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2.
Anesthesiology ; 139(6): 746-756, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37656771

RESUMO

BACKGROUND: Oliceridine (Olinvyk) is a µ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. This study was designed to determine the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test. METHODS: The study had a randomized, double-blind, placebo-controlled, partial block three-way crossover design. Experiments were performed in 20 male and female volunteers. The subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose), or placebo on three separate occasions. Before and after dosing, neurocognitive tests, cold pressor test, and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as the basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as the measure of benefit, and slowing of saccadic peak velocity and increased body sway as the measures of neurocognitive harm. RESULTS: The oliceridine and morphine C50 values, i.e., the effect-site concentrations causing 50% effect, were as follows: antinociception, 13 ± 2 and 23 ± 7 ng/ml; saccadic peak velocity, 90 ± 14 and 54 ± 15 ng/ml; and body sway, 10 ± 2 and 5.6 ± 0.8 ng/ml, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI, 0.17 to 0.7; P < 0.01) for saccadic peak velocity and 0.33 (0.16 to 0.50; P < 0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5 to 77 ng/ml, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from 0 from 0 to 100 ng/ml. Over the concentration range 15 to 50 ng/ml, the oliceridine utility was superior to that of morphine (P < 0.01). Similar observations were made for body sway. CONCLUSIONS: These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function.


Assuntos
Morfina , Compostos de Espiro , Masculino , Humanos , Feminino , Analgésicos Opioides , Receptores Opioides
3.
Br J Clin Pharmacol ; 89(1): 361-371, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35997713

RESUMO

AIM: We assessed whether total sleep deprivation (TSD) in combination with pain tests yields a reliable method to assess altered pain thresholds, which subsequently may be used to investigate (novel) analgesics in healthy subjects. METHODS: This was a two-part randomized crossover study in 24 healthy men and 24 women. Subjects were randomized 1:1 to first complete a day of nonsleep-deprived nociceptive threshold testing, followed directly by a TSD night and morning of sleep-deprived testing, or first complete the TSD night and morning sleep-deprived testing, returning 7 days later for a day of nonsleep-deprived testing. A validated pain test battery (heat, pressure, electrical burst and stair, cold pressor pain test and conditioned pain modulation [CPM] paradigm) and sleep questionnaires were performed. RESULTS: Subjects were significantly sleepier after TSD as measured using sleepiness questionnaires. Cold pressor pain tolerance (PTT, estimate of difference [ED] -10.8%, 95% CI -17.5 to -3.6%), CPM PTT (ED -0.69 mA, 95% CI -1.36 to -0.03 mA), pressure PTT (ED -11.2%, 95% CI -17.5% to -4.3%) and heat pain detection thresholds (ED -0.74 °C, 95% CI -1.34 to -0.14 °C) were significantly decreased after TSD compared to the baseline morning assessment in the combined analysis (men + women). Heat hyperalgesia was primarily driven by an effect of TSD in men, whereas cold and pressure hyperalgesia was primarily driven by the effects of TSD observed in women. CONCLUSIONS: TSD induced sex-dependent hyperalgesia on cold, heat and pressure pain, and CPM response. These results suggest that the TSD model may be suitable to evaluate (novel) analgesics in early-phase drug studies.


Assuntos
Hiperalgesia , Privação do Sono , Masculino , Humanos , Feminino , Estudos Cross-Over , Nociceptividade , Voluntários Saudáveis , Dor , Limiar da Dor , Analgésicos/farmacologia
4.
Eur J Clin Pharmacol ; 78(11): 1861-1862, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36180797

RESUMO

PURPOSE: In the wake of the coronavirus disease 2019 (COVID-19) pandemic, support in clinical trials by students of human medicine and related disciplines has become of even greater importance than in pre-pandemic times. Documentation in clinical trials adheres to the principles of Good Clinical Practice (GCP), and healthcare professionals involved in the conduct of clinical trials-including students-are obliged to perform documentation in accordance with GCP principles. Unprecedented challenges have arisen with regard to the appropriate training of students as training courses in presence had largely to be suspended due to social-distancing regulations during the heyday of the COVID-19 pandemic. Therefore, novel training formats and self-study training materials for students working in clinical trials are urgently warranted. METHODS: To overcome this shortcoming and to define a common quality standard, an interdisciplinary, multiprofessional (physicians, study nurses, medical students), and binational (Germany, The Netherlands) expert panel convened and devised the Students' guide to documentation in clinical trials. RESULTS: Following a brief description of the different roles in clinical trials (e.g., sponsor, (principal) investigator, monitor) and an introduction into the principles of GCP, the documentation of adverse events, concomitant medication, medical history, and quality control are comprehensively discussed. The Guide concludes with a trilingual medical dictionary (English, German, Dutch) and with recommendations of pertinent literature for further reading. CONCLUSION: Serving both as textbook for self-training and as (quick-) reference work for the daily routine, the Guide has specifically been designed to complement, but not to replace practical training courses for students. While primarily addressed at students of human medicine and related disciplines, the Guide can also be of high relevance and utility to other healthcare professionals involved in the conduct of clinical trials.


Assuntos
COVID-19 , Estudantes de Medicina , Ensaios Clínicos como Assunto , Documentação , Alemanha , Humanos , Pandemias
5.
Exp Brain Res ; 240(2): 631-649, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34993590

RESUMO

Sleep deprivation has been shown to increase pain intensity and decrease pain thresholds in healthy subjects. In chronic pain patients, sleep impairment often worsens the perceived pain intensity. This increased pain perception is the result of altered nociceptive processing. We recently developed a method to quantify and monitor altered nociceptive processing by simultaneous tracking of psychophysical detection thresholds and recording of evoked cortical potentials during intra-epidermal electric stimulation. In this study, we assessed the sensitivity of nociceptive detection thresholds and evoked potentials to altered nociceptive processing after sleep deprivation in an exploratory study with 24 healthy male and 24 healthy female subjects. In each subject, we tracked nociceptive detection thresholds and recorded central evoked potentials in response to 180 single- and 180 double-pulse intra-epidermal electric stimuli. Results showed that the detection thresholds for single- and double-pulse stimuli and the average central evoked potential for single-pulse stimuli were significantly decreased after sleep deprivation. When analyzed separated by sex, these effects were only significant in the male population. Multivariate analysis showed that the decrease of central evoked potential was associated with a decrease of task-related evoked activity. Measurement repetition led to a decrease of the detection threshold to double-pulse stimuli in the mixed and the female population, but did not significantly affect any other outcome measures. These results suggest that simultaneous tracking of psychophysical detection thresholds and evoked potentials is a useful method to observe altered nociceptive processing after sleep deprivation, but is also sensitive to sex differences and measurement repetition.


Assuntos
Nociceptividade , Privação do Sono , Estimulação Elétrica/métodos , Potenciais Evocados , Feminino , Humanos , Masculino , Dor , Limiar da Dor/fisiologia
6.
Clin Transl Sci ; 15(4): 981-993, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34958174

RESUMO

Selective inhibition of certain voltage-gated sodium channels (Nav s), such as Nav 1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX-128 is a highly potent and selective Nav 1.8 inhibitor that was being developed as a treatment for pain. We evaluated the safety, tolerability, and pharmacokinetics of VX-128 in healthy subjects in a single- and multiple-ascending dose (MAD) first-in-human study. Pharmacodynamics were evaluated in the MAD part using a battery of evoked pain tests. Overall, single doses of VX-128 up to 300 mg were well-tolerated, although adverse effect (AE) incidence was higher in subjects receiving VX-128 (41.7%) compared with placebo (25.0%). After multiple dosing of up to 10 days, skin rash events were observed at all dose levels (up to 100 mg once daily [q.d.]), in five of 26 (19.2%) subjects, including one subject receiving VX-128 (100 mg q.d.) who had a serious AE of angioedema. A trend in pain tolerance were observed for cold pressor- and pressure pain, which was dose-dependent for the latter. VX-128 was rapidly absorbed (median time to maximum plasma concentration between 1 and 2 h) with a half-life of ~80 h at 10 mg q.d., and approximately two-fold accumulation ratio after 10 and 30 mg q.d. Although VX-128, when given in a multiple dose fashion, resulted in early study termination due to tolerability issues, effects were observed on multiple pain tests that may support further investigation of Nav 1.8 inhibitors as pain treatments.


Assuntos
Compostos Organotiofosforados , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Dor/tratamento farmacológico
8.
Pain Med ; 22(8): 1814-1826, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-33543763

RESUMO

OBJECTIVE: To evaluate the analgesic potential, safety, tolerability, and pharmacokinetics of VX-150, a pro-drug of a highly selective NaV1.8 inhibitor, in healthy subjects. DESIGN: This was a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. SUBJECTS: Twenty healthy male subjects with an age of 18-55 years, inclusive, were enrolled. Eligibility was based on general fitness, absence of current or previous medical conditions that could compromise subject safety, and a training assessment of pain tolerance across pain tests to exclude highly tolerant individuals whose tolerance could compromise the ability to detect analgesic responses. All dosed subjects completed the study. METHODS: Subjects were randomized 1:1 to one of two sequences receiving a single VX-150 dose and subsequently placebo, or vice versa, with at least 7 days between dosing. A battery of pain tests (pressure, electrical stair, [capsaicin-induced] heat, and cold pressor) was administered before dosing and repetitively up to 10 h after dosing, with blood sampling up to 24 h after dosing. Safety was monitored throughout the study. Data were analyzed with a repeated-measures mixed-effects model. RESULTS: VX-150 induced analgesia in a variety of evoked pain tests, without affecting subject safety. Significant effects were reported for the cold pressor and heat pain thresholds. Maximum median concentration for the active moiety was 4.30 µg/mL at 4 h after dosing. CONCLUSION: Results of this proof-of-mechanism study are supportive of the potential of VX-150, a highly selective NaV1.8 channel inhibitor, to treat various pain indications.


Assuntos
Analgésicos , Limiar da Dor , Adolescente , Adulto , Analgésicos/farmacologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organotiofosforados , Adulto Jovem
9.
Genome Biol ; 17(1): 247, 2016 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-27903283

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have revealed many susceptibility loci for complex genetic diseases. For most loci, the causal genes have not been identified. Currently, the identification of candidate genes is predominantly based on genes that localize close to or within identified loci. We have recently shown that 92 of the 163 inflammatory bowel disease (IBD)-loci co-localize with non-coding DNA regulatory elements (DREs). Mutations in DREs can contribute to IBD pathogenesis through dysregulation of gene expression. Consequently, genes that are regulated by these 92 DREs are to be considered as candidate genes. This study uses circular chromosome conformation capture-sequencing (4C-seq) to systematically analyze chromatin-interactions at IBD susceptibility loci that localize to regulatory DNA. RESULTS: Using 4C-seq, we identify genomic regions that physically interact with the 92 DRE that were found at IBD susceptibility loci. Since the activity of regulatory elements is cell-type specific, 4C-seq was performed in monocytes, lymphocytes, and intestinal epithelial cells. Altogether, we identified 902 novel IBD candidate genes. These include genes specific for IBD-subtypes and many noteworthy genes including ATG9A and IL10RA. We show that expression of many novel candidate genes is genotype-dependent and that these genes are upregulated during intestinal inflammation in IBD. Furthermore, we identify HNF4α as a potential key upstream regulator of IBD candidate genes. CONCLUSIONS: We reveal many novel and relevant IBD candidate genes, pathways, and regulators. Our approach complements classical candidate gene identification, links novel genes to IBD and can be applied to any existing GWAS data.


Assuntos
Cromatina/genética , Epistasia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doenças Inflamatórias Intestinais/genética , Locos de Características Quantitativas , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla/métodos , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Subunidade alfa de Receptor de Interleucina-10/genética , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Especificidade de Órgãos/genética , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Reprodutibilidade dos Testes , Transdução de Sinais , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
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