Targeting ferroptosis with the lipoxygenase inhibitor PTC-041 as a therapeutic strategy for the treatment of Parkinson's disease.

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.

Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2024 Update.

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.

Trial of Lixisenatide in Early Parkinson's Disease.

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.

Twelve Years of Drug Prioritization to Help Accelerate Disease Modification Trials in Parkinson's Disease: The International Linked Clinical Trials Initiative.

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.

Protocol for a randomized, placebo-controlled, double-blind phase IIa study of the safety, tolerability, and symptomatic efficacy of the ROCK-inhibitor Fasudil in patients with Parkinson's disease (ROCK-PD).

Background: The Rho-kinase (ROCK) inhibitor Fasudil has shown symptomatic and disease-modifying effects in Parkinson's disease (PD) models and . 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.

Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2023 Update.

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.

Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2022 Update.

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.

Re-Analysis of the STEADY-PD II Trial-Evidence for Slowing the Progression of Parkinson's Disease.

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.

Waiting for PARIS-A Biological Target in Search of a Drug.

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.

Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2021 Update.

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.

Drug Repurposing for Parkinson's Disease: The International Linked Clinical Trials experience.

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.

The Parkinson's Disease Comprehensive Response (PDCORE): a composite approach integrating three standard outcome measures.

There is an increasing need for improved endpoints to assess clinical trial effects in Parkinson's disease. We propose the Parkinson's Disease Comprehensive Response as a novel weighted composite endpoint integrating changes measured in three established Parkinson's outcomes, including: OFF state Movement Disorder Society Unified Parkinson's Disease Rating Scale Motor Examination scores; Motor Experiences of Daily Living scores; and total good-quality ON time per day. The data source for the initial development of the composite described herein was a recent Phase II trial of glial cell line-derived neurotrophic factor.

Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease: A Randomized Clinical Trial.

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.

Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2020.

Background: The majority of current pharmacological treatments for Parkinson's disease (PD) were approved for clinical use in the second half of the last century and they only provide symptomatic relief. Derivatives of these therapies continue to be explored in clinical trials, together with potentially disease modifying therapies that can slow, stop or reverse the condition.

Objective: To provide an overview of the pharmacological therapies- both symptomatic and disease modifying- currently being clinically evaluated for PD, with the goal of creating greater awareness and opportunities for collaboration amongst commercial and academic researchers as well as between the research and patient communities.

GDNF and Parkinson's Disease: Where Next? A Summary from a Recent Workshop.

The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN).

Novel approaches to counter protein aggregation pathology in Parkinson's disease.

The primary neuropathological characteristics of the Parkinsonian brain are the loss of nigral dopamine neurons and the aggregation of alpha synuclein protein. Efforts to development potentially disease-modifying treatments have largely focused on correcting these aspects of the condition. In the last decade treatments targeting protein aggregation have entered the clinical pipeline.

The Linked Clinical Trials initiative (LCT) for Parkinson's disease.

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.

Parkinson Matters.

Recent epidemiological observations have drawn attention to the rapid rise in the burden caused by Parkinson's disease over the past years, emphasizing that Parkinson's disease is a matter of serious concern for our future generations. A recent report by Public Health England corroborates this message, by providing new insight on trends in deaths associated with neurological diseases in England between 2001 to 2014. The report indicates that mortality associated with Parkinson's disease and related disorders increased substantially between 2001 and 2014.

Nilotinib - Differentiating the Hope from the Hype.

We discuss a report in the current issue on clinical and biochemical findings from a safety trial using the cAbl tyrosine kinase inhibitor Nilotinib (150 mg or 300 mg given daily for 24 weeks) in a small group of patients with either advanced Parkinson's disease or Dementia with Lewy Bodies. Despite some side effects (one serious), the authors claim that Nilotinib, which is normally used at much higher doses for treating leukemia, is safe and tolerated. Furthermore, they report a possible benefit on motor and cognitive outcomes.

Neglected Bilateral Posterior Shoulder Fracture Dislocation in an Uncontrolled Seizure patient.

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.

Linked clinical trials--the development of new clinical learning studies in Parkinson's disease using screening of multiple prospective new treatments.

Finding new therapies for Parkinson's disease (PD) is a slow process. We assembled an international committee of experts to examine drugs potentially suitable for repurposing to modify PD progression. This committee evaluated multiple drugs currently used, or being developed, in other therapeutic areas, as well as considering several natural, non-pharmaceutical compounds.

Animal allergy among husbandry personnel in Riyadh.

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.

Prevalence of wheat allergy in Al-Kharj, Saudi Arabia.

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.

Cellular and molecular aspects of Goodpasture syndrome.

Goodpasture syndrome, a rare human autoimmune disorder, is characterized by the presence of pathogenic autoantibodies that react with the components of the glomerular basement membrane. The clinical condition of the Goodpasture syndrome is characterized by an acute necrotizing glomerulonephritis, often with accompanying pulmonary hemorrhage. Notably, the Goodpasture antigen has been localized to the noncollagenous domain of the alpha3 chain of type IV collagen.

Original Article: Investigation of Bcl-2 and PCNA in Hepatocellular Carcinoma: Relation to Chronic HCV.

Background And Objective: Bcl-2 family members can be functionally divided into anti-apoptotic and proapoptotic groups. The balance between these two groups may determine the fate of tumor cells. In hepatocellular carcinoma (HCC), this balance is often tilted towards the anti-apoptotic members in tumor cells, leading to resistance to cell death and rapid proliferation.