Pharmacogenomic biomarkers in coronary artery disease: a narrative review.

Coronary artery disease (CAD) has a high mortality rate. Despite various therapeutic targets, non-responsiveness to drugs remains a prevalent issue. Pharmacogenomics assesses the way an individual's genetic attributes affect their likely response to drug therapy. Single-nucleotide polymorphisms play a crucial role in determining these outcomes. This review offers an overview of single-nucleotide polymorphisms investigated in clinical studies and their associations with drug response/nonresponse in the treatment of CAD. A total of 104 studies of whole sets of chromosomes and several genes were explored. A total of 161 polymorphisms exhibited associations with drug response/nonresponse in CAD across diverse ethnic populations. This pool can serve as a pharmacogenomic biomarker for predicting response to drug therapy in patients with CAD.

Strategies to improve antibiotic access and a way forward for lower middle-income countries.

Antibiotics have substantially improved life expectancy in past decades through direct control or prevention of infections. However, emerging antibiotic resistance and lack of access to effective antibiotics have significantly increased the death toll from infectious diseases, making it one of the biggest threats to global health. Addressing the antibiotic crisis to meet future needs require considerable investment in both research and development along with ensuring a viable marketplace to encourage innovation. Fortunately, there has been some improvement in the number of antibiotics approved or in different phases of development through collective global efforts. However, the universal access to these essential novel and generic antibiotics, especially in low- and middle-income countries (LMICs), is challenged by poor economic incentives, regulatory hurdles and poor health infrastructure. Recently, the agenda of securing and expanding access has gained global attention. Several mechanisms are now being proposed and implemented to improve access to essential antibiotics. This review provides an insight into the major barriers to antibiotic access as well as the models proposed and implemented to mitigate accessibility issues. These models include but are not limited to market entry rewards, subscription models and transferable exclusivity vouchers. Further, global access programmes including, Global Antibiotic Research and Development Partnership, Antimicrobial Resistance Action Fund and SECURE Platform are discussed. We also propose the way forward for improving access in LMICs with suggested measures to improve access to generic and novel antibiotics.

Decanoic acid mitigates ischemia reperfusion injury by modulating neuroprotective, inflammatory and oxidative pathways in middle cerebral artery occlusion model of stroke in rats.

OBJECTIVE: Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) is an ionotropic transmembrane receptor for glutamate. AMPA receptor blockers have been reported to prevent neurological damage and enhance the post stroke recovery in rats. Decanoic acid, a medium-chain fatty acid, has been reported to exhibit non-competitive AMPA receptor antagonism. This study evaluated the effect of decanoic acid administered before and after ischemia reperfusion injury on neurological damage and post stroke recovery in rats. METHODS: Middle cerebral artery occlusion (MCAo) was performed by using the intraluminal method to induce focal cerebral ischemia. Decanoic acid (120 mg/kg) was administered orally for 1 day (5-10 min post reperfusion) in one group and for 2 days (24 h pre and 5-10 min post reperfusion) in the other group. Effect on neurological damage and post stroke recovery was assessed by neurobehavioral parameters, MRI and TTC staining along with inflammatory, oxidative, apoptotic, and neuroprotective biomarkers. RESULTS: Decanoic acid significantly reduced the MCAo induced neurological damage and infarct size. Decanoic acid treatment increased the motor coordination and grip strength. Furthermore, levels of inflammatory (TNFα, IL-1ß and IL-6), oxidative stress (MDA), apoptotic (TUNEL positive cells) and neurological injury (GFAP) biomarkers were reduced after decanoic acid treatment. Anti-inflammatory cytokine (IL-10) and neuroprotective markers (NT-3, BDNF and TrkB) were found to be significantly increased with decanoic acid treatment. CONCLUSION: This study showed protective effects of decanoic acid against ischemia reperfusion injury in rats. Anti-inflammatory, antioxidant, neuroprotective, and anti-apoptotic properties may be responsible for the beneficial effects of decanoic acid observed in the study.

AMPA receptor modulation through sequential treatment with perampanel and aniracetam mitigates post-stroke damage in experimental model of ischemic stroke.

The present study evaluates the effect of modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) by inhibiting them in the acute phase and activating them in the sub-acute phase on post-stroke recovery in middle cerebral artery occlusion (MCAo) model of stroke in rats. After 90 min of MCAo, perampanel (an AMPAR antagonist, 1.5 mg/kg i.p) and aniracetam (an AMPA agonist, 50 mg/kg i.p.) were administered for different durations after MCAo. Later, after obtaining the best time point for the antagonist and the agonist treatment protocols, sequential treatment with perampanel and aniracetam were given, and the effect on neurological damage and post stroke recovery were assessed. Perampanel and aniracetam significantly protected MCAo-induced neurological damage and diminished the infarct percentage. Furthermore, treatment with these study drugs improved the motor coordination and grip strength. Sequential treatment with perampanel and aniracetam reduced the infarct percentage as assessed by MRI. Moreover, these compounds diminished the inflammation via reducing the levels of pro-inflammatory cytokines (TNF-α, IL-1ß) and increasing the levels of anti-inflammatory cytokine (IL-10) along with reductions in GFAP expression. Moreover, the neuroprotective markers (BDNF and TrkB) were found to be significantly increased. Levels of apoptotic markers (Bax, cleaved-caspase-3; Bcl2 and TUNEL positive cells) and neuronal damage (MAP-2) were normalized with the AMPA antagonist and agonist treatment. Expressions of GluR1 and GluR2 subunits of AMPAR were significantly enhanced with sequential treatment. The present study thus showed that modulation of AMPAR improves neurobehavioral deficits and reduces the infarct percentage through anti-inflammatory, neuroprotective and anti-apoptotic effects.

Landscape of Push Funding in Antibiotic Research: Current Status and Way Forward.

The growing need for effective antibiotics is attributed to the intrinsic ability of bacteria to develop survival mechanisms. The speed at which pathogens develop resistance is at par or even faster than the discovery of newer agents. Due to the enormous cost of developing an antibiotic and poor return on investment, big pharmaceutical companies are stepping out of the antibiotic research field, and the world is now heading towards the silent pandemic of antibiotic resistance. Lack of investment in research has further led to the anemic antibiotic pipeline. To overcome these challenges, various organizations have come forward with push funding to financially assist antibiotic developers. Although push funding has somewhat reinvigorated the dwindled field of antibiotic development by bearing the financial risks of failure, the landscape is still large and staggered. Most of the funding is funneled towards the early stages; however, to carry the promising compounds forward, equal or more funding is required formid- and late-stage research. To some extent, the complexity associated with accessing the funding mechanisms has led to their underutilization. In the present review, we discuss several major push funding mechanisms, issues in their effective utilization, recent strategies adopted, and a way forward to streamline funding in antibiotic research.

Therapeutic Drug Monitoring of Voriconazole in Children with Hematologic Malignancy and Invasive Fungal Infections: An RCT from a Tertiary Care Centre in India.

INTRODUCTION: Voriconazole is a triazole anti-fungal with non-linear kinetics and a narrow therapeutic range. The objective of our study was to monitor the voriconazole serum levels in children with hematological malignancy and clinically suspected invasive fungal infections. METHODS: The study was a prospective, randomized controlled trial conducted from June 2016 to December 2017. All children who had haematologic malignancies with clinically suspected invasive fungal infections and received voriconazole as the only anti-fungal were included in the study. The children were randomly allotted into two groups; one was the group that underwent TDM, and the other, TDM, was not done. Bioassay was the method employed for TDM. The trough levels were evaluated on a sample obtained on the fifth day of starting the drug. The institute's ethics committee approved the study. RESULT: A total of 30 children were included in the study: 15 in the TDM group and 15 in the non-TDM group. The most common underlying malignancy was AML. Neutropenia due to chemotherapy sessions was these patients' most common risk factor. A favorable outcome was seen in 13/15 (86.7%) in the TDM group and 11/15 in the non-TDM group (73.3%). CONCLUSION: Only five out of 15 (33.3%) children had voriconazole serum levels within the therapeutic range. Alterations in dose had to be done in the remaining to achieve the recommended serum levels. Thus, we recommend TDM for all children of hematologic malignancy receiving voriconazole for better management. Our findings also revealed that children with AML had lower than recommended levels of voriconazole on TDM evaluation, whereas those with ALL had normal to elevated levels of voriconazole.

Drug development process and COVID-19 pandemic: Flourishing era of outsourcing.

Traditional drug development is a tedious process with involvement of enormous cost and a high attrition rate. Outsourcing drug development services to contract research organizations (CROs) has become an important strategy for cost and risk reduction, capacity building, and data generation. The therapeutic and operational expertise of these CROs has allowed pharmaceutical industry to reduce in-house infrastructure as well as research capacity. Working with specialized CROs has not only increased the rate of success but also the speed of drug discovery process. Small firms with promising molecules but limited resources and large firms interested in diversifying their dimensions are utilizing the services of efficient CROs. Globally, approximately one-third of the drug development processes are now being outsourced and the data generated by the independent third party are well appreciated during regulatory submissions. In this article, we discuss the international and national trends, outsourcing services and models, key considerations while selecting CRO, and benefits and challenges of outsourcing. Further, we discuss how the technical expertise of competent CROs was utilized when traditional ways of conducting clinical trials were disrupted by the COVID-19 pandemic. Taken together, the increasing health-care demands, COVID-19 pandemic or any other such upcoming health crisis, and recent advances in advanced technologies (machine learning and artificial intelligence, etc.) are likely to fuel global CRO market in the coming years.

Effect of add-on alpha lipoic acid on psychopathology in patients with treatment-resistant schizophrenia: a pilot randomized double-blind placebo-controlled trial.

RATIONALE: Alpha lipoic acid is known to reverse NMDA receptor hypofunction in addition to dopamine receptor blockade activity. It also enhances neurotrophic factors and has antioxidant potential. These properties combined together may be beneficial for treatment-resistant schizophrenia (TRS). OBJECTIVES: This study evaluates the effect of alpha lipoic acid (ALA) on psychopathological scores (positive, negative, cognitive), neurotrophic factors and oxidative stress in TRS. METHODS: A pilot randomized double-blind placebo-controlled parallel design trial was conducted in 20 patients with TRS. After initial screening, participants were randomized into test (add-on ALA) and control (add-on placebo) groups. After recruitment, clinical evaluations with scale for assessment of positive symptoms and negative symptoms (SAPS and SANS), schizophrenia cognitive rating scale (SCoRS), UKU side effect rating scale were done. Serum levels of BDNF, MDA, and GSH were estimated. Patients were followed up for 8 weeks, and clinical and biochemical evaluations were repeated. Adherence to medication was evaluated at follow-up. RESULTS: A significantly greater improvement was found in SANS score in the test group when compared to control (Mann-Whitney U = 17.0; p = 0.021), whereas there was no significant improvement in SAPS score (Mann-Whitney U = 41.5; p = 0.780). A significant increase in BDNF levels was observed in the control group when compared to ALA (U = 20.0; p = 0.041). No significant differences were found between the test and control groups in serum MDA (U = 30.0; p = 0.221), serum GSH (U = 40.0; p = 0.683), and medication adherence rating scale (MARS) scores (U = 44.0; p = 0.934). CONCLUSIONS: ALA supplementation improved psychopathology and decreased oxidative stress in patients with TRS. This study thus shows the potential of adjunctive ALA in TRS. TRIAL REGISTRATION: The study was prospectively registered in Clinical Trial Registry of India (CTRI/2020/03/023707 dated 02.03.2020).

Lp-PLA2 as a biomarker and its possible associations with SARS-CoV-2 infection.

Lp-PLA2 is an enzyme encoded by the PLA2G7 gene located at chromosome 6p12-21, which is included in different signal transduction pathways. The potential of serum levels of Lp-PLA2 as a marker of inflammation quantifying cardio-metabolic risk, renal impairment and oxidative stress has been explored in earlier studies. It has also been used in chronic obstructive pulmonary disease, hepatic disease, metabolic conditions and exercise tolerance. Additionally, it shows promising evidence for the assessment of risk for certain cardiovascular conditions in otherwise seemingly healthy individuals. COVID-19 has affected life and the economy globally. The identification of biomarkers to assess the sickness and treatment plan is the need of the hour. This review summarizes the pathophysiological inter-relationship between serum levels of Lp-PLA2 and COVID-19. The authors hypothesize that the estimation of Lp-PLA2 levels may help in the early identification of risk and thus may play a beneficial role in the proactive management of COVID-19.

Tideglusib Ameliorates Ischemia/Reperfusion Damage by Inhibiting GSK-3ß and Apoptosis in Rat Model of Ischemic Stroke.

OBJECTIVES: Glycogen synthase kinase-3ß (GSK-3ß), a serine/threonine protein kinase, gets activated and worsen stroke outcome after ischemia/reperfusion (I/R) injury by inducing inflammation and apoptosis. In this study, tideglusib, a selective irreversible and non-ATP competitive inhibitor of GSK-3ß, was explored in cerebral I/R damage using middle cerebral artery occlusion (MCAo) model in rats. MATERIALS AND METHODS: MCAo was done for 90 min in male Wistar rats (250-280 g) using doccol suture. In pre-treatment group, tideglusib (50 mg/kg) was administered once daily for 2 days and on the day of surgery, 30 min before MCAo. Next day, rats were examined for neurobehavioral parameters and MRI was performed to assess brain damage. In post-treatment group, tideglusib was started at 30 min after MCAo and continued for the next 2 days. After 72 h of MCAo, behavioral parameters and brain damage by MRI were assessed. Further, oxidative stress markers (MDA and GSH), inflammatory cytokines (TNF-α, IL-1ß and IL-10) and expression levels of pGSK-3ß S9, Bcl-2 and Bax were estimated in pre-treatment group. RESULTS: Tideglusib pre-treatment but not post-treatment significantly improved neurobehavioral parameters (p < 0.05) and reduced brain damage (p < 0.01) when compared with MCAo group. I/R induced changes in MDA (p < 0.01), TNF-α and IL-1ß (p < 0.05) were significantly attenuated by pre-treatment. Further, tideglusib pre-treatment ameliorated MCAo induced altered expressions of pGSK-3ß S9, Bcl-2 and Bax. CONCLUSION: The results of our exploratory study indicated prophylactic potential of tideglusib in I/R injury by modulating pGSK-3ß S9, apoptosis and neuro-inflammation.

Dihydromyricetin alleviates cerebral ischemia-reperfusion injury by attenuating apoptosis and astrogliosis in peri-infarct cortex.

OBJECTIVES: In ischemic stroke, reperfusion after thrombolysis is associated with secondary brain damage. Dihydromyricetin (DHM), a flavonoid, has shown neuroprotective effects through anti-oxidant, anti-inflammatory and anti-apoptotic properties. This study investigates the potential of DHM, given postreperfusion in middle cerebral artery occlusion (MCAo) model of stroke in rats. METHODS: MCAo surgery was performed in male Wistar rats. Reperfusion was performed after 90 min of ischemia. DHM (50 and 100 mg/kg) was administered 10-15 min and 2 h postreperfusion followed by daily dosing for 2 more days. Neurobehavioral parameters and infarct size (TTC staining) were assessed after 72 h. The effective dose (100 mg/kg) was then used to study reduction in infarct size (measured by MRI) and effect on apoptosis (evaluated by protein expression of Bax, Bcl-2 and cleaved caspase-3 and TUNEL assay) in peri-infarct cortex. Furthermore, effects of DHM on neuronal damage and activation of astrocytes were studied by immunofluorescence. RESULTS: Poststroke DHM (100 mg/kg) administered for 3 days showed significant improvements in motor-coordination and infarct damage (TTC staining and MRI). MCAo-induced altered apoptotic proteins were normalized to a significant extent in peri-infarct cortex with DHM treatment. Data from TUNEL assay were complementary to the effects on apoptotic proteins. Additionally, DHM caused a significant reduction in the number of reactive astrocytes when compared with the MCAo group. DISCUSSION: This study demonstrated the efficacy of subacute DHM treatment in ischemia/reperfusion injury by modulating apoptosis and astrogliosis in the peri-infarct cortex. This suggests the potential of DHM in attenuating disease progression.

Preclinical Stroke Research and Translational Failure: A Bird's Eye View on Preventable Variables.

Despite achieving remarkable success in understanding the cellular, molecular and pathophysiological aspects of stroke, translation from preclinical research has always remained an area of debate. Although thousands of experimental compounds have been reported to be neuro-protective, their failures in clinical setting have left the researchers and stakeholders in doldrums. Though the failures described have been excruciating, they also give us a chance to refocus on the shortcomings. For better translational value, evidences from preclinical studies should be robust and reliable. Preclinical study design has a plethora of variables affecting the study outcome. Hence, this review focusses on the factors to be considered for a well-planned preclinical study while adhering to guidelines with emphasis on the study design, commonly used animal models, their limitations with special attention on various preventable attritions including comorbidities, aged animals, time of dosing, outcome measures and physiological variables along with the concept of multicentric preclinical randomized controlled trials. Here, we provide an overview of a panorama of practical aspects, which could be implemented, so that a well-defined preclinical study would result in a neuro-protectant with better translational value.

Efficacy and Safety of Adjunctive Serotonin-Dopamine Activity Modulators in Major Depression: A Meta-Analysis of Randomized Controlled Trials.

Serotonin-dopamine activity modulators (SDAMs) have been approved as an adjunctive treatment to antidepressants in patients with inadequate response. These drugs have been proposed to have a beneficial effect on cognition, sleep-related problems, and other affective symptoms in patients with depression. Previous studies have shown inconsistent evidence and have not reported a pooled effect of the 2 drugs of this class: aripiprazole and brexpiprazole. This meta-analysis evaluated the effect of augmentation with SDAM drugs in patients with major depression. The meta-analysis protocol was made as per Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol guidelines and registered in the International Prospective Register of Ongoing Systematic Reviews. The PubMed/MEDLINE, Cochrane Clinical Trial registry, and EudraCT databases were searched with prespecified search terms. A random-effects meta-analysis was performed using the meta package in R software. Fifteen studies were included in this meta-analysis. The random-effects model analysis observed a pooled effect of 1.55 (95%CI, 1.32-1.84; prediction interval, 0.95-2.55, z = 5.19 [P < .0001]) for remission between the SDAM and placebo groups. A pooled effect of 1.58 (95%CI, 1.37-1.83; prediction interval, 1.00-2.51, z = 6.34 [P < .0001]) for adverse events and 0.72 (95%CI, 0.48-1.08; prediction interval, 0.46-1.12; z = -1.58 [P = .113]) for serious adverse events was observed. No significant publication bias was noticed. The quality of the evidence was rated as high. Adjunct SDAM increased remission in patients and had no significant effect on serious adverse events compared to placebo. Therefore, we conclude that SDAM drugs can be an effective and safe antidepressant augmentation strategy in patients with major depressive disorder.

Post Stroke Safinamide Treatment Attenuates Neurological Damage by Modulating Autophagy and Apoptosis in Experimental Model of Stroke in Rats.

Exploring and repurposing a drug have become a lower risk alternative. Safinamide, approved for Parkinson's disease, has shown neuroprotection in various animal models of neurological disorders. The present study aimed to explore the potential of safinamide in cerebral ischemia/reperfusion (I/R) in rats. Sprague-Dawley rats were used in middle cerebral artery occlusion model of stroke. The effective dose of safinamide was selected based on the results of neurobehavioral parameters and reduction in infarct size assessed 24 h post-reperfusion. For sub-acute study, the treatment with effective dose was extended for 3 days and effects on neurobehavioral parameters, infarct size (TTC staining and MRI), oxidative stress parameters (MDA, GSH, SOD, NOX-2), inflammatory cytokines (TNF-α, IL-1ß, IL-10), apoptosis (Bax, Bcl-2, cleaved caspase-3 expression, and TUNEL staining), and autophagy (pAMPK, Beclin-1, LC3-II expression) were studied. The results of dose selection study showed significant reduction (p < 0.05) in infarct size and improvement in neurobehavioral parameters with safinamide (80 mg/kg). In sub-acute study, safinamide showed significant (p < 0.05) improvement in motor coordination and infarct size reduction. Additionally, safinamide treatment significantly normalized altered redox homeostasis and inflammatory cytokine levels. However, no change was observed in expression of NOX-2 in I/R or safinamide treatment group when compared with sham. I/R induced deranged expression of apoptotic markers and increased TUNEL positive cells in cortex were significantly normalized with safinamide treatment. Further, safinamide significantly (p < 0.05) induced the expressions of autophagic proteins (Beclin-1 and LC3-II) in cortex. Overall, the results demonstrated neuroprotective potential of safinamide via anti-oxidant, anti-inflammatory, anti-apoptotic, and autophagy inducing properties. Thus, safinamide can be explored for repurposing in ischemic stroke after further exploration.

Chronic Neurological Disorders: Genetic and Epigenetic Markers for Monitoring of Pharmacotherapy.

INTRODUCTION: Chronic neurological diseases are a major cause of mortality and morbidity in the world. With increasing life expectancy in the developing world, the incidence and prevalence of these diseases are predicted to rise even further. This has also contributed to an increase in disability-adjusted life years (DALYs) for noncommunicable diseases. Treatment for such diseases also poses a challenge with multiple genetic and epigenetic factors leading to a varied outcome. Personalization of treatment is one way that treatment outcome/prognosis of disease can be improved, and pharmacogenomics plays a significant role in this context. METHODOLOGY: This article reviewed the evidence pertaining to the association of genetic and epigenetic markers with major neurological disorders like multiple sclerosis (MS), Alzheimer's disease (AD), and Parkinson's disease (PD), which are a major source of burden among neurological disorders. Types of studies included are peer-reviewed original research articles from the PubMed database (1999-2018). RESULTS: This study compiled data regarding specific genetic and epigenetic markers with a significant correlation between the clinical diagnosis of the disease and prognosis of therapy from 65 studies. In a single platform, this review highlights the clues to some vital questions, such as why interferon beta (IFN-ß) therapy fails to improve symptoms in all MS patients? why cholinesterase inhibitors fail to improve cognitive impairment in a subset of people suffering from AD? or why some individuals on levodopa (L-DOPA) for PD suffer from side-effects ranging from dyskinesia to hallucination while others do not? CONCLUSION: This article summarizes the genetic and epigenetic factors that may either require monitoring or help in deciding future pharmacotherapy in a patient suffering from MS, AD, and PD. As the health care system develops and reaches newer heights, we expect more and more of these biomarkers to be used as pharmacotherapeutic outcome indicators.

Antibody-drug conjugates, cancer immunotherapy, and metronomic chemotherapy as novel approaches in cancer management.

Treatment of cancer is a major challenge even though the pathophysiology is becoming clearer with time. A number of new chemical entities are developed to target cancer growth inhibition, but the targeted delivery of these products still needs novel research. This is of utmost importance not only for higher efficacy but also for a reduction in systemic toxicity and cost of treatment. Although multiple novel targets and molecules are being researched, most of them could not pass the regulatory approval process, due to low benefit-risk ratio and lack of target specificity. Failure of a majority of these drugs was in part due to their superiority claimed via surrogate markers. Despite these, currently, more than 100 chemotherapeutic agents are in practice. This review paper discusses in detail the molecular basis, drug discovery, and pros and cons over conventional treatment approaches of three novel approaches in cancer therapy, i.e., (i) antibody-drug conjugates, (ii) cancer immunotherapy, and (iii) metronomic chemotherapy. All the drugs developed using these three novel approaches were compared against the established treatment regimens in clinical trials with clinical end points, such as overall survival, progression-free survival, and quality of life.

Heme oxygenase-1 modulation: A potential therapeutic target for COVID-19 and associated complications.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to infect hundred thousands of people every day worldwide. Since it is a novel virus, research continues to update the possible therapeutic targets when new evidence regarding COVID-19 are gathered. This article presents an evidence-based hypothesis that activating the heme oxygenase-1 (HO-1) pathway is a potential target for COVID-19. Interferons (IFNs) have broad-spectrum antiviral activity including against SARS-CoV-2. Induction of HO-1 and increase in the heme catabolism end-product confer antiviral activity. IFN activation results in inhibition of viral replication in various viral infections. COVID-19 induced inflammation as well as acute respiratory distress syndrome (ARDS), and coagulopathies are now known major causes of mortality. A protective role of HO-1 induction in inflammation, inflammation-induced coagulation, and ARDS has been reported. Based on an association of HO-1 promoter polymorphisms and disease severity, we propose an evaluation of the status of these polymorphisms in COVID-19 patients who become severely ill. If an association is established, it might be helpful in identifying patients at high risk. Hence, we hypothesize that HO-1 pathway activation could be a therapeutic strategy against COVID-19 and associated complications.

Evaluation of sodium valproate loaded nanoparticles in acute and chronic pentylenetetrazole induced seizure models.

BACKGROUND AND PURPOSE: Efficacy of sodium valproate in epilepsy is limited by its poor blood brain barrier penetration and side effects. Nanoparticles may offer a better drug delivery system to overcome these limitations. This study evaluated the efficacy of sodium valproate encapsulated in nanoparticles in pentylenetetrazole (PTZ) induced acute and kindling models of seizures in male Wistar rats. METHODS: Poly lactic-co-glycolic acid (PLGA) based, polysorbate 80 stabilized sodium valproate loaded nanoparticles (nano sodium valproate) and rhodamine loaded nanoparticles (RLN) were formulated by double emulsion- solvent evaporation method and characterized for their size, shape, zeta potential and drug loading percentage. RLN was used to demonstrate blood brain barrier (BBB) permeability of nanoparticles. Serum drug levels were estimated using high performance liquid chromatography. The efficacy of standard sodium valproate (300 mg/kg) and nano sodium valproate (∼300, ∼150 and ∼75 mg/kg of sodium valproate) were evaluated in experimental animal models of seizures along with their effects on behavioral and oxidative stress parameters. Drugs were administered 60 min before PTZ in acute model. In the kindling model, drugs were administered every day while PTZ was administered on alternate days 60 min after drug administration. All the study drugs/compounds were administered intraperitoneally. RESULTS: RLN were observed to be clustered in cortex which implied that the nanoparticles crossed BBB. Both standard sodium valproate and nano sodium valproate reached therapeutic serum level at 15 min and 1 h, but were undetectable in serum at 24 h. In acute PTZ (60 mg/kg) model, nano sodium valproate (∼300 mg/kg of sodium valproate) and standard sodium valproate showed protection against seizures till 6 h and 4 h, respectively. There were significant behavioral impairment and oxidative stress with standard sodium valproate in acute model as compared to nano sodium valproate at 6 h. In kindling model, induced with PTZ (30 mg/kg, every alternate day for 42 days), complete protection from seizures was observed with nano sodium valproate (∼150 mg/kg and ∼75 mg/kg of sodium valproate) and standard sodium valproate (300 mg/kg). Similarly, significant protection from behavioral impairment and oxidative stress was observed with standard sodium valproate and nano sodium valproate as compared to PTZ. CONCLUSION: When compared to conventional therapy, nano sodium valproate showed protection from seizures at reduced doses and for a longer duration in animal models of epilepsy. This study suggests the potential of nano sodium valproate in the treatment of epilepsy.

Neuro-protective effect of monomethyl fumarate on ischemia reperfusion injury in rats: Role of Nrf2/HO1 pathway in peri-infarct region.

Post stroke recanalization has been associated with increased risk of oxidative stress. Stimulating endogenous antioxidant pathway by activation of nuclear factor erythroid-2-related factor-2 (Nrf2) plays a key role in neuronal defense against inflammation and oxidative stress in penumbra. Here, we explored whether monomethyl fumarate (MMF) could produce neuro-protection after ischemia/reperfusion (I/R) injury via Nrf2/HO1 activation. In male SD rats, middle cerebral artery was occluded for 90 min and confirmed using Laser Doppler flowmeter. MMF (10, 20 and 40 mg/kg) was administered in two divided doses at 30 min post ischemia and 5-10 min after reperfusion. After 24 h, effect on neurobehavioral parameters, infarct damage by TTC staining and MRI, oxidative stress and inflammatory cytokines were assessed. Expression studies of nuclear Nrf2 and cytoplasmic HO1 were performed in peri-infarct cortex and striatum; followed by dual immunofluorescence study to check the specific cell type. I/R induced neurobehavioral deficits and infarct damage were significantly (p < 0.05) attenuated by MMF (20 and 40 mg/kg). MMF, 20 mg/kg, significantly normalized I/R induced altered redox status and increased levels of TNF-α, IL-1ß in the ipsilateral cortex. MRI data showed significantly reduced infarct in cortex but not in striatum after MMF treatment. Expression of nuclear Nrf2 and cytoplasmic HO1 were significantly (p < 0.05) increased in peri-infarct cortex after treatment with MMF. Additionally, dual immunofluorescence showed increased Nrf2 expression in neurons and HO1 expression in neurons as well as astrocytes in peri-infarct cortex after MMF treatment. Our results show the neuro-protective potential of MMF probably by restricting the progression of damage from striatum to cortex through activation of Nrf2/HO1 pathway in peri-infarct cortex.