere of coal mines was proved to be contaminated during the extraction by multiple-component mixture, where the volatile monomers are gaseous, vaporous or absorbed by the dust particles.