Beneficial immune-modulatory effects of the N-163 strain of Aureobasidium pullulans-produced 1,3-1,6 Beta glucans in Duchenne muscular dystrophy: Results of an open-label, prospective, exploratory case-control clinical study.

Background: This exploratory case-control study is to evaluate the effects of supplementation of Aureobasidium pullulans-N-163 strain produced 1,3-1,- 6 beta glucan in young patients with Duchenne muscular dystrophy (DMD). Methods: Twenty-seven male subjects aged 5-19 years with DMD were included, nine in the control arm and 18 in the treatment arm to receive N-163 beta glucan along with conventional therapies for 45 days. While performing the analysis, steroid usage was also taken into consideration, those not administered steroids (Steroid -ve) (Control, n = 5; treatment, n = 9), those administered steroids (Steroid +ve) (Control, n = 4; treatment, n = 9). Results: IL-6 showed a significant decrease in the treatment groups, especially the N-163 Steroid -ve group. IL-13 decreased in both treatment groups and TGF-ß levels showed a significant decrease in the treatment groups, especially the N-163 Steroid -ve group, (p < 0.05). Dystrophin levels increased by up to 32% in the treatment groups compared to the control. Medical research council (MRC) grading showed slight improvement in muscle strength improvement in 12 out of 18 patients (67%) in the treatment group and four out of nine (44%) subjects in the control group. Conclusion: Supplementation with the N-163 beta glucan food supplement produced beneficial effects: a significant decrease in inflammation and fibrosis markers, increase in serum dystrophin and slight improvement in muscle strength in DMD subjects over 45 days, thus making this a potential adjunct treatment for DMD after validation. Trial registration: The study was registered in Clinical trials registry of India, CTRI/2021/05/033346. Registered on 5th May, 2021.

Protective and Pain-Killer Effects of AMC3, a Novel N-Formyl Peptide Receptors (FPRs) Modulator, in Experimental Models of Rheumatoid Arthritis.

Rheumatoid arthritis is an autoimmune disorder that causes chronic joint pain, swelling, and movement impairment, resulting from prolonged inflammation-induced cartilage and bone degradation. The pathogenesis of RA, which is still unclear, makes diagnosis and treatment difficult and calls for new therapeutic strategies to cure the disease. Recent research has identified FPRs as a promising druggable target, with AMC3, a novel agonist, showing preclinical efficacy in vitro and in vivo. In vitro, AMC3 (1-30 µM) exhibited significant antioxidant effects in IL-1ß (10 ng/mL)-treated chondrocytes for 24 h. AMC3 displayed a protective effect by downregulating the mRNA expression of several pro-inflammatory and pro-algic genes (iNOS, COX-2, and VEGF-A), while upregulating genes essential for structural integrity (MMP-13, ADAMTS-4, and COLIAI). In vivo, AMC3 (10 mg kg-1) prevented hypersensitivity and restored postural balance in CFA-injected rats after 14 days. AMC3 attenuated joint alterations, reduced joint inflammatory infiltrate, pannus formation, and cartilage erosion. Chronic AMC3 administration reduced transcriptional changes of genes causing excitotoxicity and pain (EAATs and CCL2) and prevented morphological changes in astrocytes, including cell body hypertrophy, processes length, and thickness, caused by CFA in the spinal cord. This study demonstrates the usefulness of AMC3 and establishes the groundwork for further research.

Efficacy of N-163 beta-glucan in beneficially improving biomarkers of relevance to muscle function in patients with muscular dystrophies in a pilot clinical study.

Background: Muscular dystrophies other than Duchenne muscular dystrophy (DMD) are genetic diseases characterized by increasing muscle weakness, loss of ambulation, and ultimately cardiac and respiratory failure. There are currently no effective therapeutics available. Having demonstrated the efficacy of a N-163 strain of Aureobasidium Pullulans (Neu-REFIX) produced B-1, 3-1,6-Glucan in pre-clinical and clinical studies of Duchenne muscular dystrophy (DMD) earlier, we assessed the effectiveness of this novel Beta glucan in the other muscular dystrophies in the present study. Methods: In this 60-day study, six patients with muscular dystrophies other than DMD consumed one 8g gel of Neu-REFIX beta-glucan along with their usual standard of care treatment regimen, and their biomarkers of relevance to muscle function such as serum calcium (SC), creatine phosphokinase (CPK), and alkaline phosphatase (ALP) levels along with functional improvement criteria, which is, Medical research council (MRC) scale and North Star Ambulatory assessment (NSAA), assessed at baseline and following the intervention. Results: After the intervention, the SC levels significantly decreased from a mean baseline value of 9.28 mg/dL to 8.31 mg/dL (p-value = 0.02). With a p-value of 0.29, the mean CPK value dropped from 2192.33 IU/L to 1567.5 IU/L. Following the intervention, the ALP levels dropped from 200.33 to 75.5 U/L (p-value = 0.15). MRC scale improved in three out of six patients. NSAA remained stable. There were no adverse effects. Conclusion: This study has proven the safety of Neu REFIX beta-glucan food supplement and its efficacy in improving both plasma biomarkers and functional parameters of muscle in a short duration of 2 months. Further validation by evaluation of muscle function for a longer duration is recommended to confirm the efficacy of Neu-REFIX food supplement as a potential adjuvant DMT in muscular dystrophies.

PHREND®-A Real-World Data-Driven Tool Supporting Clinical Decisions to Optimize Treatment in Relapsing-Remitting Multiple Sclerosis.

Background: With increasing availability of disease-modifying therapies (DMTs), treatment decisions in relapsing-remitting multiple sclerosis (RRMS) have become complex. Data-driven algorithms based on real-world outcomes may help clinicians optimize control of disease activity in routine praxis. Objectives: We previously introduced the PHREND® (Predictive-Healthcare-with-Real-World-Evidence-for-Neurological-Disorders) algorithm based on data from 2018 and now follow up on its robustness and utility to predict freedom of relapse and 3-months confirmed disability progression (3mCDP) during 1.5 years of clinical practice. Methods: The impact of quarterly data updates on model robustness was investigated based on the model's C-index and credible intervals for coefficients. Model predictions were compared with results from randomized clinical trials (RCTs). Clinical relevance was evaluated by comparing outcomes of patients for whom model recommendations were followed with those choosing other treatments. Results: Model robustness improved with the addition of 1.5 years of data. Comparison with RCTs revealed differences <10% of the model-based predictions in almost all trials. Treatment with the highest-ranked (by PHREND®) or the first-or-second-highest ranked DMT led to significantly fewer relapses (p < 0.001 and p < 0.001, respectively) and 3mCDP events (p = 0.007 and p = 0.035, respectively) compared to non-recommended DMTs. Conclusion: These results further support usefulness of PHREND® in a shared treatment-decision process between physicians and patients.

The search for disease-modifying agents in decompensated cirrhosis: From drug repurposing to drug discovery.

Patients with decompensated cirrhosis are currently managed through targeted strategies aimed at preventing or treating specific complications. In contrast, a disease-modifying agent should, by definition, be aimed at globally addressing 'decompensated cirrhosis'. To be defined as a disease-modifying agent in decompensated cirrhosis, interventions need to demonstrate an unequivocal benefit on the course of disease in well-designed and adequately powered randomised clinical trials with hard endpoints (i.e. patient survival). These trials also need to define the target population, dosage and timing of administration, factors guiding treatment, temporary or permanent stopping rules, transferability to daily clinical practice, cost-effectiveness, and global treatment access. By eliminating the underlying cause of cirrhosis, aetiologic treatments can still influence the course of decompensated disease by halting or slowing down disease progression or even inducing reversion to the compensated state. In contrast, there remains an unmet clinical need for disease-modifying agents which can antagonise key pathophysiological mechanisms of decompensated cirrhosis, such as portal hypertension, gut translocation, circulatory dysfunction, systemic inflammation, and immunological dysfunction. However, in the last few years, the repurposing of "old drugs" that have already been prescribed for more limited indications in hepatology or for other diseases has provided a few candidates, including human albumin, statins, and poorly absorbable oral antibiotics, which are under further evaluation in large-scale randomised clinical trials. New disease-modifying agents are also expected to be identified in the next decade through the systematic repurposing of existing drugs and the development of novel molecules which are currently undergoing pre-clinical or early clinical testing.

Comparative treatment effectiveness of oral fingolimod and conventional injectable disease-modifying agents in multiple sclerosis.

STUDY OBJECTIVE: To compare the effectiveness of oral fingolimod and conventional injectable disease-modifying agents (DMAs) using the composite endpoint of relapse or DMA treatment switch in patients with multiple sclerosis (MS). DESIGN: A retrospective longitudinal cohort study. DATA SOURCE: IBM MarketScan Commercial Claims and Encounters Database from 2010-2012. PATIENTS: Adults (≥18 years) with MS diagnosis (ICD-9-CM:340) who newly initiated DMAs. INTERVENTION: Oral fingolimod and conventional injectable DMAs (interferon beta and glatiramer acetate). MEASUREMENTS: Composite endpoint of time to relapse or DMA treatment switch. MAIN RESULTS: The incident study cohort consisted of 1997 MS patients who initiated oral fingolimod (15.6%) or injectable (84.4%) DMAs. The proportion of patients who had a composite endpoint (relapse/DMA treatment switch) in oral fingolimod and injectable DMA users was found to be 16.72% and 27.16%, respectively. The Cox PH regression model with stabilized IPTW revealed that fingolimod is equally effective as conventional injectable DMAs in reducing the risk of experiencing the composite endpoint of relapse or DMA switch (adjusted hazard ratio [aHR]: 0.67, 95% CI: 0.43-1.03). Additional analysis among patients who were adherent also found no significant difference in the composite endpoint (aHR: 0.70, 95% CI 0.49-1.15) between oral fingolimod and injectable DMA users. CONCLUSIONS: Oral fingolimod has similar effectiveness as conventional injectable DMAs in reducing the risk of experiencing the composite endpoint (relapse or DMA treatment switch). In addition, when assessed independently, oral fingolimod showed no difference in reducing the time to relapse or DMA treatment switch compared to injectable DMAs.

Factors associated with oral fingolimod use over injectable disease- modifying agent use in multiple sclerosis.

Background: Fingolimod is the first approved oral disease-modifying agent (DMA) in 2010 to treat Multiple Sclerosis (MS). There is limited real-world evidence regarding the determinants associated with fingolimod use in the early years. Objective: The objective of this study was to examine the factors associated with fingolimod prescribing in the initial years after the market approval. Methods: A retrospective, longitudinal study was conducted involving adults (≥18 years) with MS from the 2010-2012 IBM MarketScan. Individuals with MS were selected based on ICD-9-CM: 340 and a newly initiated DMA prescription. Based on the index/first DMA prescription, patients were classified as fingolimod or injectable users. All covariates were measured during the six months baseline period prior to the index date. Multivariable logistic regression was performed to determine the predisposing, enabling, and need factors, conceptualized as per the Andersen Behavioral Model (ABM), associated with prescribing of fingolimod versus injectable DMA for MS. Results: The study cohort consisted of 3118 MS patients receiving DMA treatment. Of which, 14.4% of patients with MS initiated treatment with fingolimod within two years after the market entry, while the remaining 85.6% initiated with injectable DMAs. Multivariable regression revealed that the likelihood of prescribing oral DMA increased by 2-3 fold during 2011 and 2012 compared to 2010. Patients with ophthalmic (adjusted odds ratio [aOR]-2.60), heart (aOR-2.21) and urinary diseases (aOR-1.37) were more likely to receive fingolimod. Patients with other neurological disorders (aOR-0.50) were less likely to receive fingolimod than those without neurological disorders. Use of symptomatic medication (for impaired walking (aOR-2.60), bladder dysfunction (aOR-1.54), antispasmodics (aOR-1.48), and neurologist consultation (aOR-1.81) were associated with higher odds of receiving fingolimod. However, patients with non-MS associated emergency visits (aOR-0.64) had lower odds of receiving fingolimod than those without emergency visits. Conclusions: During the initial years after market approval, patients with highly active MS were more likely to receive oral fingolimod than injectable DMAs. More research is needed to understand the determinants of newer oral DMAs.

Comparative Adherence Trajectories of Oral Fingolimod and Injectable Disease Modifying Agents in Multiple Sclerosis.

BACKGROUND: Oral fingolimod is convenient to use than injectable disease modifying agents (DMAs) in patients with multiple sclerosis (MS). However, the existing literature regarding the comparative adherence trajectories between oral fingolimod and injectable DMAs is limited. OBJECTIVE: To compare the adherence trajectories between oral DMA, fingolimod, and injectable DMAs in patients with MS. METHODS: A retrospective longitudinal study was conducted using adults (≥18 years) with MS (ICD-9-CM: 340 and a DMA prescription) from the IBM MarketScan Commercial Claims and Encounters Database between 2010 and 2012. Patients were grouped into oral fingolimod or injectable DMA users based on the index DMA among patients with MS. The annual DMA adherence trajectories, based on the proportion of days covered (PDC), were examined using group-based trajectory modeling (GBTM) during the one-year follow-up period after treatment initiation. Multivariable multinomial logistic regression using stabilized inverse probability treatment weights (IPTW) was performed to assess the association between the DMA route of administration (Oral vs Injectable) and the adherence trajectory groups. The balance of covariates between oral and injectable DMAs before and after IPTW was checked against a standardized difference threshold of 0.25. RESULTS: The study cohort consisted of 1,700 MS patients who were initiated with oral (15.8%) or injectable (84.2%) DMAs between 2010 and 2012. The adherence rates (PDC≥0.8) in oral fingolimod and injectable DMA users were found to be 64.7% and 50.8%, respectively. The GBTM grouped individuals in the study cohort into three adherence trajectories - rapid discontinuers (23.5%), complete adherers (49.9%), and slow decliners (26.6%). The multinomial logistic regression model with stabilized IPTW revealed that oral fingolimod users had higher odds to be a complete adherer (adjusted odds ratio [AOR]: 2.78, 95% CI: 1.85-4.16) or a slow discontinuer (AOR: 2.62, 95% CI: 1.70-4.05) than injectable DMA users. CONCLUSIONS: Oral DMA fingolimod was associated with better adherence than injectable DMAs across group-based trajectories. Further research is warranted to evaluate the adherence trajectories with newer oral DMAs introduced in the last decade for MS.

Neurorestorative effects of sub-chronic administration of ambroxol in rodent model of Parkinson's disease.

Disease-modifying agents are unmet medical need for Parkinson's disease (PD). Drugs are under clinical trial to halt its progression, such as ambroxol due to its glucocerebrosidase (GCase)-stimulating activity. However, the neurorestorative effect of ambroxol is not yet investigated in any of the well-established PD models in vivo. Ambroxol was administered as 400 mg/kg orally twice a day from D-28 to D-70 after the unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA) in male rats. Behavioral parameters were observed every week, and at last, tyrosine hydroxylase (TH), dopamine transporter (DAT), glucocerbrosidase (GCase) enzymatic and mitochondrial complex-I activity, α-synuclein levels, and Nissl's staining were performed. Behavioral functions were progressively recovered. Ambroxol restored TH and DAT levels on D-71 as the markers of dopaminergic cell and extracellular DA concentration respectively, indicating the recovery of dopaminergic system. Factors involved in PD pathogenesis such as GCase enzymatic and mitochondrial complex-I activity were restored, and α-synuclein pathology was decreased by ambroxol. GCase deficiency is involved in mitochondrial impairment and formation of oligomeric α-synuclein aggregates which negatively affect mitochondrial function. Nissl bodies were also normalized. Therefore, both the GCase-stimulating and α-synuclein pathology-diminishing effects of ambroxol may be responsible for increment in mitochondrial function and restoration of dopaminergic system. These may act as significant mechanisms for disease-modifying potential of ambroxol. The current study provides the preclinical evidence to support the neurorestorative potential of ambroxol in 6-OHDA-induced hemiparkinson's rat model and indicates its possible use as disease-modifying agent in PD.

Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm.

Hereditary ATTR (ATTRm) amyloidosis (also called transthyretin-type familial amyloid polyneuropathy [ATTR-FAP]) is an autosomal-dominant, adult-onset, rare systemic disorder predominantly characterized by irreversible, progressive, and persistent peripheral nerve damage. TTR gene mutations (e.g. replacement of valine with methionine at position 30 [Val30Met (p.Val50Met)]) lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, which form amyloid fibrils that deposit in peripheral nerves and various organs, giving rise to peripheral and autonomic neuropathy and several non-disease specific symptoms.Phenotypic and genetic variability and non-disease-specific symptoms often delay diagnosis and lead to misdiagnosis. Red-flag symptom clusters simplify diagnosis globally. However, in Japan, types of TTR variants, age of onset, penetrance, and clinical symptoms of Val30Met are more varied than in other countries. Hence, development of a Japan-specific red-flag symptom cluster is warranted. Presence of progressive peripheral sensory-motor polyneuropathy and ≥1 red-flag sign/symptom (e.g. family history, autonomic dysfunction, cardiac involvement, carpal tunnel syndrome, gastrointestinal disturbances, unexplained weight loss, and immunotherapy resistance) suggests ATTR-FAP. Outside of Japan, pharmacotherapeutic options are first-line therapy. However, because of positive outcomes (better life expectancy and higher survival rates) with living donor transplant in Japan, liver transplantation remains first-line treatment, necessitating a Japan-specific treatment algorithm.Herein, we present a consolidated review of the ATTR-FAP Val30Met landscape in Japan and summarize findings from a medical advisory board meeting held in Tokyo on 18th August 2016, at which a Japan-specific ATTR-FAP red-flag symptom cluster and treatment algorithm was developed. Beside liver transplantation, a TTR-stabilizing agent (e.g. tafamidis) is a treatment option. Early diagnosis and timely treatment using the Japan-specific red-flag symptom cluster and treatment algorithm might help guide clinicians regarding apt and judicious use of available treatment modalities.

Novel drug delivery of dual acting prodrugs of hydroxychloroquine with aryl acetic acid NSAIDs: Design, kinetics and pharmacological study.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by restricted movements of joints of hand, feet, elbow, knees and neck but principally the synovial joints. Though etiopathology is not exactly known, treatment paradigms are evolving to provide a tighter control over symptoms and disease progression. Current trend is introduction of disease modifying anti-rheumatoid drugs (DMARDs) at early stages. Hydroxychloroquine (HCQ) and nonsteroidal anti-inflammatory drugs (NSAIDs) are two mechanistically different categories widely used in the management of RA where the first arrests the disease progression while the latter offers symptomatic relief. Present work aims at minimizing problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs by designing their mutual ester prodrugs. Synthesis of prodrugs was achieved by CDI coupling and structures were confirmed by IR, 1H-NMR, 13C-NMR, mass spectroscopy and elemental analysis. Prodrugs resisted hydrolysis in acidic environment of the stomach but exhibited significant release in small intestine. Upon oral administration of prodrugs to rats, 40.5-49% HCQ and 53.4-66.8% of NSAIDs were recovered in 8.5-10 h in blood. Urine and feces samples pooled over a period of 24 h exhibited 2.3-3.5% and 0.75-0.9% of HCQ, respectively, without any presence of intact prodrugs or NSAIDs. Prodrugs were pharmacologically evaluated for analgesic and anti-inflammatory activities using standard animal models. Among all, prodrugs of HCQ with licofelone (HL) and aceclofenac (HA) produced superior analgesia, improved weight gain, normalization of joint diameter/paw volume than HCQ and physical mixtures of HCQ and NSAIDs. Hematological and biochemical studies indicated significant step up in RBC, Hb, platelet count, total protein nutrient (TPN) levels and step down in WBC, serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) by the treatment with HL and HA. Through these novel codrugs, problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs were well addressed. These dual acting mutual prodrugs of two mechanistically different anti-arthritic agents could be explored further as promising strategy for effective management of RA.

Alemtuzumab in multiple sclerosis: an update.

Since the introduction of IFN-ß, disease-modifying treatments, acting through various immune mechanisms, have been shown to reduce disease activity and severity in relapsing multiple sclerosis. Nevertheless, there remain patients for whom these treatments are incompletely effective, poorly tolerated or contraindicated. Alemtuzumab is a humanized monoclonal antibody that works by selectively depleting circulating lymphocytes. It is given as an intravenous infusion of 12 mg daily for 5 days, then a year later for 3 days. Effectiveness in patients with active relapsing-remitting multiple sclerosis has been demonstrated in two Phase III clinical trials, where it outperformed IFN-ß-1a 44 mcg on clinical and radiographic efficacy measures. Its side effect profile, including infusion-associated reactions, infections and secondary autoimmunity, coupled with its long-lasting biological effect, requires patients to commit to close monitoring while on the drug and for 4 years after the final infusion. For select patients with active disease, alemtuzumab offers a powerful therapeutic option.

Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer's Disease?

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. Huperzine A (HupA) is a natural inhibitor of acetylcholinesterase (AChE) derived from the Chinese folk medicine Huperzia serrata (Qian Ceng Ta). It is a licensed anti-AD drug in China and is available as a nutraceutical in the US. A growing body of evidence has demonstrated that HupA has multifaceted pharmacological effects. In addition to the symptomatic, cognitive-enhancing effect via inhibition of AChE, a number of recent studies have reported that this drug has "non-cholinergic" effects on AD. Most important among these is the protective effect of HupA on neurons against amyloid beta-induced oxidative injury and mitochondrial dysfunction as well as via the up-regulation of nerve growth factor and antagonizing N-methyl-d-aspartate receptors. The most recent discovery that HupA may reduce brain iron accumulation lends further support to the argument that HupA could serve as a potential disease-modifying agent for AD and also other neurodegenerative disorders by significantly slowing down the course of neuronal death.

Combotherapy and current concepts as well as future strategies for the treatment of Alzheimer's disease.

It has been estimated that 35.6 million people globally had dementia in 2010 and the prevalence of dementia has been predicted to double every 20 years. Thus, 115.4 million people may be living with dementia in 2050. Alzheimer's disease (AD) is the leading cause of dementia and is present in 60%-70% of people with dementia. Unfortunately, there are few approved drugs that can alleviate the cognitive or behavioral symptoms of AD dementia. Recent studies have revealed that pathophysiological changes related to AD occur decades before the appearance of clinical symptoms of dementia. This extended preclinical phase of AD provides a critical chance for disease-modifying agents to halt or delay the relentless process of AD. Although several trials targeting various pathological processes are ongoing, the examination of the combined use of different approaches to combat AD seems warranted. In this article, we will review current therapies, future strategies, and ongoing clinical trials for the treatment of AD with a special focus on combination therapies. Furthermore, preventive strategies for cognitively normal subjects in the presymptomatic stages of AD will also be addressed. In this review, we discuss current hypotheses of the disease process. In the decades since the approval of cholinesterase inhibitors, no new drug has ultimately demonstrated clear success in clinical trials. Given the difficulties that have been encountered in attempts to identify a single drug that can treat AD, we must pursue effective multi-target strategies, ie, combination therapies. The combination of cholinesterase inhibitors and memantine is considered well tolerated and safe, and this combination benefits patients with moderate-to-severe AD. In contrast, with the exception of adjuvant therapies of conventional drugs, combinations of different disease-modifying agents with different mechanisms may have promising synergic effects and benefit cognition, behavior, and daily living function.

Oxaliplatin-induced oxidative stress in nervous system-derived cellular models: could it correlate with in vivo neuropathy?

Oxaliplatin is a platinum-organic drug with antineoplastic properties used for colorectal cancer. With respect to the other platinum derivates oxaliplatin induces only a mild hematological and gastrointestinal toxicity. Its limiting side effect is its neurotoxicity, which results in a sensory neuropathy. Repeated oxaliplatin treatment in the rat led to a neuropathic pain characterized by a significant oxidative damage throughout the nervous system. The natural antioxidants silibinin and α-tocopherol reduce redox alteration and prevent pain. Starting from the "oxidative hypothesis" as a molecular basis of chemotherapy-induced neurotoxicity, we decided to explore deep inside the mechanisms of oxaliplatin neurotoxicity and search for a cellular system useful for screening antioxidant compounds that can reduce oxaliplatin neurotoxicity. Focusing on various constituents of the central nervous system, we used the neuronal-derived cell line SH-SY5Y and primary cultures of rat cortical astrocytes. Oxaliplatin significantly increased superoxide anion production and induced lipid peroxidation (malonyldialdehyde levels) and protein (carbonylated proteins) and DNA oxidation (8-OH-dG levels). Silibinin and α-tocopherol (10µM) were able to reduce the oxidative damage in both cell types. These antioxidants fully protected astrocytes from the caspase 3 apoptotic signaling activation induced by oxaliplatin. The damage prevention effects of silibinin and α-tocopherol on nervous system-derived cells did not interfere with the oxaliplatin antineoplastic in vitro mechanism as evaluated on a human colon adenocarcinoma cell line (HT29). Moreover, neither silibinin nor α-tocopherol modified the oxaliplatin-induced apoptosis in HT29 cells, suggesting a different antiapoptotic profile in normal vs tumoral cells for these antioxidant compounds. In conclusion, because data obtained in in vitro cellular models parallel the in vivo study we propose cell models to investigate oxaliplatin neurotoxicity and to screen possible therapeutic adjuvant agents.