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1.
J Med Chem ; 64(22): 16553-16572, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34783240

RESUMO

The leaves of Mitragyna speciosa (kratom), a plant native to Southeast Asia, are increasingly used as a pain reliever and for attenuation of opioid withdrawal symptoms. Using the tools of natural products chemistry, chemical synthesis, and pharmacology, we provide a detailed in vitro and in vivo pharmacological characterization of the alkaloids in kratom. We report that metabolism of kratom's major alkaloid, mitragynine, in mice leads to formation of (a) a potent mu opioid receptor agonist antinociceptive agent, 7-hydroxymitragynine, through a CYP3A-mediated pathway, which exhibits reinforcing properties, inhibition of gastrointestinal (GI) transit and reduced hyperlocomotion, (b) a multifunctional mu agonist/delta-kappa antagonist, mitragynine pseudoindoxyl, through a CYP3A-mediated skeletal rearrangement, displaying reduced hyperlocomotion, inhibition of GI transit and reinforcing properties, and (c) a potentially toxic metabolite, 3-dehydromitragynine, through a non-CYP oxidation pathway. Our results indicate that the oxidative metabolism of the mitragynine template beyond 7-hydroxymitragynine may have implications in its overall pharmacology in vivo.

2.
ERJ Open Res ; 7(3)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34549047

RESUMO

Background: Quality of life has improved dramatically over the past two decades in people with cystic fibrosis (CF). Quantification has been enabled by patient-reported outcome measures (PROMs); however, many are lengthy and can be challenging to use in routine clinical practice. We propose a short-form PROM that correlates well with established quality-of-life measures. Methods: We evaluated the utility of a 10-item score (AWESCORE) by measuring reliability, validity and responsiveness in adults with CF. The questions were developed by thematic analysis of survey questions to patients in a single adult CF centre. Each question was scored using a numerical rating scale 0 to 10. Total scores ranged from 0 to 100. Test-retest reliability was assessed over 24 h. To determine validity, comparisons were sought between stable subjects and those in pulmonary exacerbation, and between AWESCORE and Cystic Fibrosis Questionnaire - Revised (CFQ-R). Responsiveness to pulmonary exacerbation in individual subjects was evaluated. Results: Five domains, each with two questions, were identified for respiratory, physical, nutritional, psychological and general health. A total of 246 consecutive adults attending the outpatient clinic completed the AWESCORE. Scores were higher during clinical stability compared to pulmonary exacerbation (mean± sd): 73±11 versus 48±11 (p<0.001). Each domain scored worse during an acute exacerbation (p<0.001). No differences in reliability were observed in scores on retesting using Bland-Altman comparison. The CFQ-R scores (mean±sd: 813±125) and AWESCORE (81±13) were moderately correlated (Pearson's r=0.649; p=0.002). Conclusions: The AWESCORE is valid, reliable and responsive to altered health status in CF.

3.
J Med Chem ; 64(18): 13873-13892, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34505767

RESUMO

Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OCH3 group with phenyl (4), methyl (5), or 3'-furanyl [6 (SC13)] substituents demonstrated partial agonism with a lower efficacy than DAMGO or morphine in heterologous G-protein assays and synaptic physiology. In assays limiting MOR reserve, the G-protein efficacy of all three was comparable to buprenorphine. 6 (SC13) showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning in mice. These results suggest the possibility of activating MOR minimally (G-protein Emax ≈ 10%) in cell lines while yet attaining maximal antinociception in vivo with reduced opioid liabilities.

4.
Pediatr Pulmonol ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499432

RESUMO

BACKGROUND: Exercise testing is important in people with cystic fibrosis (pwCF). The aim was to develop an incremental maximal step test to assess exercise capacity across the range of pwCF, without floor or ceiling effects, within restrictions of space, and infection prevention. METHODS: The step test was developed in adults with stable CF. Subjects assisted in selecting: step height, start rate, increments, stage and test duration parameters. Equipment to externally pace and time the test and measure exercise parameters were selected. Reasons for stopping, criteria for achieving a maximal test, and key outcome measures were determined. Documentation to record and standardize the test and instructions to set up the metronome and timer App were developed. Infection control practices were considered. RESULTS: Eight subjects were recruited to develop the Alfred Step Test Exercise Protocol (A-STEP) on a 20 cm portable step. The A-STEP package included a pretest information sheet, clinical assessment and instructions, recording worksheet, and the metronome/timer instructions. The test started at 18 steps/min. Each level increased by two steps/min to a maximum of 48 steps (Level 16). Results were presented as mean (SD) [range] for: age 30.63 (5.89) [21-39] years; FEV1 58.13 (18.33) [32-89]%; levels: 10.31 (3.29) [6-15.5]. The A-STEP required space of 2 m2 and complied with current infection control guidelines. CONCLUSIONS: The A-STEP is a new incremental maximal step test to assess exercise capacity in pwCF, without floor or ceiling effects. It addresses the issues of space restrictions and the need for strict infection prevention in the clinical setting.

5.
Adv Nutr ; 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34157098

RESUMO

Lutein, zeaxanthin, and meso-zeaxanthin are the only carotenoids found in the human macula and may have a role in visual function. These carotenoids are reported to protect the retina, and thus vision, as antioxidants and by acting as a blue light filter. Our objective was to determine a minimum concentration of lutein/zeaxanthin intake that is associated with a statistically significant and/or clinically important change in macular pigment optical density (MPOD) among adults with healthy eyes. We searched Ovid MEDLINE, CENTRAL, and the Commonwealth of Agriculture Bureau for English-language studies through to July 2020. Two reviewers screened results to identify studies that evaluated supplements or dietary sources of lutein/zeaxanthin on MPOD among adults with healthy eyes. One reviewer extracted data and assessed strength of evidence, which was confirmed by a second reviewer. Two independent reviewers assessed the risk of bias. Meta-analyses were stratified by total lutein/zeaxanthin dose. We included 46 studies (N = 3189 participants; mean age = 43 y; 42% male). There was no statistically significant change in MPOD among studies evaluating <5 mg/d of total lutein/zeaxanthin intake which primarily assessed dietary interventions for 3-6 mo (pooled mean difference, 0.02; 95% CI: -0.01 to 0.05). The pooled mean increase in MPOD was 0.04 units (95% CI: 0.02 to 0.07) among studies evaluating 5 to <20 mg/d of lutein/zeaxanthin and was 0.11 units (95% CI: 0.06 to 0.16) among studies evaluating ≥20 mg/d of lutein/zeaxanthin for 3-12 mo. MPOD increased with lutein/zeaxanthin intake, particularly at higher doses, among adults with healthy eyes. The effects of lutein/zeaxanthin intake at doses <5 mg/d or from dietary sources is less clear. Increased lutein/zeaxanthin intake can help with maintaining ocular health. Future research is needed to determine the minimum dose and duration of lutein/zeaxanthin intake that is associated with a clinically important change in MPOD or visual function.

6.
ACS Chem Neurosci ; 12(11): 2003-2012, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34019387

RESUMO

σ-1 receptors (σ1R) modulate nociceptive signaling, driving the search for selective antagonists to take advantage of this promising target to treat pain. In this study, a new series of benzylpiperazinyl derivatives has been designed, synthesized, and characterized for their affinities toward σ1R and selectivity over the σ-2 receptor (σ2R). Notably, 3-cyclohexyl-1-{4-[(4-methoxyphenyl)methyl]piperazin-1-yl}propan-1-one (15) showed the highest σ1R receptor affinity (Ki σ1 = 1.6 nM) among the series with a significant improvement of the σ1R selectivity (Ki σ2/Ki σ1 = 886) compared to the lead compound 8 (Ki σ2/Ki σ1 = 432). Compound 15 was further tested in a mouse formalin assay of inflammatory pain and chronic nerve constriction injury (CCI) of neuropathic pain, where it produced dose-dependent (3-60 mg/kg, i.p.) antinociception and anti-allodynic effects. Moreover, compound 15 demonstrated no significant effects in a rotarod assay, suggesting that this σ1R antagonist did not produce sedation or impair locomotor responses. Overall, these results encourage the further development of our benzylpiperazine-based σ1R antagonists as potential therapeutics for chronic pain.


Assuntos
Receptores sigma , Analgésicos/farmacologia , Animais , Hiperalgesia/tratamento farmacológico , Ligantes , Camundongos , Relação Estrutura-Atividade
7.
J Endocr Soc ; 5(4): bvab011, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33644622

RESUMO

We sought to systematically review the effect of gender-affirming hormone therapy on psychological outcomes among transgender people. We searched PubMed, Embase, and PsycINFO through June 10, 2020 for studies evaluating quality of life (QOL), depression, anxiety, and death by suicide in the context of gender-affirming hormone therapy among transgender people of any age. We excluded case studies and studies reporting on less than 3 months of follow-up. We included 20 studies reported in 22 publications. Fifteen were trials or prospective cohorts, one was a retrospective cohort, and 4 were cross-sectional. Seven assessed QOL, 12 assessed depression, 8 assessed anxiety, and 1 assessed death by suicide. Three studies included trans-feminine people only; 7 included trans-masculine people only, and 10 included both. Three studies focused on adolescents. Hormone therapy was associated with increased QOL, decreased depression, and decreased anxiety. Associations were similar across gender identity and age. Certainty in this conclusion is limited by high risk of bias in study designs, small sample sizes, and confounding with other interventions. We could not draw any conclusions about death by suicide. Future studies should investigate the psychological benefits of hormone therapy among larger and more diverse groups of transgender people using study designs that more effectively isolate the effects of hormone treatment.

8.
Cell Mol Neurobiol ; 41(5): 1131-1143, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33433723

RESUMO

Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea "kratom" and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5 days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3 days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.

9.
Drug Alcohol Depend ; 216: 108310, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-33017752

RESUMO

BACKGROUND: Made as a tea, the Thai traditional drug "kratom" reportedly possesses pharmacological actions that include both a coca-like stimulant effect and opium-like depressant effect. Kratom has been used as a substitute for opium in physically-dependent subjects. The objective of this study was to evaluate the antinociception, somatic and physical dependence produced by kratom tea, and then assess if the tea ameliorated withdrawal in opioid physically-dependent subjects. METHODS: Lyophilized kratom tea (LKT) was evaluated in C57BL/6J and opioid receptor knockout mice after oral administration. Antinociceptive activity was measured in the 55 °C warm-water tail-withdrawal assay. Potential locomotor impairment, respiratory depression and locomotor hyperlocomotion, and place preference induced by oral LKT were assessed in the rotarod, Comprehensive Lab Animal Monitoring System, and conditioned place preference assays, respectively. Naloxone-precipitated withdrawal was used to determine potential physical dependence in mice repeatedly treated with saline or escalating doses of morphine or LKT, and LKT amelioration of morphine withdrawal. Data were analyzed using one- and two-way ANOVA. RESULTS: Oral administration of LKT resulted in dose-dependent antinociception (≥1 g/kg, p.o.) absent in mice lacking the mu-opioid receptor (MOR) and reduced in mice lacking the kappa-opioid receptor. These doses of LKT did not alter coordinated locomotion or induce conditioned place preference, and only briefly reduced respiration. Repeated administration of LKT did not produce physical dependence, but significantly decreased naloxone-precipitated withdrawal in morphine dependent mice. CONCLUSIONS: The present study confirms the MOR agonist activity and therapeutic effect of LKT for the treatment of pain and opioid physical dependence.


Assuntos
Mitragyna , Dependência de Morfina/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Receptores Opioides mu/agonistas , Chá , Analgésicos Opioides/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Liofilização/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfina/administração & dosagem , Dependência de Morfina/fisiopatologia , Dependência de Morfina/psicologia , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Medição da Dor/métodos , Extratos Vegetais/isolamento & purificação , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/deficiência , Receptores Opioides mu/deficiência
10.
AAPS J ; 22(5): 94, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32691179

RESUMO

The sigma-2 receptor has been cloned and identified as Tmem97, which is a transmembrane protein involved in intracellular Ca2+ regulation and cholesterol homeostasis. Since its discovery, the sigma-2 receptor has been an extremely controversial target, and many efforts have been made to elucidate the functional role of this receptor during physiological and pathological conditions. Recently, this receptor has been proposed as a potential target to treat neuropathic pain due to the ability of sigma-2 receptor agonists to relieve mechanical hyperalgesia in mice model of chronic pain. In the present work, we developed a highly selective sigma-2 receptor ligand (sigma-1/sigma-2 selectivity ratio > 1000), 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H- benzo[d]imidazol-2(3H)-one (CM398), with an encouraging in vitro and in vivo pharmacological profile in rodents. In particular, radioligand binding studies demonstrated that CM398 had preferential affinity for sigma-2 receptor compared with sigma-1 receptor and at least four other neurotransmitter receptors sites, including the norepinephrine transporter. Following oral administration, CM398 showed rapid absorption and peak plasma concentration (Cmax) occurred within 10 min of dosing. Moreover, the compound showed adequate, absolute oral bioavailability of 29.0%. Finally, CM398 showed promising anti-inflammatory analgesic effects in the formalin model of inflammatory pain in mice. The results collected in this study provide more evidence that selective sigma-2 receptor ligands can be useful tools in the development of novel pain therapeutics and altogether, these data suggest that CM398 is a suitable lead candidate for further evaluation.


Assuntos
Analgésicos/farmacologia , Receptores sigma/agonistas , Analgésicos/síntese química , Analgésicos/uso terapêutico , Animais , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Masculino , Camundongos , Ratos Sprague-Dawley
11.
Ann Surg ; 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32487804

RESUMO

OBJECTIVE: Acute Pancreatitis (AP) is sudden onset pancreas inflammation that causes systemic injury with a wide and markedly heterogeneous range of clinical consequences. Here, we hypothesized that this observed clinical diversity corresponds to diversity in molecular subtypes that can be identified in clinical and multiomics data. SUMMARY BACKGROUND DATA: Observational cohort study. n = 57 for the discovery cohort (clinical, transcriptomics, proteomics, and metabolomics data) and n = 312 for the validation cohort (clinical and metabolomics data). METHODS: We integrated coincident transcriptomics, proteomics, and metabolomics data at serial time points between admission to hospital and up to 48 hours after recruitment from a cohort of patients presenting with acute pancreatitis. We systematically evaluated 4 different metrics for patient similarity using unbiased mathematical, biological, and clinical measures of internal and external validity.We next compared the AP molecular endotypes with previous descriptions of endotypes in a critically ill population with acute respiratory distress syndrome (ARDS). RESULTS: Our results identify 4 distinct and stable AP molecular endotypes. We validated our findings in a second independent cohort of patients with AP.We observed that 2 endotypes in AP recapitulate disease endotypes previously reported in ARDS. CONCLUSIONS: Our results show that molecular endotypes exist in AP and reflect biological patterns that are also present in ARDS, suggesting that generalizable patterns exist in diverse presentations of critical illness.

12.
Br J Pharmacol ; 177(18): 4209-4222, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32562259

RESUMO

BACKGROUND AND PURPOSE: The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-d-Pro-Phe-Trp]) is a multifunctional µ-opioid receptor and κ-opioid receptor agonist and κ-opioid receptor antagonist that produces antinociception and prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference (CPP). We hypothesized that an analogue of CJ-15,208, cyclo[Pro-Sar-Phe-d-Phe], would demonstrate multifunctional µ-opioid receptor and κ-opioid receptor ligand activity, producing potent antinociception with fewer liabilities than selective µ-opioid receptor agonists, while preventing both drug- and stress-induced reinstatement of morphine-induced CPP. EXPERIMENTAL APPROACH: The opioid receptor agonist and antagonist activity of cyclo[Pro-Sar-Phe-d-Phe] was characterized after i.c.v. and i.p. administration to C57BL/6J or transgenic opioid receptor "knockout" mice using the 55°C warm-water tail-withdrawal assay. Liabilities of locomotor coordination, respiration and spontaneous ambulation, and direct rewarding or aversive properties were assessed. Finally, the ability of cyclo[Pro-Sar-Phe-d-Phe] to block morphine- and stress-induced reinstatement of extinguished CPP was determined. KEY RESULTS: cyclo[Pro-Sar-Phe-d-Phe] demonstrated dose-dependent, short-lasting antinociception, with an ED50 (and 95% confidence interval) of 0.15 (0.05-0.21) nmol i.c.v. and 1.91 (0.40-3.54) mg·kg-1 i.p., mediated by µ- and κ-opioid receptors. The macrocyclic tetrapeptide also demonstrated potent dose-dependent κ-opioid receptor antagonist-like activity at 2.5, but not at 4.5, h after administration. cyclo[Pro-Sar-Phe-d-Phe] displayed reduced liabiities compared with morphine, attributed to its additional activity at κ-receptors. Pretreatment with cyclo[Pro-Sar-Phe-d-Phe] prevented stress- and drug-induced reinstatement of extinguished morphine-place preference responses in a time-dependent manner. CONCLUSIONS AND IMPLICATIONS: These data suggest that cyclo[Pro-Sar-Phe-d-Phe] is a promising lead compound for both the treatment of pain with reduced sideeffects and preventing both drug- and stress-induced relapse in morphine-abstinent subjects.


Assuntos
Morfina , Preparações Farmacêuticas , Receptores Opioides mu , Analgésicos Opioides/farmacologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Antagonistas de Entorpecentes , Receptores Opioides , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores
14.
ACS Chem Neurosci ; 11(9): 1324-1336, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32251585

RESUMO

Substance abuse remains a serious public health crisis, affecting millions of people worldwide. Macrocyclic tetrapeptides like CJ-15,208 and [d-Trp]CJ-15,208 demonstrate opioid activity shown to attenuate the rewarding effects of cocaine in conditioned place preference assays in mice, making them promising lead compounds for treating substance abuse. In the present study, we report the rational design, synthesis, conformational analysis, and continued pharmacological evaluation of the novel macrocyclic tetrapeptide cyclo[Pro-Sar-Phe-d-Phe] to further explore this unique molecular scaffold. This peptide was rationally designed based on X-ray and NMR structures of related macrocyclic tetrapeptides. Following synthesis, its solution-phase conformations were determined by NMR and molecular modeling. The peptide adopted multiple conformations in polar solvents, but a single conformation in chloroform that is stabilized by intramolecular hydrogen bonding. The peptide is orally bioavailable, producing antinociception and antagonism of kappa opioid receptor (KOR) stimulation following oral administration in a mouse 55 °C warm-water tail-withdrawal assay. Notably, cyclo[Pro-Sar-Phe-d-Phe] blocked both stress- and drug-induced reinstatement of cocaine and morphine conditioned place preference in mice following oral administration, and displayed a decreased side-effect profile compared to morphine. Thus, cyclo[Pro-Sar-Phe-d-Phe] is a promising lead compound for the treatment of substance abuse.


Assuntos
Analgésicos Opioides , Antagonistas de Entorpecentes , Administração Oral , Animais , Camundongos , Camundongos Endogâmicos C57BL , Oligopeptídeos , Peptídeos Cíclicos , Receptores Opioides kappa , Receptores Opioides mu
17.
J Clin Virol ; 121: 104204, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31743836

RESUMO

BACKGROUND: Nucleic acid amplification tests (NAATs), such as PCR, are preferred for respiratory virus testing, due to superior diagnostic accuracy and faster turnaround time. Panther Fusion® Respiratory Assays (Fusion), which includes FluA/B/RSV (FFABR), Paraflu and AdV/hMPV/RV, offers a modular approach to syndromic testing on a fully automated platform while improving gene targets and expanding the test menu. OBJECTIVES AND STUDY DESIGN: We evaluated Fusion using 275 consecutive nasopharyngeal specimens previously used in an analysis of five PCRs, as well as 225 archived specimens. RESULTS: Of the combined 500 specimens, 134 were positive for influenza A (FluA), 54 for FluB, 65 for RSV, 64 for parainfluenza (PIV), 24 for adenovirus (AdV), 21 for humanmetapneumovirus (hMPV), and 40 for rhinovirus (RV) with Fusion. Of the positive samples Fusion correlated with historical results for all but one, despite multiple freeze-thaws cycles of this collection. Fusion was positive for an additional 33 samples, including 11 FluAs, 7 RSVs, 3 PIV3s, 3 AdV, 6 hMPV and 3 RVs. These samples were retested with corresponding Prodesse (Pro) assays using quadruple sample volume. This resolver test confirmed Fusion results for an additional 4 FluAs, 4 RSVs, 1 PIV3 and 3 AdVs. The sensitivity and specificity ranges of Fusion were 99-100% and 98-100%. Limit of detection (LOD) analyses were performed on a variety of Flu isolates. The LODs ranged from 2.69 to 2.99 log copies/ml and demonstrated superior LOD as compared to previously published data for some assays or to concurrent analyses with two new commercial tests.


Assuntos
Técnicas de Amplificação de Ácido Nucleico/métodos , Infecções Respiratórias/diagnóstico , Viroses/diagnóstico , Vírus/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Automação Laboratorial , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Nasofaringe/virologia , Técnicas de Amplificação de Ácido Nucleico/instrumentação , Infecções Respiratórias/virologia , Sensibilidade e Especificidade , Viroses/virologia , Adulto Jovem
18.
Ann Intern Med ; 171(7): 474-484, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31476766

RESUMO

Background: Delirium is an acute disorder marked by impairments in attention and cognition, caused by an underlying medical problem. Antipsychotics are used to prevent delirium, but their benefits and harms are unclear. Purpose: To conduct a systematic review evaluating the benefits and harms of antipsychotics for prevention of delirium in adults. Data Sources: PubMed, Embase, CENTRAL, CINAHL, and PsycINFO from inception through July 2019, without restrictions based on study setting, language of publication, or length of follow-up. Study Selection: Randomized, controlled trials (RCTs) that compared an antipsychotic with placebo or another antipsychotic, and prospective observational studies with a comparison group. Data Extraction: One reviewer extracted data and graded the strength of the evidence, and a second reviewer confirmed the data. Two reviewers independently assessed the risk of bias. Data Synthesis: A total of 14 RCTs were included. There were no differences in delirium incidence or duration, hospital length of stay (high strength of evidence [SOE]), and mortality between haloperidol and placebo used for delirium prevention. Little to no evidence was found to determine the effect of haloperidol on cognitive function, delirium severity (insufficient SOE), inappropriate continuation, and sedation (insufficient SOE). There is limited evidence that second-generation antipsychotics may lower delirium incidence in the postoperative setting. There is little evidence that short-term use of antipsychotics was associated with neurologic harms. In some of the trials, potentially harmful cardiac effects occurred more frequently with antipsychotic use. Limitations: There was significant heterogeneity in antipsychotic dosing, route of antipsychotic administration, assessment of outcomes, and adverse events. There were insufficient or no data available to draw conclusions for many of the outcomes. Conclusion: Current evidence does not support routine use of haloperidol or second-generation antipsychotics for prevention of delirium. There is limited evidence that second-generation antipsychotics may lower the incidence of delirium in postoperative patients, but more research is needed. Future trials should use standardized outcome measures. Primary Funding Source: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018109552).


Assuntos
Antipsicóticos/uso terapêutico , Delírio/prevenção & controle , Hospitalização , Cognição , Eletrocardiografia , Haloperidol/uso terapêutico , Coração/efeitos dos fármacos , Mortalidade Hospitalar , Humanos , Tempo de Internação , Estudos Observacionais como Assunto , Cuidados Paliativos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença
19.
Ann Intern Med ; 171(7): 485-495, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31476770

RESUMO

Background: Delirium is common in hospitalized patients and is associated with worse outcomes. Antipsychotics are commonly used; however, the associated benefits and harms are unclear. Purpose: To conduct a systematic review evaluating the benefits and harms of antipsychotics to treat delirium in adults. Data Sources: PubMed, Embase, CENTRAL, CINAHL, and PsycINFO from inception to July 2019 without language restrictions. Study Selection: Randomized controlled trials (RCTs) of antipsychotic versus placebo or another antipsychotic, and prospective observational studies reporting harms. Data Extraction: One reviewer extracted data and assessed strength of evidence (SOE) for critical outcomes, with confirmation by another reviewer. Risk of bias was assessed independently by 2 reviewers. Data Synthesis: Across 16 RCTs and 10 observational studies of hospitalized adults, there was no difference in sedation status (low and moderate SOE), delirium duration, hospital length of stay (moderate SOE), or mortality between haloperidol and second-generation antipsychotics versus placebo. There was no difference in delirium severity (moderate SOE) and cognitive functioning (low SOE) for haloperidol versus second-generation antipsychotics, with insufficient or no evidence for antipsychotics versus placebo. For direct comparisons of different second-generation antipsychotics, there was no difference in mortality and insufficient or no evidence for multiple other outcomes. There was little evidence demonstrating neurologic harms associated with short-term use of antipsychotics for treating delirium in adult inpatients, but potentially harmful cardiac effects tended to occur more frequently. Limitations: Heterogeneity was present in terms of dose and administration route of antipsychotics, outcomes, and measurement instruments. There was insufficient or no evidence regarding multiple clinically important outcomes. Conclusion: Current evidence does not support routine use of haloperidol or second-generation antipsychotics to treat delirium in adult inpatients. Primary Funding Source: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018109552).


Assuntos
Antipsicóticos/uso terapêutico , Delírio/tratamento farmacológico , Hospitalização , Cognição , Eletrocardiografia , Haloperidol/uso terapêutico , Coração/efeitos dos fármacos , Mortalidade Hospitalar , Humanos , Tempo de Internação , Estudos Observacionais como Assunto , Cuidados Paliativos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Fatores de Tempo
20.
Int J Rheum Dis ; 22(10): 1900-1904, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31531960

RESUMO

OBJECTIVES: To measure serial interleukin (IL)-6 levels in newly diagnosed patients with giant cell arteritis (GCA), treated in a randomized controlled trial of modified-release prednisone (MR) vs immediate-release prednisolone (IR) used in a tapering regimen conforming to British Society for Rheumatology GCA guidelines. METHODS: Patients (n = 12) were randomized into 2 treatment arms (7 MR, 5 IR) and followed over 26 weeks. We measured IL-6 with additional markers. RESULTS: A significantly higher overall mean IL-6 level (P < .05) was seen in IR (mean = 12.15, standard error [SE] = 1.90) compared with MR (mean = 4.39, SE = 1.84). Mean collagen type 1 cross-linked C-telopeptide (CTX) concentration was significantly higher (P < .05) in both groups at week 4 (mean = 0.29, SE = 0.04) compared with week 26 (mean = 0.13, SE = 0.02). MR patients had adrenocorticotropic hormone (ACTH) suppression compared with IR (P < .05) throughout without differences in cortisol levels (P = .34). No significant differences were seen between arms in other markers. CONCLUSION: Our study suggests that elevated levels of IL-6 in new GCA are better suppressed by MR prednisone compared with IR prednisolone. CTX was significantly reduced in both treatment arms indicating early metabolic effect of glucocorticoids on bone. ACTH suppression with MR prednisone may reflect a greater impact on the hypothalamic-pituitary-adrenal axis although cortisol was not affected. MR prednisone warrants further investigation in GCA.


Assuntos
Arterite de Células Gigantes/tratamento farmacológico , Interleucina-6/sangue , Prednisolona/administração & dosagem , Prednisona/administração & dosagem , Administração Oral , Idoso , Biomarcadores/sangue , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Esquema de Medicação , Estudos de Viabilidade , Feminino , Seguimentos , Arterite de Células Gigantes/sangue , Arterite de Células Gigantes/diagnóstico , Glucocorticoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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