Opicapone, a Novel Catechol-O-methyl Transferase Inhibitor, for Treatment of Parkinson's Disease "Off" Episodes.

Parkinson's Disease (PD) is a common neurodegenerative disorder and the leading cause of disability. It causes significant morbidity and disability through a plethora of symptoms, including movement disorders, sleep disturbances, and cognitive and psychiatric symptoms. The traditional pathogenesis theory of PD involves the loss of dopaminergic neurons in the substantia nigra (SN). Classically, treatment is pursued with an assortment of medications that are directed at overcoming this deficiency with levodopa being central to most treatment plans. Patients taking levodopa tend to experience "off episodes" with decreasing medication levels, causing large fluctuations in their symptoms. These off episodes are disturbing and a source of morbidity for these patients. Opicapone is a novel, peripherally acting Catechol-O-methyl transferase (COMT) inhibitor that is used as adjunctive therapy to carbidopa/levodopa for treatment and prevention of "off episodes." It has been approved for use as an adjunct to levodopa since 2016 in Europe and has recently (April 2020) gained FDA approval for use in the USA. By inhibiting COMT, opicapone slows levodopa metabolism and increases its availability. Several clinical studies demonstrated significant improvement in treatment efficacy and reduction in duration of "off episodes." The main side effect demonstrated was dyskinesia, mostly with the 100mg dose, which is higher than the approved, effective dose of 50mg. Post-marketing surveillance and analysis are required to further elucidate its safety profile and contribute to patient selection. This paper reviews the seminal and latest evidence in the treatment of PD "off episodes" with the novel drug Opicapone, including efficacy, safety, and clinical indications.

Opicapone for the Treatment of Parkinson's Disease "Off" Episodes: Pharmacology and Clinical Considerations.

Parkinson's disease (PD) is a common neurodegenerative disorder. It is also the fastest-growing neurodegenerative disorder and has more than doubled between 1990 and 2016. Parkinson's disease causes significant morbidity and disability from motor dysfunction, sleep disturbances, and cognitive and psychiatric symptoms. This paper reviews recent evidence in the treatment of PD "off" episodes with the novel drug opicapone, including its efficacy, safety, and clinical indications. Opicapone is a novel, peripherally acting catechol-O-methyl transferase (COMT) inhibitor used as adjunctive therapy to carbidopa/levodopa for treatment and prevention of "off" episodes. It has been approved for use as an adjunct to levodopa since 2016 in Europe and has recently (April 2020) gained FDA approval for use in the USA. By inhibiting COMT, opicapone slows levodopa metabolism and increases its availability. Several clinical studies demonstrated significant improvement in treatment efficacy and reduction in the duration of "off" episodes The main side effect demonstrated was dyskinesia, mostly with the 100 mg dose, which is higher than the approved, effective dose of 50 mg.

Monomethyl Fumarate (MMF, Bafiertam) for the Treatment of Relapsing Forms of Multiple Sclerosis (MS).

Multiple sclerosis (MS) is a prevalent neurologic autoimmune disorder affecting two million people worldwide. Symptoms include gait abnormalities, perception and sensory losses, cranial nerve pathologies, pain, cognitive dysfunction, and emotional aberrancies. Traditional therapy includes corticosteroids for the suppression of relapses and injectable interferons. Recently, several modern therapies-including antibody therapy and oral agents-were approved as disease-modifying agents. Monomethyl fumarate (MMF, Bafiertam) is a recent addition to the arsenal available in the fight against MS and appears to be well-tolerated, safe, and effective. In this paper, we review the evidence available regarding the use of monomethyl fumarate (Bafiertam) in the treatment of relapsing-remitting MS.

Software for designing rigorous and replicable preclinical research: The Experimental Design Accelerator.

In recent years, there have been concerns about research practices in basic and preclinical biomedical research. There have been problems with non-replicable results, and experimental designs lacking internal validity or external or translational validity. The Experimental Design Accelerator (XDA) is Internet-based, interactive software designed to help those trying to design, conduct and document rigorous, replicable and relevant experiments. It leads the investigator step-by-step through a series of decisions that will define the experimental design. It provides background regarding the significance of each decision and the advantages and disadvantages of each possible choice. For example, it leads the researcher to address issues such as choosing a research model, developing testable hypotheses, identifying extraneous variables, dealing with random and systematic error, picking appropriate sample size and picking appropriate statistical analyses. There are also sections to help conduct the experiment consistent with its design and to document the study to facilitate accurate replication. Helpful features include access to an online statistics book and provisions for rapid contact with consulting experts. A number of potential uses for such novel interactive software tools will be discussed.

A subtype-specific neuropeptide FF receptor antagonist attenuates morphine and nicotine withdrawal syndrome in the rat.

Considerable evidence suggests the Neuropeptide FF (NPFF) and related peptides exert pro-nociceptive and anti-opiate actions, particularly at the supra-spinal level, which may contribute to opiate dependence. The FF1 receptor subtype appears to be primarily responsible for anti-opiate effects. In contrast, stimulation of the FF2 receptor primarily induces pro-opiate effects. AC-262620 is a small molecule, systemically active, selective FF1 receptor antagonist. An initial experiment showed that 10 mg/kg i.p. AC-262620 significantly reduced subsequent naloxone-precipitated somatically expressed withdrawal signs in rats infused s.c. for seven days with 0.3 mg/kg/hr morphine sulfate. A second experiment showed that the same dose of AC-262620 significantly reduced subsequent spontaneous withdrawal signs 23.75 h after termination of seven days s.c. infusion of 0.6 mg/kg/hr morphine sulfate. Chronic nicotine intake may contribute to dependence by overstimulating opiate receptors through release of opiate peptides. By analogy to opiate dependence, it was hypothesized that FF1 receptor activation contributes to nicotine dependence and withdrawal syndrome. AC-262620 significantly reduced somatically expressed withdrawal signs precipitated by the nicotinic antagonist mecamylamine in rats infused for seven days with nicotine bitartrate. Taken together, these findings suggest that NPFF or related neuropeptides contribute to opiate, as well as nicotine, dependence and withdrawal syndrome through the FF1 receptor.

Validation and scopolamine-reversal of latent learning in the water maze utilizing a revised direct platform placement procedure.

The Morris water maze is routinely used to explore neurobiological mechanisms of working memory. Humans can often acquire working memory relevant to performing a task by mere sensory observation, without having to actually perform the task followed by reinforcement. This can be modeled in the water maze through direct placement of a rat on the escape platform so that it can observe the location, and then assessing the subject's performance in swimming back to the platform. However, direct placement procedures have hardly been studied for two decades, reflecting a controversy about whether direct placement resulted in sufficiently rapid and direct swims back to the platform. In the present study, utilizing revised training methods, a more comprehensive measure of trajectory directness, a more rigorous sham-trained control procedure and an optimal placement-test interval, rats swam almost directly back to the platform in under 4s, significantly more quickly and directly than sham-trained subjects. Muscarinic cholinergic mechanisms, which are inactivated by scopolamine, are essential to memory for standard learning paradigms in the water maze. This experiment determined whether this would also be true for latent learning. ANOVA revealed significant negative effects of scopolamine on both speed and accuracy of trajectory, as well as significant positive effects of direct placement training vs. sham-training. In a probe trial, placement-trained animals without scopolamine spent significantly more time and path length in the target quadrant than trained rats with scopolamine and sham-trained rats without scopolamine. Scopolamine impairments are likely due to effects on memory, since the same dose had little effect on performance with a visible platform. The revised direct placement model offers a means of further comparing the neural mechanisms of latent learning with those of standard instrumental learning.

Reversal of morphine tolerance by a compound with NPFF receptor subtype-selective actions.

Neuropeptide FF (NPFF) modulates opiate actions. It has pro-nociceptive effects, primarily through the NPFF receptor 1 subtype, and anti-nociceptive effects, primarily through the NPFFR2 subtype. AC-263093 is a small l, organic, systemically active molecule that was previously shown to functionally activate NPFFR2, but not NPFFR1. It was hypothesized that AC-263093 would attenuate morphine tolerance. Rats were tested for radiant heat tail-flick latency before and after 5 mg/kg morphine sulfate s.c. They were then rendered morphine-tolerant by continuous subcutaneous infusion of 17.52 mg/kg/day morphine sulfate. On the seventh day of infusion, they were retested for analgesia 10 and 20 min after 5mg/kg morphine sulfate s.c. Tolerance was indicated by reduction of morphine analgesia from the pre-infusion test. Fifty minutes prior to morphine challenge, rats received either 10 mg/kg i.p. AC-263093 or injection vehicle alone. AC-2623093-treated rats had far smaller tolerance scores than control rats. This drug effect was significant, p = 0.015. The same dose of AC-263093 had almost no analgesic effect in non-tolerant, saline-infused rats. In vitro experiments revealed that AC-263093 had equal affinity for NPFFR1 and NPFFR2, and functionally inactivated NPFFR1, in addition to its previously shown ability to activate NPFFR2. Thus, altering the balance between activation of NPFF receptor subtypes may provide one approach to reversing opiate tolerance.