Levomet (melevodopa) / Chiesi - LARVOL DELTA

Axon terminal hypertrophy of striatal projection neurons with levodopa-induced dyskinesia priming (MDS Congress 2023) - "Increased GABA storage in axon terminals of the direct pathway neurons represents the priming process of LID."

CNS Disorders • Parkinson's Disease

Human aromatic amino acid decarboxylase is an asymmetric and flexible enzyme: implication in AADC deficiency. (PubMed, Protein Sci) - "Here, for the first time, we solved the crystal structure of human holoAADC in the internal aldimine (1.9 Å) and in the external aldimine (2.4 Å) of the substrate analog L-Dopa methylester...The structural integrity of this peripheral protein region is essential to catalysis, as assessed by both artificial and 37 AADC deficiency pathogenic variants leading to the interpretation that structural dynamics in protein regions far from the active site is essential for catalytic loop flexibility and the acquirement of a correct catalytically competent structure. This could represent the molecular basis for pathogenicity prediction in AADC deficiency."

Journal • CNS Disorders • Genetic Disorders • Movement Disorders • Parkinson's Disease • Targeted Protein Degradation

Axon terminal hypertrophy of striatal projection neurons with levodopa-induced dyskinesia priming. (PubMed, Front Neurosci) - "6-hydroxydopamine-lesioned hemiparkinsonian rats were randomly allocated to receive saline injections (placebo group, 14 days; n = 4), injections of 6 mg/kg levodopa methyl ester combined with 12.5 mg/kg benserazide (levodopa-treated groups, 3-day-treatment; n = 4, 7-day-treatment; n = 4, 14-day-treatment; n = 4), or injections of 6 mg/kg levodopa methyl ester with 12.5 mg/kg benserazide and 1 mg/kg 8-hydroxy-2-(di-n-propylamino)tetralin for 14 days (8-OH-DPAT-treated group; n = 4). The AIM score increased with levodopa treatment, as did the hypertrophy of axon terminals in the GPi, showing an increased number of synaptic vesicles in hypertrophied terminals. Increased GABA storage in axon terminals of the direct pathway neurons represents the priming process of LID."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Development and Validation of a New LC-MS/MS Bioanalytical Method for the Simultaneous Determination of Levodopa, Levodopa Methyl Ester, and Carbidopa in Human Plasma Samples. (PubMed, Molecules) - "Reinjection reproducibility was assessed. The described method was successfully applied to a 45-year-old male patient to compare the pharmacokinetic behavior of an L-DOPA-based medical treatment involving commercially available Mucuna pruriens extracts and an LDME/carbidopa (100/25 mg) formulation."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Coupling between GPR143 and dopamine D2 receptor is required for selective potentiation of dopamine D2 receptor function by L-3,4-dihydroxyphenylalanine in the dorsal striatum. (PubMed, J Neurochem) - "Administration of non-effective dose of L-DOPA methyl ester augmented the quinpirole-induced hypolocomotion in WT mice but not in Gpr143 mice...Intracerebroventricular administration of a peptide that disrupted the interaction mitigated quinpirole-induced behavioral changes in WT mice but not in Gpr143 mice. These findings provide evidence that coupling between GPR143 and DRD2 is required for selective DRD2 modulation by L-DOPA in the dorsal striatum."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • DRD1 • DRD2 • GPR143

Preparation and detailed characterization of the thiomer chitosan-cysteine as a suitable mucoadhesive excipient for nasal powders. (PubMed, Int J Pharm) - "Thereafter, nasal powder formulations were prepared using the polymer and the antiparkinsonian drug levodopa methyl ester hydrochloride by freeze-drying to investigate their nasal applicability. Based on the in vitro studies, these powders might be suitable for reducing the off periods of Parkinson's disease because of their expected higher in vivo mucoadhesion."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

A Bio-Based Supramolecular Adhesive: Ultra-High Adhesion Strengths at both Ambient and Cryogenic Temperatures and Excellent Multi-Reusability. (PubMed, Adv Sci (Weinh)) - "Herein, castor oil, melevodopa, and iron ions are used as building blocks to construct a novel bio-based supramolecular adhesive (BSA) with outstanding adhesion performances...In addition, the BSA displays excellent multi-reusability with more than 87% of the original adhesion strength remaining even after reuse for ten times. It is highly anticipated that this line of research will provide a new insight into designing bio-based adhesives with outstanding adhesion performances and excellent multi-reusability."

Journal

Phosphodiesterase 9 inhibition prolongs the antiparkinsonian action of l-DOPA in parkinsonian non-human primates. (PubMed, Neuropharmacology) - "PDE9i was administered as monotherapy and co-administration with l-DOPA at two predetermined doses (suboptimal and threshold s.c. doses of l-Dopa methyl ester plus benserazide) using a controlled blinded protocol to assess motor disability, l-DOPA -induced dyskinesias (LID), and other neurologic drug effects...These results indicate that cGMP upregulation interacts with dopamine signaling to enhance the l-DOPA reversal of parkinsonian motor disability. Therefore, striatal PDE9 inhibition may be further explored as a strategy to improve motor responses to l-DOPA in PD."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Development of a Novel MR Colonography via Iron-Based Solid Lipid Nanoparticles. (PubMed, Int J Nanomedicine) - "SLNs were prepared with the simultaneous loading of trivalent Fe ions (Fe), levodopa methyl ester (DM), and fluorescein isothiocyanate (FITC)...Confocal fluorescence microscopy confirmed that FeDM-FITC-SLNs were mainly distributed in the intestinal mucosa and tumor capsule. Iron-based SLNs are promising alternatives for contrast enhancement at T1-weighted MRI and will help in the differential diagnosis of intestinal bowel diseases (IBDs)."

Journal • Colorectal Adenocarcinoma • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Oncology • Ulcerative Colitis

Development of a Hydrophobicity-Controlled Delivery System Containing Levodopa Methyl Ester Hydrochloride Loaded into a Mesoporous Silica. (PubMed, Pharmaceutics) - "The API was successfully loaded into the silica, resulting in a reduced surface area. The release studies indicated that the release rate significantly decreased (p < 0.05) with increasing hydrophobicity. The products with controlled release can reduce the off period frequency."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Comparison of patient rated treatment response with measured improv ement in Parkinson's disease (J Neurol Neurosurg Psychiatry) - P=NA, N=133; PD pts' subjective ratings of their degree of improvement often do not accurately reflect the degree of objective change in parkinsonian impairment or disability; Clinicians should record a simple measure of motor impairment before and after treatment to assess treatment response more accurately

Clinical data • Parkinson's Disease

Partial Tablet Coating by 3D Printing. (PubMed, Int J Pharm) - "The aim of this work was to partially coat tablets with a glyceride, namely Precirol ATO 5 using a semi-solids 3D printer as an approach for tuning the release of two Active Pharmaceutical Ingredients (APIs), the hydrophilic methyl-levodopa hydrochloride (Melevodopa) and the lipophilic Acyclovir. The percentage of the tablet surface coated, the number of coating layers as well as the coated sides of the tablet where the parameters which controlled the release profile for both APIs. Different dissolution profiles have been achieved by tuning these simple parameters, which revealed a non-Fickian release mechanism regardless of the API."

Journal • APP

A systematic review on the clinical experience with melevodopa/carbidopa fixed combination in patients with Parkinson disease. (PubMed, Minerva Med) - "Data from literature have shown that melevodopa/carbidopa in a highly soluble formulation as effervescent oral tablets is effective in improving control of motor complications in PD patients compared to conventional levodopa. Further research is needed to confirm this evidence in large controlled trials and to explore if melevodopa/carbidopa may have a potential role in the earlier phases of the disease or in special PD populations."

Clinical • Journal • Review