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1.
Ther Adv Musculoskelet Dis ; 15: 1759720X231192315, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37694182

RESUMEN

Achieving a good outcome for a person with Psoriatic Arthritis (PsA) is made difficult by late diagnosis, heterogenous clinical disease expression and in many cases, failure to adequately suppress inflammatory disease features. Single-centre studies have certainly contributed to our understanding of disease pathogenesis, but to adequately address the major areas of unmet need, multi-partner, collaborative research programmes are now required. HIPPOCRATES is a 5-year, Innovative Medicines Initiative (IMI) programme which includes 17 European academic centres experienced in PsA research, 5 pharmaceutical industry partners, 3 small-/medium-sized industry partners and 2 patient-representative organizations. In this review, the ambitious programme of work to be undertaken by HIPPOCRATES is outlined and common approaches and challenges are identified. It is expected that, when completed, the results will ultimately allow for changes in the approaches to diagnosing, managing and treating PsA allowing for better short-term and long-term outcomes.


Improving outcomes in Psoriatic Arthritis Psoriatic Arthritis (PsA) is a form of arthritis which is found in approximately 30% of people who have the skin condition, Psoriasis. Frequently debilitating and progressive, achieving a good outcome for a person with PsA is made difficult by late diagnosis, disease clinical features and in many cases, failure to adequately control features of inflammation. Research studies from individual centres have certainly contributed to our understanding of why people develop PsA but to adequately address the major areas of unmet need, multi-centre, collaborative research programmes are now required. HIPPOCRATES is a 5-year, Innovative Medicines Initiative (IMI) programme which includes 17 European academic centres experienced in PsA research, 5 pharmaceutical industry partners, 3 small-/medium-sized industry partners and 2 patient representative organisations (see appendix). In this review, the ambitious programme of work to be undertaken by HIPPOCRATES is outlined and common approaches and challenges are identified. The participation of patient research partners in all stages of the work of HIPPOCRATES is highlighted. It is expected that, when completed, the results will ultimately allow for changes in the approaches to diagnosing, managing and treating PsA allowing for improvements in short-term and long-term outcomes.

2.
Br J Clin Pharmacol ; 86(2): 338-351, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31658377

RESUMEN

AIMS: The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of secukinumab with different devices for subcutaneous (s.c.) administration of 2 mL. METHODS: A phase 1 study in healthy subjects with 6 devices to administer 2 mL injection volumes was conducted to evaluate the serum PK, safety and tolerability of secukinumab following single s.c. injection of 300 mg in the abdomen (either side) or in the thigh (either leg). Primary PK endpoints were maximum observed serum concentration and area under the serum concentration-time curve. The impact of device, site and side of injection on serum exposure was evaluated. In a phase 3 study in psoriasis patients, PK of secukinumab was evaluated following multiple s.c. injections of 300 mg by either 2 × 1-mL prefilled syringe or 1 × 2-mL prefilled syringe. RESULTS: Mean serum concentration-time profiles for administration as 2 × 1 mL injections or as 1 × 2 mL injections were similar. With an injection volume of 2 mL, perceived injection pain was not different from 2 × 1 mL injections. A nonclinically significant difference in PK endpoints was observed between thigh and abdomen. Results with a 2 mL prefilled syringe in a 1-year phase 3 study in patients confirmed PK results observed in the phase 1 study. CONCLUSION: Collective evidence from both studies demonstrated that 2-mL injections of secukinumab into the abdomen or thigh using different devices resulted in comparable PK characteristics and were all well tolerated without noticeable local reactions.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Psoriasis , Anticuerpos Monoclonales Humanizados/uso terapéutico , Voluntarios Sanos , Humanos , Inyecciones Subcutáneas , Psoriasis/tratamiento farmacológico
3.
Clin Pharmacol Ther ; 106(6): 1380-1388, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31228872

RESUMEN

This open-label disease-drug-drug interaction study assessed whether blockade of the interleukin (IL)-17A pathway by secukinumab and subsequent downregulation of inflammatory cytokines like IL-6 or high-sensitivity C-reactive protein affects the pharmacokinetics (PKs) of a sensitive probe substrate of the cytochrome P450 3A4 isoform (CYP3A4). The PKs of midazolam, metabolized by CYP3A4, was evaluated before and after 7 and 35 days of treatment initiation of subcutaneous secukinumab at a dose of 300 mg weekly in 24 patients with moderate-to-severe psoriasis. Although demonstrating the expected decrease in downstream inflammatory cytokines, secukinumab had no clinically relevant effects on the PKs of midazolam, provided substantial clinical benefit, and was generally well tolerated. In summary, blockade of IL-17A signaling in patients with moderate-to-severe psoriasis does not significantly affect CYP3A4 enzyme activities and, therefore, the use of secukinumab is unlikely to influence the PKs of CYP3A4 substrates.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Citocromo P-450 CYP3A/metabolismo , Hipnóticos y Sedantes/farmacocinética , Midazolam/farmacocinética , Psoriasis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Interacciones Farmacológicas , Femenino , Humanos , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto Joven
4.
Psychopharmacology (Berl) ; 233(13): 2429-39, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27178435

RESUMEN

RATIONALE: Hypofunction of NMDA receptors has been implicated in neuropsychiatric disorders including schizophrenia. NMDA receptor neurotransmission can be enhanced through inhibition of glycine reuptake by the glycine transporter type 1 (GlyT1). OBJECTIVES: The primary objective of these studies was to explore the relationship between plasma exposure and glycine cerebrospinal fluid (CSF) concentrations following administration of bitopertin and RG7118 in healthy volunteers. METHODS: The bitopertin study comprised four dose levels (3, 10, 30 and 60 mg) administered once daily for 10 days. In the RG7118 study, placebo, 15 or 30 mg RG7118 was administered once daily for 28 days. CSF samples were taken on day -2 and day 10, and day -1 and day 26 for bitopertin and RG7118, respectively. RESULTS: Twenty-two and 24 subjects participated in the bitopertin and RG7118 study, respectively. In the bitopertin study, CSF glycine concentrations showed a dose-dependent increase from baseline to day 10. The geometric mean ratios (coefficient of variation) of AUC0-12 h on day 10 over baseline were 1.3 (17 %), 1.3 (49 %), 1.7 (18 %) and 2.3 (14 %) after 3, 10, 30 and 60 mg, respectively. In the RG7118 study, the geometric mean ratio of glycine concentration (CV) on day 26 at 6 h post-dose over time-matched baseline was approx. 1.9 (24 and 15 %) for 15 and 30 mg. CONCLUSIONS: The mechanism of action of bitopertin and RG7118, i.e. inhibition of glycine reuptake in the brain, was confirmed. The maximal increase observed in healthy volunteers was similar to the one observed in animals showing the good translatability of this biomarker.


Asunto(s)
Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Glicina/líquido cefalorraquídeo , Voluntarios Sanos , Imidazoles/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Piperazinas/farmacología , Sulfonas/farmacología , Transmisión Sináptica/efectos de los fármacos , Adulto , Área Bajo la Curva , Encéfalo/efectos de los fármacos , Humanos , Imidazoles/farmacocinética , Masculino , Inhibidores de la Captación de Neurotransmisores/farmacocinética , Piperazinas/farmacocinética , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Sulfonas/farmacocinética
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