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1.
N Engl J Med ; 390(13): 1176-1185, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38598572

RESUMEN

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).


Asunto(s)
Antiparkinsonianos , Agonistas Receptor de Péptidos Similares al Glucagón , Enfermedad de Parkinson , Péptidos , Humanos , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Personas con Discapacidad , Método Doble Ciego , Trastornos Motores/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Péptidos/administración & dosificación , Péptidos/efectos adversos , Péptidos/uso terapéutico , Resultado del Tratamiento , Agonistas Receptor de Péptidos Similares al Glucagón/administración & dosificación , Agonistas Receptor de Péptidos Similares al Glucagón/efectos adversos , Agonistas Receptor de Péptidos Similares al Glucagón/uso terapéutico , Progresión de la Enfermedad , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/uso terapéutico , Inyecciones Subcutáneas
2.
Mov Disord ; 37(2): 334-342, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34766657

RESUMEN

BACKGROUND: Recent examination of the STEADY-PD III isradipine clinical trial data concluded that early-stage Parkinson's disease (PD) participants who had longer exposure to isradipine had a significant delay in their need for symptomatic medication, as well as a lower medication burden at the end of the trial. These findings suggest that greater exposure to isradipine might slow disease progression. OBJECTIVES: To test this hypothesis, the data from the STEADY-PD II isradipine clinical trial, in which an extended-release (ER) formulation of the drug was used, was re-examined. METHODS: The re-analysis of the STEADY-PD II data was restricted to participants assigned placebo or tolerable isradipine treatment (10 mg isradipine/day or less). The effect of isradipine treatment was assessed by Unified Parkinson's Disease Rating Scale (UPDRS) at the end of the 52-week trial, rather than by last observation carried forward at the beginning of symptomatic therapy. RESULTS: Participant cohorts were well-matched for baseline disability, initial disease progression, and time to initiation of symptomatic therapy. Participants given 10 mg/day ER isradipine had significantly smaller total and part 3 UPDRS scores at the end of the trial than did the placebo cohort. Post hoc adjustment for symptomatic therapy diminished the statistical significance of these differences. In those participants not taking a monoamine oxidase B inhibitor, the progression in UPDRS scores also was significantly reduced. CONCLUSIONS: These results are consistent with the recent secondary analysis of the STEADY-PD III clinical trial-suggesting that clinically attainable brain exposure to isradipine may slow early-stage PD progression. © 2021 International Parkinson and Movement Disorder Society.


Asunto(s)
Enfermedad de Parkinson , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Método Doble Ciego , Humanos , Isradipino/uso terapéutico , Pruebas de Estado Mental y Demencia , Inhibidores de la Monoaminooxidasa/uso terapéutico , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico
3.
Mov Disord ; 36(2): 306-316, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33184908

RESUMEN

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra and accumulation of iron and alpha-synuclein; it follows a characteristic pattern throughout the nervous system. Despite decades of successful preclinical neuroprotective studies, no drug has then shown efficacy in clinical trials. Considering this dilemma, we have reviewed and organized solutions of varying importance that can be exclusive or additive, and we outline approaches to help generate successful development of neuroprotective drugs for PD: (1) select patients in which the targeted mechanism is involved in the pathological process associated with the monitoring of target engagement, (2) combine treatments that target multiple pathways, (3) establish earliest interventions and develop better prodromal biomarkers, (4) adopt rigorous methodology and specific disease-relevant designs for disease-modifying clinical trials, (5) customize drug with better brain biodistribution, (6) prioritize repurposed drugs as a first line approach, and (7) adapt preclinical models to the targeted mechanisms with translational biomarkers to increase their predictive value. © 2020 International Parkinson and Movement Disorder Society.


Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Humanos , Neuroprotección , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Sustancia Negra/metabolismo , Distribución Tisular , alfa-Sinucleína/metabolismo
4.
Cochrane Database Syst Rev ; 7: CD012990, 2020 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-32700772

RESUMEN

BACKGROUND: Parkinson's disease (PD) is a progressive disorder characterised by both motor and non-motor problems. Glucagon-like peptide-1 (GLP-1) receptor agonists, licensed for treatment of type 2 diabetes, work by stimulating GLP-1 receptors in the pancreas, which triggers the release of insulin. GLP-1 receptors have been found in the brain. Insulin signalling in the brain plays a key role in neuronal metabolism and repair and in synaptic efficacy, but insulin signalling is desensitised in the brain of people with PD. Researchers are exploring the neuroprotective effects of GLP-1 receptor agonists in neurodegenerative disorders such as PD. OBJECTIVES: To evaluate the effectiveness and safety of GLP-1 receptor agonists for Parkinson's disease. SEARCH METHODS: We searched the Cochrane Movement Disorders Group trials register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; and Ovid MEDLINE and Embase. We also searched clinical trials registries, and we handsearched conference abstracts. The most recent search was run on 25 June 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of adults with PD that compared GLP-1 receptor agonists with conventional PD treatment, placebo, or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We rated the quality of evidence using GRADE. We resolved discrepancies between the two data extractors by consultation with a third review author. MAIN RESULTS: Through our searches, we retrieved 99 unique records, of which two met our inclusion criteria. One double-blind study of exenatide versus placebo randomised 62 participants, who self-administered exenatide or placebo for 48 weeks and were followed up at 60 weeks after a 12-week washout. One single-blind study of exenatide versus no additional treatment randomised 45 participants; participants in the intervention group self-administered exenatide for 12 months, and all participants were followed up at 14 months and 24 months following absence of exenatide for 2 months and 12 months, respectively. These trials had low risk of bias, except risk of performance bias was high for Aviles-Olmos 2013. Exenatide versus placebo Primary outcomes We found low-certainty evidence suggesting that exenatide improves motor impairment as assessed by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in the off-medication state (mean difference (MD) -3.10, 95% confidence interval (CI) -6.11 to -0.09). The difference in scores was slightly greater when scores were adjusted for baseline severity of the condition (as reported by study authors) (MD -3.5, 95% CI -6.7 to -0.3), exceeding the minimum clinically important difference (MCID). We found low-certainty evidence suggesting that exenatide has little or no effect on health-related quality of life (HRQoL) as assessed by the Parkinson's Disease Questionnaire (PDQ)-39 Summary Index (SI) (MD -1.80, 95% CI -6.95 to 3.35), the EuroQol scale measuring health status in five dimensions (EQ5D) (MD 0.07, 95% CI -0.03 to 0.16), or the EQ5D visual analogue scale (VAS) (MD 5.00, 95% CI -3.42 to 13.42). Eight serious adverse events (SAEs) were recorded, but all were considered unrelated to the intervention. Low-certainty evidence suggests that exenatide has little or no effect on weight loss (risk ratio (RR) 1.25, 95% CI 0.89 to 1.76). Exenatide versus no treatment Primary outcomes at 14 months We found very low-certainty evidence suggesting that exenatide improves motor impairment as assessed by MDS-UPDRS Part III off medication (MD -4.50, 95% CI -8.64 to -0.36), exceeding the MCID. We are uncertain whether exenatide improves HRQoL as assessed by the PDQ-39 SI (MD 3.50, 95% CI -2.75 to 9.75; very low-quality evidence). We found very low-certainty evidence suggesting that exenatide has little or no effect on the number of SAEs (RR 1.60, 95% 0.40 to 6.32). We found very low-certainty evidence suggesting that exenatide may lead to weight loss (MD -2.40 kg, 95% CI -4.56 to -0.24). Primary outcomes at 24 months We found evidence as reported by study authors to suggest that exenatide improves motor impairment as measured by MDS-UPDRS Part III off medication (MD 5.6 points, 95% CI 2.2 to 9.0). Exenatide may not improve HRQoL as assessed by the PDQ-39 SI (P = 0.682) and may not result in weight loss (MD 0.1 kg, 95% CI 3.0 to 2.8). AUTHORS' CONCLUSIONS: Low- or very low-certainty evidence suggests that exenatide may improve motor impairment for people with PD. The difference in motor impairment observed between groups may persist for some time following cessation of exenatide. This raises the possibility that exenatide may have a disease-modifying effect. SAEs were unlikely to be related to treatment. The effectiveness of exenatide for improving HRQoL, non-motor outcomes, ADLs, and psychological outcomes is unclear. Ongoing studies are assessing other GLP-1 receptor agonists.


Asunto(s)
Exenatida/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Enfermedad de Parkinson/tratamiento farmacológico , Sesgo , Método Doble Ciego , Exenatida/administración & dosificación , Exenatida/efectos adversos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Placebos/administración & dosificación , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Autoadministración , Método Simple Ciego
5.
Eur J Neurosci ; 49(3): 307-315, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30269406

RESUMEN

The Linked Clinical Trials (LCT) initiative is a drug repurposing programme specifically aimed at identifying drugs that can slow the progression of Parkinson's disease (PD). Tom Isaacs was one of the key people behind the idea of LCT in 2011. He ensured it became a priority of The Cure Parkinson's Trust (CPT), a philanthropic funding body based in the UK which Tom had co-founded 7 years earlier. During the latter 6 years of his life, Tom Isaacs was heavily involved in the LCT initiative and held the programme dear to his heart. This article describes the genesis of LCT and how the LCT scientific committee evaluates candidate drugs. From 2012, this committee has met annually to prioritise drugs suitable for repurposing in PD. This article does not catalogue every clinical trial within the LCT programme, but describes the 10 clinical trials that emerged either directly, or as an offspring from discussions, at the first meeting of the LCT scientific committee. Some, but not all, are funded by CPT, and all 10 trials are now either completed or ongoing. These trials use drugs developed to address one of the four therapeutic targets: glucagon-like peptide 1 receptor, iron, and c-abl tyrosine kinase. We conclude the LCT programme has already sparked a large number of promising clinical trials aimed at slowing PD progression. In doing so, it is a major legacy of Tom Isaacs, carrying the torch he once lit and conveying a sense of urgency for new and life-transforming therapies for people with PD.


Asunto(s)
Ensayos Clínicos como Asunto/organización & administración , Reposicionamiento de Medicamentos , Enfermedad de Parkinson/tratamiento farmacológico , Humanos , Internacionalidad , Desarrollo de Programa
6.
Pak J Med Sci ; 31(4): 1018-20, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26430452

RESUMEN

Posterior dislocation of the shoulder is a rare injury that occurs secondary to trauma and seizures. Diagnosis is often missed and treatment is challenging. Neglected posterior dislocation is associated with Hill-Sachs lesion which leads to locking of dislocation. Correct diagnosis is achieved by history taking, a physical examination and appropriate imaging. In neglected shoulder dislocation with uncontrolled seizure and humeral head defects of up to 45% the McLaughlin procedure shows excellent results at follow-up.

8.
Front Aging Neurosci ; 16: 1308577, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38419648

RESUMEN

Background: The Rho-kinase (ROCK) inhibitor Fasudil has shown symptomatic and disease-modifying effects in Parkinson's disease (PD) models in vitro and in vivo. In Japan, Fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995 and shows a favourable safety profile. Objectives/design: To investigate the safety, tolerability, and symptomatic efficacy of ROCK-inhibitor Fasudil in comparison to placebo in a randomized, national, multicenter, double-blind phase IIa study in patients with PD. Methods/analysis: We plan to include 75 patients with at least 'probable' PD (MDS criteria), Hoehn and Yahr stages 1-3, and age 30-80 years in 13 German study sites. Patients must be non-fluctuating and their response to PD medication must have been stable for 6 weeks. Patients will be randomly allocated to treatment with the oral investigational medicinal product (IMP) containing either Fasudil in two dosages, or placebo, for a total of 22 days. As primary analysis, non-inferiority of low/high dose of Fasudil on the combined endpoint consisting of occurrence of intolerance and/or treatment-related serious adverse events (SAEs) over 22 days will be assessed in a sequential order, starting with the lower dose. Secondary endpoints will include tolerability alone over 22 days and occurrence of treatment-related SAEs (SARs) over 22 and 50 days and will be compared on group level. Additional secondary endpoints include efficacy on motor and non-motor symptoms, measured on established scales, and will be assessed at several timepoints. Biomaterial will be collected to determine pharmacokinetics of Fasudil and its active metabolite, and to evaluate biomarkers of neurodegeneration. Ethics/registration/discussion: After positive evaluation by the competent authority and the ethics committee, patient recruitment started in the 3rd quarter of 2023. ROCK-PD is registered with Eudra-CT (2021-003879-34) and clinicaltrials.gov (NCT05931575). Results of this trial can pave way for conducting extended-duration studies assessing both symptomatic efficacy and disease-modifying properties of Fasudil.

9.
J Parkinsons Dis ; 14(5): 899-912, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39031388

RESUMEN

Background: For the past five years, our annual reports have been tracking the clinical development of new drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD). These reviews have followed the progress both of "symptomatic treatments" (ST - improves/reduces symptoms of the condition) and "disease-modifying treatments" (DMT - attempts to delay/slow progression by addressing the underlying biology of PD). Efforts have also been made to further categorize these experimental treatments based on their mechanisms of action and class of drug. Methods: A dataset of clinical trials for drug therapies in PD using trial data downloaded from the ClinicalTrials.gov online registry was generated. A breakdown analysis of all the studies that were active as of January 31st, 2024, was conducted. This analysis involved categorizing the trials based on both the mechanism of action (MOA) and the drug target. Results: There were 136 active Phase 1-3 trials evaluating drug therapies for PD registered on ClinicalTrials.gov, as of January 31, 2024. Of these trials, 76 (56%) were classified as ST trials and 60 (44%) were designated DMT. More than half (58%) of the trials were in Phase 2 testing stage, followed by Phase 1 (30%) and Phase 3 (12%). 35 of the trials were registered since our last report, with the remaining 101 trials appearing in at least one earlier report. Conclusions: The drug development pipeline for PD remains in a robust state with a wide variety of approaches being developed and evaluated in Phase 1 and 2. Yet again, however, only a limited number of DMTs are transitioning to Phase 3.


The development of new medical therapies, particularly for neurodegenerative conditions, is a long process that involves multiple phases of testing before a treatment is approved for use in a doctor's clinic. The first phase assesses the short-term safety of a drug ­ most often in healthy volunteers but sometimes in people affected by the disease. The second phase explores the short-term safety and preliminary efficacy of the agent in people affected by the disease of interest, and the third phase investigates long-term safety and efficacy in a large group of people affected by the disease. For a disease like Parkinson's disease, where the causes of the condition are not well understood, drugs targeting different biological pathways need to be tested to determine which ones may be useful in treating the symptoms, and which could be administered to slow down or stop the progression of the condition. Here, we provide an annual report on the current landscape of both these clinical testing efforts. In total, we reviewed 136 active studies evaluating therapies for Parkinson's disease registered on a clinical trial database called 'ClinicalTrials.gov'. Of these trials, approximately 55% were testing experimental symptomatic treatments, while the rest were focused on slowing down disease progression. More than half (58%) of the studies were in the second phase of clinical testing (short-term safety and preliminary efficacy), but only three studies were found to be testing treatments to stop the progression of Parkinson's in the Phase 3 testing. We concluded that the drug development pipeline for Parkinson's is robust, but more progress needs to be made with late-stage testing of treatments to slow the disease.


Asunto(s)
Antiparkinsonianos , Ensayos Clínicos como Asunto , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/uso terapéutico
10.
PLoS One ; 19(9): e0309893, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39292705

RESUMEN

Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 10 million people worldwide. Ferroptosis, a recently identified form of regulated cell death characterized by 15-lipoxygenase-mediated hydroperoxidation of membrane lipids, has been implicated in neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Pharmacological inhibition of 15 -lipoxygenase to prevent iron- and lipid peroxidation-associated ferroptotic cell death is a rational strategy for the treatment of Parkinson's disease. We report here the characterization of PTC-041 as an anti-ferroptotic reductive lipoxygenase inhibitor developed for the treatment of Parkinson's disease. In these studies, PTC-041 potently protects primary human Parkinson's disease patient-derived fibroblasts from lipid peroxidation and subsequent ferroptotic cell death and prevents ferroptosis-related neuronal loss and astrogliosis in primary rat neuronal cultures. Additionally, PTC-041 prevents ferroptotic-mediated α-synuclein protein aggregation and nitrosylation in vitro, suggesting a potential role for anti-ferroptotic lipoxygenase inhibitors in mitigating pathogenic aspects of synucleinopathies such as Parkinson's disease. We further found that PTC-041 protects against synucleinopathy in vivo, demonstrating that PTC-041 treatment of Line 61 transgenic mice protects against α-synuclein aggregation and phosphorylation as well as prevents associated neuronal and non-neuronal cell death. Finally, we show that. PTC-041 protects against 6-hydroxydopamine-induced motor deficits in a hemiparkinsonian rat model, further validating the potential therapeutic benefits of lipoxygenase inhibitors in the treatment of Parkinson's disease.


Asunto(s)
Ferroptosis , Inhibidores de la Lipooxigenasa , Enfermedad de Parkinson , Animales , Ferroptosis/efectos de los fármacos , Inhibidores de la Lipooxigenasa/farmacología , Inhibidores de la Lipooxigenasa/uso terapéutico , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Ratas , Ratones , alfa-Sinucleína/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Araquidonato 15-Lipooxigenasa/metabolismo , Células Cultivadas , Masculino
11.
J Parkinsons Dis ; 14(4): 657-666, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38578902

RESUMEN

In 2011, the UK medical research charity Cure Parkinson's set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinson's disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.


Asunto(s)
Ensayos Clínicos como Asunto , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/uso terapéutico
12.
J Ayub Med Coll Abbottabad ; 25(1-2): 52-6, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-25098054

RESUMEN

BACKGROUND: Wheat allergy has been suggested to represent an important allergic disease. This study collates clinical and laboratory aspects in patients with wheat allergy in Al-Kharj city, Saudi Arabia. METHODS: Total and specific IgE were measured in 15 suspected cases of wheat allergy. Protein allergenicity was assessed with Western blotting. RESULTS: Significant elevation of total and specific IgE was found in 4 cases. Basophlia was also demonstrated on blood film. Western blotting results showed 2 bands (83 and 40 kDa). CONCLUSION: Wheat allergy must also be considered when planning treatment of asthma and eczema of adult patients.


Asunto(s)
Hipersensibilidad al Trigo/diagnóstico , Hipersensibilidad al Trigo/epidemiología , Adulto , Basófilos/metabolismo , Humanos , Inmunoglobulina E/sangre , Persona de Mediana Edad , Prevalencia , Arabia Saudita/epidemiología , Triticum/inmunología
13.
J Ayub Med Coll Abbottabad ; 25(1-2): 133-5, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-25098077

RESUMEN

BACKGROUND: The importance of specific animal allergy in immunopathology of asthma and atopic diseases remained to be defined. METHODS: We measured total and specific IgE. Western blotting of some allergens was also characterised. RESULT: There was a significant elevation of IgE in 3 persons among 15 samples collected. Western blotting showed common husbandry allergens from 3 sources that have common allergenicity. CONCLUSION: Exposure to animal products exacerbates allergic asthma in adults, suggesting that preventive measures should be taken to reduce their sensitivity.


Asunto(s)
Crianza de Animales Domésticos , Hipersensibilidad/diagnóstico , Enfermedades Profesionales/diagnóstico , Adulto , Animales , Asma/complicaciones , Humanos , Inmunoglobulina E/sangre , Persona de Mediana Edad
14.
J Parkinsons Dis ; 13(4): 427-439, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37302040

RESUMEN

BACKGROUND: Since 2020, annual reports on the clinical development of new drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD) have been generated. These reviews have followed the progress of both "symptomatic treatments" (ST - improves/reduces symptoms of the condition) and "disease modifying treatments" (DMT - attempts to delay/slow progression by addressing the underlying biology of PD). Additional efforts have been made to further categorize these experimental treatments based on their mechanisms of action and class of drug. METHODS: A dataset of clinical trials for drug therapies in PD was obtained using trial data downloaded from the ClinicalTrials.gov online registry. A breakdown analysis of all the studies that were active as of January 31st, 2023, was conducted. RESULTS: There was a total of 139 clinical trials registered on the ClinicalTrials.gov website as active (with 35 trials newly registered since our last report). Of these trials, 76 (55%) were considered ST and 63 (45%) were designated DMT. Similar to previous years, approximately a third of the studies were in Phase 1 (n = 47; 34%), half (n = 72, 52%) were in Phase 2 and there were 20 (14%) studies in Phase 3. Novel therapies again represented the most dominant group of experimental treatments in this year's report with 58 (42%) trials testing new agents. Repurposed drugs are present in a third (n = 49, 35%) of trials, with reformulations and new claims representing 19% and 4% of studies, respectively. CONCLUSIONS: Our fourth annual review of active clinical trials evaluating ST and DMT therapeutics for PD demonstrates that the drug development pipeline is dynamic and evolving. The slow progress and lack of agents transitioning from Phase 2 to Phase 3 is concerning, but collective efforts by various stakeholders are being made to accelerate the clinical trial process, with the aim of bringing new therapies to the PD community sooner.


Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico
15.
J Parkinsons Dis ; 12(4): 1073-1082, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35527571

RESUMEN

BACKGROUND: As the international community dealt with the ongoing COVID-19 pandemic, important progress continued to be made in the development of new drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD) in 2021. This progress included both "symptomatic treatments" (ST - improves/reduces symptoms of the condition) and "disease modifying treatments" (DMT - attempts to delay/slow progression by addressing the underlying biology of PD), which can be categorised further based on their mechanisms of action and class of drug. OBJECTIVE: This report continues previous efforts to provide an overview of the pharmacological therapies - both ST and DMT - in clinical trials for PD during 2021- 2022, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst all stakeholders, including industry, academia, advocacy organizations, and most importantly patient community. METHODS: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of January 31st 2022. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. RESULTS: There was a total of 147 clinical trials registered on the ClinicalTrials.gov website as active during the period of analysis. Of these trials, 91 (62%)were investigating STs, while 56 (38%)focused on DMTs. Approximately 1/3 of the studies (34.7%; 51 trials) were in Phase 1, while over half of the trials were in Phase 2 (50.3%; 74 trials). Only 15% (22 trials) of the studies were in Phase 3, of which only 3 trials were evaluating DMTs. Novel therapeutics (42%)were the most common type of agents being tested across all phases of testing, followed by repurposed agents (34%)and reformulations (20%). CONCLUSION: Despite significant global health constraints, the development of new drug-based therapies for PD continued in 2021. Hopefully with a shift towards a post-pandemic world in which COVID-19 is better managed, we will see an increase in the number of clinical trials focused on drug development for PD. The need for more Phase 3 studies for DMTs remains acute.


Asunto(s)
Desarrollo de Medicamentos , Enfermedad de Parkinson , COVID-19 , Ensayos Clínicos como Asunto , Humanos , Pandemias , Enfermedad de Parkinson/tratamiento farmacológico
16.
J Parkinsons Dis ; 12(1): 95-103, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34744054

RESUMEN

A recent breakthrough paper published in Science Translational Medicine has provided compelling evidence that inhibition of Parkin Interacting Substrate (PARIS) may offer clinical researchers an important new therapeutic approach since it shows considerable promise as an important biological target potentially capable of pharmaceutical intervention to slow long term neurodegeneration in patients with Parkinson's disease (PD). We present several PD-relevant perspectives on this paper that were not discussed in that otherwise entirely scientific narrative. We also outline the some of the work leading up to it, including the massive drug screen that proved necessary to discover a clinically suitable inhibitor of PARIS (Farnesol), as well as relevant PD research within the wider drug class, issues surrounding its future formulation, and next steps in translating this new knowledge into the clinic to evaluate possible long-term PD patient benefits.


Asunto(s)
Neuronas Dopaminérgicas , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Proteínas Represoras , Ubiquitina-Proteína Ligasas
17.
Front Neurosci ; 15: 653377, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33815053

RESUMEN

The international Linked Clinical Trials (iLCT) program for Parkinson's to date represents one of the most comprehensive drug repurposing programs focused on one disease. Since initial planning in 2010, it has rapidly grown - giving rise to seven completed, and 15 ongoing, clinical trials of 16 agents each aimed at delivering disease modification in Parkinson's disease (PD). In this review, we will provide an overview of the history, structure, process, and progress of the program. We will also present some examples of agents that have been selected and prioritized by the program and subsequently evaluated in clinical trials. Our goal with this review is to provide a template that can be considered across other therapeutic areas.

18.
J Parkinsons Dis ; 11(3): 891-903, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34151864

RESUMEN

BACKGROUND: Despite the COVID-19 pandemic, there has been considerable activity in the clinical development of novel and improved drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD) during 2020. The agents that were investigated can be divided into "symptomatic" (alleviating the features of the condition) and "disease modifying" (attempting to address the underlying biology of PD) treatments, ST and DMT respectively, with further categorisation possible based on mechanism of action and class of therapy. OBJECTIVE: Our goal in this report was to provide an overview of the pharmacological therapies -both ST and DMT - in clinical trials for PD during 2020-2021, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst commercial and academic researchers as well as between the research and patient communities. METHODS: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of February 18th 2021. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. RESULTS: We identified 142 trials on ClinicalTrials.gov and 14 studies on the WHO registries that met our analysis criteria. Of these 156 trials, 91 were ST and 65 were DMT, Of the 145 trials registered on ClinicalTrials.gov in our 2020 analysis, 45 fell off the list and 42 were added. Despite this change, the balance of ST to DMT; the distribution across phases; the profile of therapeutic categories; and the proportion of repurposed therapies (33.5%); all remained very similar. There are only two DMTs in phase 3, and we identified 33 in-between-phase projects. CONCLUSIONS: Despite the effects of the coronavirus pandemic, investment and effort in clinical trials for PD appears to remain strong. There has been little change in the profile of the clinical trial landscape even though, over the past year, there has been considerable change to the content of the list.


Asunto(s)
Antiparkinsonianos , Ensayos Clínicos como Asunto/estadística & datos numéricos , Desarrollo de Medicamentos , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/uso terapéutico , COVID-19 , Humanos
19.
Parkinsonism Relat Disord ; 90: 134-141, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34561166

RESUMEN

OBJECTIVE: Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials' failures to demonstrate disease-modifying benefit, and potential solutions. METHODS: The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD. RESULTS: Important lessons can be learned from previous attempts, as well as from other fields. The selection process for therapeutic targets and agents differs among various organizations committed to therapeutic development. The areas identified as critical to target in future research include the development of relevant biomarkers, refinements of the targeted patient populations, considerations of novel trial designs, and improving collaborations between all stakeholders. CONCLUSIONS: We identify potential barriers to progress in disease modification for Parkinson's and propose a set of research priorities that may improve the likelihood of success.


Asunto(s)
Descubrimiento de Drogas , Enfermedad de Parkinson/tratamiento farmacológico , Biomarcadores/análisis , Humanos , National Institute of Neurological Disorders and Stroke (U.S.) , Estados Unidos
20.
JAMA Neurol ; 78(3): 312-320, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33315105

RESUMEN

Importance: There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD). Objectives: To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers. Design, Setting, and Participants: This was a 6-month, multicenter, randomized parallel-group, double-blind, placebo-controlled trial. Recruitment was from November 20, 2017, to December 28, 2018, and follow-up ended on September 9, 2019. The study was conducted at 25 US sites. The study approached 173 patients, of whom 48 declined, 125 were screened, and 76 who received a stable regimen of PD medications were enrolled (39% screen failure). Interventions: Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by 2-month off-drug evaluation. Main Outcomes and Measures: The primary outcomes were safety and tolerability. The tolerability end point was defined as the ability to complete the study while receiving the assigned dose. An active arm was considered tolerable if the percentage of participants meeting the tolerability end point for that group was not significantly lower than the percentage observed in the placebo group. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinson's Disease Rating Scale [MDS-UPDRS], Part II OFF/ON). Exploratory outcomes included serum and CSF pharmacokinetic profile, and CSF dopaminergic biomarkers. Results: At baseline, mean (SD) participants' age was 64.6 (7.5) years, 52 were male (68%), mean (SD) disease duration was 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score was 66.4 (19.3), ON score was 48.4 (16.2), and Montreal Cognitive Assessment score was 27.1 (2.2). The number of participants who completed the study receiving the assigned dose were 21 (84%), 19 (76%), and 20 (77%) in the placebo, 150-mg, and 300-mg arms, respectively. Both active doses had acceptable safety profile. The most common reasons for drug suspension were asymptomatic, dose-dependent elevations of amylase, and/or lipase. Nilotinib, 150 mg and 300 mg, exhibited worse MDS-UPDRS-3 ON scores compared with placebo, achieving significance for nilotinib, 300 mg, at month 1 (P < .01). There was no difference in the change of MDS-UPDRS-3 OFF from baseline to 6 months between groups (P = .17). Cerebrospinal fluid/serum ratio of nilotinib concentration was 0.2% to 0.3%. There was no evidence of treatment-related alteration of dopamine metabolites in the CSF. Conclusions and Relevance: While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low CSF exposure and lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in PD. Trial Registration: ClinicalTrials.gov Identifier: NCT03205488.


Asunto(s)
Progresión de la Enfermedad , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Proteínas Tirosina Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Pirimidinas/metabolismo , Resultado del Tratamiento
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