Atremorine

Atremorine (E-PodoFavalin-15999) is a novel biopharmaceutical product obtained by non-denaturing biotechnological processing of structural components of Vicia faba L. (the broad bean or fava bean), developed at the EuroEspes Biomedical Research Center (now International Center of Neuroscience and Genomic Medicine, Bergondo, A Coruna, Spain) under the direction of Ramon Cacabelos for the prevention and treatment of Parkinson's disease (PD) and related dopamine-dependent disorders. Unlike synthetic levodopa (L-DOPA) formulations, Atremorine is a complex bioproduct containing a standardized concentration of approximately 25 mg of natural L-DOPA per gram of product, together with vegetal proteins, unsaturated fatty acids, minerals, vitamins, vegetal fiber, starch, carotenoid pigments, and phytosterols, all of which are proposed to contribute synergistically to its pharmacological activity and to confer neuroprotective properties absent from purified synthetic L-DOPA.

Preclinical studies in cell culture (human neuroblastoma SH-SY5Y cells, hippocampal slices under oxygen-glucose deprivation, striatal slices under 6-hydroxydopamine-induced neurotoxicity) and in animal models (MPTP-induced parkinsonism in mice) have demonstrated that Atremorine protects dopaminergic neurons against neurotoxic insult, inhibits microglial activation, and improves motor function [1, 2, 3]. Clinical studies in over 600 Parkinson's disease patients have confirmed that Atremorine is a potent enhancer of catecholaminergic neurotransmission: a single 5 g oral dose produces a dramatic increase in plasma dopamine levels within one hour, with over 97 percent of patients responding [4, 5]. In drug-free PD patients, plasma dopamine levels increase from approximately 12 pg/mL to approximately 6,463 pg/mL; in patients receiving conventional antiparkinsonian therapy, dopamine levels increase from approximately 1,322 pg/mL to approximately 16,029 pg/mL, indicating substantial potentiation of conventional dopaminergic pharmacotherapy [5, 6]. The dopamine response is accompanied by significant changes in circulating catecholamines (adrenaline, noradrenaline) and in dopamine-regulated hormones (reductions in prolactin, cortisol, and growth hormone), with no significant effect on serotonin or histamine levels [4].

The variability in the Atremorine-induced dopamine response is highly attributable to pharmacogenetic factors. Polymorphic variants in pathogenic genes (notably APOE), metabolic genes (CYP2D6, CYP2C9, CYP2C19, CYP3A4/5), and neurotransmitter transporter genes (SLC6A3/DAT, SLC6A2/NET, SLC6A4/SERT) exert genotype-dependent effects on the magnitude of the dopamine response [5, 7, 8]. APOE-3 carriers are the best responders and APOE-4 carriers are the worst; CYP2D6 normal metabolizers respond most strongly and CYP2D6 poor metabolizers respond least [5, 7]. Atremorine also exerts epigenetic activity, increasing global DNA methylation in both transgenic Alzheimer's disease mice (3xTg model) and in PD patients, with upregulation of the de novo DNA methyltransferase DNMT3a [9]. The coadministration of Atremorine with conventional antiparkinsonian drugs allows dose reduction of the conventional agents by 25 to 50 percent, with enhancement of clinical benefits and reduction of short- and long-term adverse drug reactions [5, 6]. The compound is covered by European Patent EP3225245A1 and related filings. It is not approved by any major regulatory authority as a pharmaceutical; it is classified and distributed as a bioproduct or nutraceutical. This monograph reviews the composition, extraction, neuroprotective pharmacology, clinical dopaminergic evidence, pharmacogenomic determinants of response, handling, stack interactions, safety profile, and comparative positioning of Atremorine against five alternative dopaminergic and neuroprotective interventions for Parkinson's disease.