RESUMEN
SFX-01 is a novel drug for clinical delivery of sulforaphane (SFN). SFN is a potent nuclear factor erythroid 2-related factor 2 activator that reduces inflammation and oxidation, improving outcomes after subarachnoid haemorrhage (SAH) in animal models. This was a multi-centre, double-blind, placebo-controlled, parallel-group randomised clinical trial to evaluate the safety, pharmacokinetics and efficacy of 28 days of SFX-01 300 mg BD in patients aged 18-80 with spontaneous SAH and high blood load on CT. Primary outcomes were (1) safety, (2) plasma and CSF SFN and metabolite levels and (3) vasospasm on transcranial doppler ultrasound. Secondary outcomes included CSF haptoglobin and malondialdehyde and clinical outcome on the modified Rankin Scale (mRS) and SAH outcome tool (SAHOT). A total of 105 patients were randomised (54 SFX-01, 51 placebo). There were no differences in adverse events other than nausea (9 SFX-01 (16.7%), 1 placebo (2.0%)). SFN, SFN-glutathione and SFN-N-acetyl-cysteine AUClast were 16.2, 277 and 415 h × ng/ml. Plasma SFN was higher in GSTT1 null individuals (t = 2.40, p = 0.023). CSF levels were low with many samples below the lower limit of quantification and predicted by the CSF/serum albumin ratio (R2 = 0.182, p = 0.039). There was no difference in CSF haptoglobin (1.981 95%CI 0.992-3.786, p = 0.052) or malondialdehyde (1.12 95%CI 0.7477-1.687, p = 0.572) or middle cerebral artery flow velocity (1.04 95%CI 0.903-1.211, p = 0.545) or functional outcome (mRS 1.647 95%CI 0.721-3.821, p = 0.237, SAHOT 1.082 95%CI 0.464-2.525, p = 0.855). SFX-01 is safe and effective for the delivery of SFN in acutely unwell patients. SFN penetrated CSF less than expected and did not reduce large vessel vasospasm or improve outcome. Trial registration: NCT02614742 clinicaltrials.gov.
RESUMEN
The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV-2) and its expansion to a worldwide pandemic resulted in efforts to assess and develop interventions to reduce the disease burden. Despite the introduction of vaccine programmes against SARS-CoV-2, global incidence levels in early 2022 remained high, demonstrating a need for the development of physiologically relevant models, which are essential for the identification of alternative antiviral strategies. The hamster model of SARS-CoV-2 infection has been widely adopted due to similarities with humans in terms of host cell entry mechanism (via ACE2), and aspects of symptomology and virus shedding. We have previously described a natural transmission hamster model that better represents the natural course of infection. In the present study, we have conducted further testing of the model using the first-in-class antiviral Neumifil, which has previously shown promise against SARS-CoV-2 after a direct intranasal challenge. Neumifil is an intranasally delivered carbohydrate-binding module (CBM) which reduces the binding of viruses to their cellular receptor. By targeting the host cell, Neumifil has the potential to provide broad protection against multiple pathogens and variants. This study demonstrates that using a combination of a prophylactic and therapeutic delivery of Neumifil significantly reduces the severity of clinical signs in animals infected via a natural route of transmission and indicates a reduction of viral loads in the upper respiratory tract. Further refinements of the model are required in order to ensure the adequate transmission of the virus. However, our results provide additional data to the evidence base of Neumifil efficacy against respiratory virus infection and demonstrate that the transmission model is a potentially valuable tool for testing antiviral compounds against SARS-CoV-2.
Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Cricetinae , Humanos , SARS-CoV-2/metabolismo , Antivirales/farmacología , Antivirales/uso terapéutico , Antivirales/química , CarbohidratosRESUMEN
The rapid global spread of severe acute respiratory coronavirus 2 (SARS-CoV-2) has resulted in an urgent effort to find efficacious therapeutics. Broad-spectrum therapies which could be used for other respiratory pathogens confer advantages, as do those based on targeting host cells that are not prone to the development of resistance by the pathogen. We tested an intranasally delivered carbohydrate-binding module (CBM) therapy, termed Neumifil, which is based on a CBM that has previously been shown to offer protection against the influenza virus through the binding of sialic acid receptors. Using the recognised hamster model of SARS-CoV-2 infection, we demonstrate that Neumifil significantly reduces clinical disease severity and pathological changes in the nasal cavity. Furthermore, we demonstrate Neumifil binding to the human angiotensin-converting enzyme 2 (ACE2) receptor and spike protein of SARS-CoV-2. This is the first report describing the testing of this type of broad-spectrum antiviral therapy in vivo and provides evidence for the advancement of Neumifil in further preclinical and clinical studies.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Peptidil-Dipeptidasa A , Carbohidratos , Cricetinae , Humanos , Peptidil-Dipeptidasa A/metabolismo , SARS-CoV-2 , Glicoproteína de la Espiga del CoronavirusRESUMEN
BACKGROUND: Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a master transcriptional regulator of the protective cellular response to oxidative stress. Sulforaphane is a Nrf2 activator but is unstable at ambient temperature. SFX-01 is a novel composition comprised of synthetic sulforaphane stabilised within the pocket of an α-cyclodextrin complex. Here we tested the efficacy of SFX-01 in murine relapsing experimental autoimmune encephalomyelitis (EAE), a model of relapsing-remitting MS (RRMS). METHODS: Relapsing EAE was induced in female SJL mice using immunization against PLP139-151. In the therapeutic experiment, the aim was to model initiation of treatment after diagnosis in RRMS, so treatment was started at day 19, one day prior to the expected relapse onset. In the prophylactic experiment, mice were treated from the time of immunization and followed for three weeks. RESULTS: SFX-01 reduced residual disability in both experiments. Most of this effect was mediated by a decrease in maximum severity of relapses and improved recovery during follow-up. Histological examination of the spinal cord was consistent with the clinical findings, with improvement in demyelination and the number of apoptotic cells, but not inflammatory cell infiltration, compared to the vehicle group. CONCLUSIONS: SFX-01 is efficacious in EAE. In first-in-man and phase II clinical trials for other indications, SFX-01 was found to be well-tolerated. A trial comparing BG-12 and SFX-01 would address whether SFX-01 can offer RRMS patients a better option with respect to efficacy and tolerability.
Asunto(s)
Anticarcinógenos/uso terapéutico , Encefalomielitis Autoinmune Experimental/complicaciones , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Isotiocianatos/uso terapéutico , Resultado del Tratamiento , Animales , Evaluación de la Discapacidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Encefalomielitis Autoinmune Experimental/inducido químicamente , Femenino , Adyuvante de Freund/toxicidad , Estimación de Kaplan-Meier , Ratones , Proteína Proteolipídica de la Mielina/toxicidad , Fragmentos de Péptidos/toxicidad , Sulfóxidos , Factores de TiempoAsunto(s)
Agonistas Adrenérgicos beta/uso terapéutico , Asma/tratamiento farmacológico , Asma/mortalidad , Errores de Medicación , Adolescente , Asma/diagnóstico , Servicios de Salud/economía , Servicios de Salud/estadística & datos numéricos , Humanos , Cooperación del Paciente , Educación del Paciente como Asunto , Investigación/economía , Proyectos de InvestigaciónRESUMEN
1. Non-steroidal anti-inflammatory drugs (NSAIDs) are effective anti-inflammatory and analgesic drugs although they also induce unwanted side effects due to the inhibition of the physiological effects regulated by prostaglandins. This has led to the search for new compounds with fewer side effects, such as the nitro-NSAIDs (NO-NSAIDs). Paracetamol is an analgesic drug devoid of some of the side effect of the NSAIDs but without anti-inflammatory activity. NCX-701 is a nitric oxide releasing version of paracetamol with anti-inflammatory and analgesic properties. 2. We have tested, in the single motor unit technique, the antinociceptive actions of intravenous cumulative doses of NCX-701 vs paracetamol, studying their antinociceptive effects in responses to noxious mechanical and electrical stimulation (wind-up). 3. Paracetamol did not induce any significant effect at the doses tested (maximum of 480 micromol kg(-1), 72.5 mg kg(-1)). NCX-701 however was very effective in reducing responses to noxious mechanical stimulation (32+/-10% of control response) and wind-up (ED(50) of 147+/-1 micromol kg(-1), 41.5+/-0.3 mg kg(-1)). The inhibition was not reversed by 1 mg kg(-1) of the opioid antagonist naloxone. In control experiments performed with either the vehicle or the NO donor NOC-18, no significant changes were observed in the nociceptive responses studied. 4. We conclude that NCX-701 is a very effective non-opioid antinociceptive agent in normal animals and its action is located mainly at central areas. The antinociceptive effect was not due solely to the release of NO.