The Interplay of Mitochondrial Bioenergetics and Dopamine Agonists as an Effective Disease-Modifying Therapy for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurological ailment with a slower rate of advancement that is more common in older adults. The biggest risk factor for PD is getting older, and those over 60 have an exponentially higher incidence of this condition. The failure of the mitochondrial electron chain, changes in the dynamics of the mitochondria, and abnormalities in calcium and ion homeostasis are all symptoms of Parkinson's disease (PD). Increased mitochondrial reactive oxygen species (mROS) and an energy deficit are linked to these alterations. Levodopa (L-DOPA) is a medication that is typically used to treat most PD patients, but because of its negative effects, additional medications have been created utilizing L-DOPA as the parent molecule. Ergot and non-ergot derivatives make up most PD medications. PD is successfully managed with the use of dopamine agonists (DA). To get around the motor issues produced by L-DOPA, these dopamine derivatives can directly excite DA receptors in the postsynaptic membrane. In the past 10 years, two non-ergoline DA with strong binding properties for the dopamine D2 receptor (D2R) and a preference for the dopamine D3 receptor (D3R) subtype, ropinirole, and pramipexole (PPx) have been developed for the treatment of PD. This review covers the most recent research on the efficacy and safety of non-ergot drugs like ropinirole and PPx as supplementary therapy to DOPA for the treatment of PD.

Induced pluripotent stem cells-based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis.

It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs-based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs-based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS-specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double-blind, randomized, placebo-controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient-derived iPSCs-motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA-seq data showed that ROPI treatment suppressed the sterol regulatory element-binding protein 2-dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.

Maiden voyage: induced pluripotent stem cell-based drug screening for amyotrophic lateral sclerosis.

Using patient-derived induced pluripotent stem cells, neurodegenerative disease phenotypes have been recapitulated and their pathogenesis analysed leading to significant progress in drug screening. In amyotrophic lateral sclerosis, high-throughput screening using induced pluripotent stem cells-derived motor neurons has identified candidate drugs. Owing to induced pluripotent stem cell-based drug evaluation/screening, three compounds, retigabine, ropinirole and bosutinib, have progressed to clinical trials. Retigabine blocks hyperexcitability and improves survival in amyotrophic lateral sclerosis patient-derived motor neurons. In a randomized clinical trial (n = 65), treatment with retigabine reduced neuronal excitability after 8 weeks. Ropinirole, identified in a high-throughput screening, attenuates pathological phenotypes in patient-derived motor neurons. In a trial limited by a small sample size (n = 20), ropinirole was tolerable and had clinical benefits on function and survival. A phase 1 study of bosutinib has reported safety and tolerability for 12 weeks. Thus, these clinical trials show safety and positive effects and confirm the reliability of stem cell-based drug discovery. This novel strategy leads to reduced costs and time when compared to animal testing and opens new avenues for therapy in intractable diseases.

Development of Eudragit RS 100 Microparticles Loaded with Ropinirole: Optimization and In Vitro Evaluation Studies.

The current study aimed to develop novel pH independent microparticles loaded with ropinirole (ROP) for sustained drug release. Eudragit RS 100 was used as release retardant and microparticles were fabricated by oil-in-oil emulsion solvent evaporation method. A three-factor three-level Box-Behnken design using Design-Expert software was employed to optimize formulation variables. Ropinirole loaded microparticles were evaluated with respect to morphology, particle size, encapsulation efficiency, and in vitro release profile. Optical microscopy and SEM micrographs indicated spherical shape with smooth surface and well-defined boundary. The particle size was in the range of 98.86 to 236.29 µm, being significantly increased with increasing polymer concentration. Higher polymer load also increased the thickness of internal polymer network, which led to reduced drug loss and higher entrapment efficiency (89%). The cumulative in vitro release was found to be in the range of 54.96 to 99.36% during the release studies (12 h) following zero order release kinetics and non-Fickian diffusion pattern. The developed microparticles have the potential to sustain the release of ropinirole, which may lead to a reduction in its adverse effects and improved management of Parkinson's disease.

Metabolic changes in de novo Parkinson's disease after dopaminergic therapy: A proton magnetic resonance spectroscopy study.

The aim of this study was to assess metabolic changes in the motor cortex in de novo Parkinson's disease (PD) patients before and after therapy with ropinirole. Twenty de novo drug-naïve PD patients and 15 healthy controls underwent conventional magnetic resonance imaging and proton magnetic resonance spectroscopy imaging ((1)H-MRSI). The resonance intensities of N-acetylaspartate (NAA) and choline (Cho) were normalized for the resonance intensities of creatine (Cr). At baseline, lower NAA/Cr and NAA/Cho ratios and higher Cho/Cr ratios were found in the motor cortex of PD patients compared with controls (p<0.001). Ten months after ropinirole treatment, PD patients showed a significant clinical improvement in the UPDRS motor sub-scores (p<0.001) and an increase of NAA/Cr and NAA/Cho ratios (p<0.006 and p=0.01, respectively). A highly significant correlation between NAA/Cr and NAA/Cho ratios and UPDRS motor sub-scores was observed (r=-0.981 and r=-0.983, respectively). We could argue that the ropinirole efficacy to improve the motor performances is the result of partial restoration of neuronal functions, due to the increase of NAA in motor cortex.

Pharmacologic Treatment of Restless Legs Syndrome / 대한정신약물학회지

Restless legs syndrome (RLS) is defined as the urge to move one's legs, accompanied by unpleasant sensations in one's limbs, and is typically more severe at night. Sleep hygiene measures should be recommended and all causes of secondary RLS such as iron deficiency and medications (antidepressants, antiemetics, antipsychotics, and antihistamines) should be excluded before pharmacological treatment of RLS is initiated. In view of evidence of their efficacy and tolerability, ropinorole, pramipexole, gabapentin, and oral iron should be considered as first-line treatments for RLS. Ropinirole and pramipexole are the only drugs approved for the treatment of RLS in Korea. Ropinirole is metabolized by cytochrome P450 1A2 in the liver. On the other hand, pramipexole is metabolized only to a minor degree, and urinary excretion is the major route of elimination; thus, doses of pramipexole should be reduced in patients with impaired renal functioning. Gabapentin, which is known to be effective for pain and sleep disturbances in patients with RLS, is also secreted unmodified by the kidneys. An oral iron supplement is recommended for patients with low normal serum ferritin levels (< or = 75 ng/mL). Levodopa, pergolide, cabergoline, valproic acid, carbamazepine, and IV iron dextran are classified as second-line treatments. Clonazepam, bupropion, and some opioids can also be used in patients with RLS. In conclusion, pharmacological treatment of RLS should be individualized according to the physical status of patients as well as their RLS symptoms, and augmentation should be carefully monitored when dopaminergic agents are used for long periods.

Ropinirole for the treatment of restless legs syndrome.

Dopaminergic agents, anticonvulsants, benzodiazepines, opiates, and iron supplementation comprise the classes of medications commonly used to treat restless legs syndrome (RLS), which is a disorder that is estimated to affect about 1 in 10 individuals worldwide and impacts an affected patient's sleep, mood, daytime function, and quality of life. RLS is characterized by an urge to move the legs that is worse at bedtime and at rest; the symptoms are temporarily relieved by leg movement. It is frequently accompanied by periodic limb movements during sleep (PLMS), which may independently disrupt sleep and may cause daytime drowsiness. Dopaminergic agents are considered to be first-line therapy in the management of RLS as well as PLMS. Ropinirole (Requip((R)), GlaxoSmithKline) is a dopamine agonist that was the first medication approved by the US Food and Drug Administration (FDA) for the treatment of moderate-to-severe primary RLS. Based on several large-scale clinical trials and open-label clinical series, this medication has been demonstrated to be effective and safe in treating the motor symptoms of RLS and improving sleep quality.