Effect of CYP2C19 polymorphism on response to bortezomib-based therapy in multiple myeloma patients.

BACKGROUND: Bortezomib, a commonly used anti-myeloma drug, is metabolized by liver microsomal enzymes which may be polymorphic and responsible for lack of response in 30% patients. Hence, the association of CYP2C19 polymorphism with treatment response was explored in this study. METHODS: Treatment naive multiple myeloma (MM) patients, eligible for bortezomib-based induction treatment, were recruited as per the inclusion - exclusion criteria. The genotyping of CYP2C19 was done using polymerase chain reaction-restriction fragment length polymorphism for *2, *3 and *17 alleles. The incidence and severity of peripheral neuropathy were noted at follow-up visits and graded as per CTCAE criteria ver 5.0. RESULTS: Total 220 patients were recruited from August 2016 till May 2021; with a mean age of 55.6 (9.5) years and 65.9% males. Bortezomib+cyclophosphamide+dexamethasone (41.8%) and bortezomib+lenalidomide+dexamethasone (38.2%) were the most prescribed regimens. The CYP2C19 was polymorphic in 38.6%, 2.3% and 23.7% patients for *2, *3 and *17 allele respectively. There were 195 treatment responders and 25 non-responders, and CYP2C19*2 allele was different between responders and non-responders (p = 0.02). All extensive metabolisers (n = 54) were noted to be treatment responders. Peripheral neuropathy was reported by 23.2% patients. The frequency of peripheral neuropathy was somewhat lower in patients having either *2/*2 or *3/*3 allele pattern for CYP2C19 (p = 0.44). CONCLUSIONS: Polymorphism in CYP2C19 enzyme is likely to have an impact on bortezomib treatment response and peripheral neuropathy. The study suggests the role of pharmacogenetics in personalised treatment of MM.

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.

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.

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.

Cognitive Dysfunction and Anxiety Resulting from Synaptic Downscaling, Hippocampal Atrophy, and Ventricular Enlargement with Intracerebroventricular Streptozotocin Injection in Male Wistar Rats.

Insulin-resistant brain state is proposed to be the early sign of Alzheimer's disease (AD), which can be studied in the intracerebroventricular streptozotocin (ICV-STZ) rodent model. ICV-STZ is reported to induce sporadic AD with the majority of the disease hallmarks as phenotype. On the other hand, available experimental evidence has used varying doses of STZ (< 1 to 3 mg/kg) and studied its effect for different study durations, ranging from 14 to 270 days. Though these studies suggest 3 mg/kg of ICV-STZ to be the optimum dose for progressive pathogenesis, the reason for such is elusive. Here, we sought to investigate the mechanism of action of 3 mg/kg ICV-STZ on cognitive and non-cognitive aspects at a follow-up interval of 2 weeks for 2 months. On the 60th day, we examined the layer thickness, cell density, ventricular volume, spine density, protein expression related to brain metabolism, and mitochondrial function by histological examination. The findings suggest a progressive loss of a spatial, episodic, and avoidance memory with an increase in anxiety in a span of 2 months. Furthermore, hippocampal neurodegeneration, ventricular enlargement, diffused amyloid plaque deposition, loss of spine in the dentate gyrus, and imbalance in energy homeostasis were found on the 60th day post-injection. Interestingly, AD rats showed a uniform fraction of time spent in four quadrants of the water maze with a change in strategy when they were exposed to height. Our findings reveal that ICV-STZ injection at a dose of 3 mg/kg can cause cognitive and neuropsychiatric abnormalities due to structural loss both at the neuronal as well as the synaptic level, which is tightly associated with the change in neuronal metabolism.

Effect of morphine administration after status epilepticus on epileptogenesis in rats.

INTRODUCTION: Morphine is widely used in patients and has been reported to alter seizure threshold, but its role in the development of epilepsy is unknown. In this study, role of morphine administration in the development of epilepsy using the status epilepticus (SE) model was determined in rats. METHODS: Rats experiencing SE with lithium-pilocarpine (LiP) were randomized into four groups- saline, morphine low dose (5 mg/kg, s.c.), morphine high dose (5-20 mg/kg, s.c.), and naloxone (1 mg/kg, s.c.). Treatments were started 90 min after termination of SE and repeated twice daily for next three days. Rats were video monitored daily for 21 days to determine onset and frequency of spontaneous convulsive seizures (SS). RESULTS: Morphine in low doses increased frequency of SS (1.51 ± 0.15 vs LiP 0.60 ± 0.12 seizures/rat/day, p-value = 0.0026) and seizures occurred during handling (SDH) (0.08 ± 0.02 vs LiP control 0.01 ± 0.01) (p-value = 0.0018). In high doses, no significant change in SS and SDH was found as compared to LiP. No effect of morphine on the onset of SS and percentage of rats experienced SS was found. No effect of naloxone per se was found on SS. CONCLUSION: Morphine administration after SE does not affect epileptogenesis as no change in the onset of SS and percentage of rats experiencing SS was found. However, it might alter the susceptibility and frequency of SS. As no other study is available with a similar finding, it needs further evaluation.

Characterization of potentially inappropriate medications use in Indian elderly population and their impact on quality of life using Beers criteria.

Background: Polypharmacy is principal cause of potentially inappropriate medications (PIMs) in elderly patients, which include over prescribing, under prescribing, and misprescribing. Methods: Elderly subjects (≥60 years), of either sex, receiving two or more medications for one or more chronic ailments, attending Geriatrics Outpatient Department (OPD), at All India Institute of Medical Sciences (AIIMS) New Delhi, were included. Their prescriptions were assessed for PIMs by using Beers criteria 2015 and were further followed up at least once in 6 months for adverse events, telephonically. The results were analyzed by using suitable regression models and correlation analysis. Results: Three hundred eighty patients average age of 65.4 ± 4.7 years were enrolled. Eighty-eight percent of the people were having greater than or equal to two ailments. Each patient was prescribed 6.7 ± 2.1 medications with 65% of prescriptions having one or more PIMs. Out of the total prescribed drugs, 15% were satisfying Beers criteria for PIMs. There were 63 adverse drug reactions (ADRs) reported. A statistically significant correlation was observed among comorbidities, number of prescribed medications, PIMs, and ADRs. Quality of life (QOL) of the elderly patients was negatively corelated with polypharmacy and female sex. Conclusion: A risk-benefit analysis of prescribed medications is part and parcel of prescribing, especially in elderly patients. In order to decrease further risks associated with inappropriate prescribing, there is need for indigenous guidelines and intensive training.

Evaluation of serum glucose-regulated protein 78 (GRP78) as a biomarker of treatment response to bortezomib-based induction regimen in multiple myeloma: A cross-sectional pilot study.

GRP78 overexpression in myeloma cells has been associated with bortezomib resistance in multiple myeloma (MM). However, serum GRP78 as a maker of bortezomib-based treatment response remains unexplored. The objective of the study was to evaluate serum GRP78 levels in MM patients who underwent a bortezomib-based induction regimen. This cross-sectional study included adult MM patients (n=30) who completed at least four cycles of bortezomib-based induction therapy. Healthy volunteers (n=30) and newly diagnosed MM patients (n=19) were also recruited to identify the disease-associated change in GRP78 levels. Serum GRP78 was estimated by ELISA. Surface and intracellular expression of GRP78 in bone marrow plasma cells was evaluated in ten MM patients by flow cytometry. Among 30 MM patients [median (range): 52 (38-68) years; 20 males] who completed at least four cycles of bortezomib-based induction therapy, 20 were responders and 10 were non-responders. Serum GRP78 levels were not significantly different between responders [median (IQR): 5.2 (3.1, 8.0) µg/ml] and non-responders [median (IQR): 4.3 (0.1, 7.1) µg/ml] (p=0.4). Although non-significant (p=0.3), median serum GRP78 was higher in newly diagnosed patients when compared to healthy volunteers. Bone marrow plasma cells ranged from 0.2 to 57.8% in the analyzed samples. Intracellular GRP78 expression in bone marrow plasma cells was higher (1.6 to 5 times) when compared to surface expression. To conclude, serum GRP78 levels vary widely in different MM patient groups but did not correlate with response to a bortezomib-based induction regimen.

Status Analysis of Herbal Drug Therapies in Epilepsy: Advancements in the Use of Medicinal Plants with Anti-inflammatory Properties.

BACKGROUND: The use of plants and plant products in health care has shown an exponential increase in the past two decades. INTRODUCTION: In-spite of the availability of well-established pharmacotherapy for epilepsy, a large no of the population still explores alternative treatments due to refractory seizures, adverse effects of drugs, chronic treatment, inaccessibility of standard therapies in rural areas and the social stigma attached to the disease. Various studies on medicinal plants showed the protective effect of herbals in animal models of epilepsy. METHODS: In the present review, a status analysis of the traditional use of various medicinal plants in epilepsy with a special focus on plats having anti-inflammatory potential is recorded. RESULT AND CONCLUSION: The shortcomings of research on medicinal plants which need to be explored further in order to tackle the growing need for safer and effective drugs for epilepsy are discussed. Overall, there is a huge scope of herbal drugs in CNS disorders, especially epilepsy, either as an adjunct by reducing the dose and thus side effects of standard anti-epileptic drugs or as a standalone agent. Although, there is still an urgent need of well planned randomized controlled clinical trials to validate their efficacy and safety.

Pharmacodynamic and pharmacokinetic interactions of hydroalcoholic leaf extract of Centella asiatica with valproate and phenytoin in experimental models of epilepsy in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica (CA) is commonly used herbal medicine for treatment of epilepsy. CA has CYP2C9, CYP2D6 and CYP3A4 enzymes inhibition property and used as an adjuvant therapy with conventional antiepileptic drugs (AEDs). That may be responsible for herb-drug interaction. AIM OF THE STUDY: The present study was planned to evaluate interactions profile of hydroalcoholic extract Centella asiatica (HECA) with antiepileptic drugs in experimental models of epilepsy in rats. MATERIALS AND METHODS: Wistar rats (175-200 g) were used. In the pharmacodynamic interaction study, seizures were induced using pentylenetetrazole (PTZ) (60 mg/kg, i.p.) and maximal electroshock seizure (MES) (70 mA for 0.2 s). The therapeutic and sub-therapeutic doses of valproate (VPA) and phenytoin (PHT) were co-administrated with HECA in PTZ and MES model of seizures respectively. Behavioural parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were also assessed. In the pharmacokinetic interaction study, the serum levels of the VPA and PHT were estimated at different time intervals by HPLC and pharmacokinetic parameters were analyzed by WinNonlin software. RESULTS: The VPA and PHT produced complete protection against seizures in their therapeutic doses but not with sub-therapeutic doses. However, co-administration of HECA with a sub-therapeutic dose of VPA and PHT enhanced the protection of seizures and significantly (p < 0.001) attenuated the seizure induced oxidative stress and cognitive impairment. It also significantly increased (p < 0.001) serum levels of VPA and PHT. The alterations in pharmacokinetic parameters (maximum serum concentration, area under the curve, clearance) of AEDs were also found with co-administration of HECA. CONCLUSION: The results suggested that co-administration of HECA could improve the therapeutic efficacy of VPA and PHT. But, alteration in pharmacokinetic parameters revel that needs critical medical supervision to avoid any toxic reactions.

Prescription pattern of antiepileptic drugs in a tertiary care center of India.

OBJECTIVES: The present study aimed to determine the pattern of prescription of antiepileptic drugs (AEDs) in a cohort of patients with epilepsy (PWE) attending a tertiary care center of North India. MATERIALS AND METHODS: Demographic variables including age, gender, age at onset, type and frequency of seizures, and prescription of all AEDs (dose and duration) were noted. Descriptive analysis of the use of AEDs was done, and their different combinations were studied. RESULTS: A total of 1187 prescriptions were evaluated. Demography showed 65.7% of males; mean age of 21.9 years (range: 2-77 years), generalized seizures (53%), and focal seizures (47%). Only 21.8% of the patients were seizure free with no seizure in 1 year of treatment. The five most frequently prescribed AEDs out of 12 AEDs were sodium valproate (VPA) (49.6%), clobazam (CLB) (39.3%), levetiracetam (LEV) (28.4%), carbamazepine (CBZ) (27.3%), and phenytoin (PHT) (26.5%). Monotherapy was effective in 36.6% of the patients. Sodium VPA (39.4%), PHT (25.6%), and CBZ (20.1%) were commonly used as monotherapy. Polytherapy was required in 63.4% of the patients, and most commonly prescribed combinations were PHT + CLB (n = 53), sodium VPA + CLB (n = 62), CBZ + CLB (n = 45), PHT + sodium VPA + CLB (n = 28), and CBZ + sodium VPA + CLB (n = 31). CONCLUSIONS: Polytherapy is a very common practice in our tertiary care center. Sodium VPA, a highly prescribed AED, results in good control of generalized seizures, whereas focal seizures are well controlled by CBZ alone as well as in combination. The present study highlights the commonly prescribed combinations of AEDs resulting in control of different types of seizures.

1 H NMR metabolomic profiling elucidated attenuation of neurometabolic alterations by lercanidipine in MCAo model in rats.

OBJECTIVES: Stroke is a leading cause of death and disability worldwide with limited therapeutic interventions. The current study explored proton nuclear magnetic resonance spectroscopy (1 H NMR)-based metabolomic approach to elucidate the effect of lercanidipine on neurometabolic alterations in transient model of ischaemic stroke in rats. METHODS: In the present investigation, male Wistar rats were subjected to middle cerebral artery occlusion (MCAo) for 2 h followed by reperfusion using intraluminal filament method. Rats were randomly divided into three groups as vehicle-treated sham control, vehicle-treated MCAo control and lercanidipine-treated MCAo. Vehicle or lercanidipine (0.5 mg/kg, i.p.) was administered 120 min post-reperfusion. The rat brain cortex tissues were isolated 24 h post-MCAo and were investigated by 1 H NMR spectroscopy through perchloric extraction method. KEY FINDINGS: A total of 23 metabolites were altered significantly after cerebral ischaemic-reperfusion injury in MCAo control as compared to sham control rats. Lercanidipine significantly reduced the levels of valine, alanine, lactate, acetate and tyrosine, while N-acetylaspartate, glutamate, glutamine, aspartate, creatine/phosphocreatine, choline, glycerophosphorylcholine, taurine, myo-inositol and adenosine di-phosphate were elevated as compared to MCAo control. CONCLUSIONS: Present study illustrates effect of lercanidipine on neurometabolic alterations which might be mediated through its antioxidant, anti-inflammatory, vasodilatory and anti-apoptotic property in MCAo model of stroke.

Evaluation of adverse drug reaction profile of antiepileptic drugs in persons with epilepsy: A cross-sectional study.

INTRODUCTION: Newer antiepileptic drugs (AEDs) are preferred over conventional AEDs with the perception of better safety profile and efficacy though there is a lack of confirmatory evidence. The present study assessed the adverse drug reactions' (ADRs) profile of AEDs prescribed in persons with epilepsy (PWE) as per the System Organ Class (SOC) and compared them on the basis of demographics and treatment pattern. MATERIAL AND METHODS: This prospective, cross-sectional, and observational study was conducted in PWE attending Neurology Outpatient-Department from February 2016 to April 2019 who were presented with any ADR. World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale was used for the causality assessment of suspected ADRs. RESULTS: Among the 1011 PWE on AEDs, male:female ratio was 622:389, adult:pediatric ratio 736:275, and conventional:newer AEDs ratio 624:387. Among monotherapy PWE (47.1%), commonly used AEDs were levetiracetam (34.4%), valproic acid (22.9%), carbamazepine (18.3%), phenytoin (11.9%), and other AEDs (12.5%). A total of 1990 ADRs (1.96 ADRs per PWE) were reported as per SOC; among them, newer vs. conventional AEDs did not reveal any significant difference; however, monotherapy vs. polytherapy showed differences in nervous system disorders (p = 0.01) and skin and subcutaneous tissue disorders (p = 0.005). Causality assessment revealed 0.3% certain, 27.3% probable, 61.3% possible, and 11.1% unlikely association of ADRs with AEDs. Depending on the ADRs, there was either withdrawal of AED (0.9%), reduction in dose (48.4%), or continuation in the same dose as before (50.7%). CONCLUSION: The ADR analysis showed that newer AEDs were associated with a similar trend of ADRs as that of conventional AEDs. Thus, the choice among newer and conventional AEDs should preferably focus on the experience of better efficacy in addition to safety data.

Seizure recurrence risk in persons with epilepsy undergoing antiepileptic drug tapering.

OBJECTIVES: Antiepileptic drug (AED) tapering in persons with epilepsy (PWE) after 2-3 years of seizure freedom is still debatable because of the risk of seizure recurrence. Tapering patterns have wide variability and could impact seizure recurrence; this study aimed to find out the correlation between them. MATERIAL AND METHODS: This prospective, observational independent assessor study enrolled PWE undergoing AED tapering in a tertiary care hospital. Data collected included demography, seizure history, AED treatment, and investigational findings. Tapering pattern was assessed based on seizure-free period and AED dose before onset of tapering, dose reduction percentage and frequency, duration of tapering, and follow-up. These variables were compared among the PWE with seizure recurrence and no seizure recurrence. RESULTS: Among 408 enrolled PWE, 181 were on AED monotherapy: levetiracetam (73), valproate (45), carbamazepine (44), phenytoin (16), and clobazam (3). With a minimum 19 (maximum 41 months) follow-up, seizure recurrence was reported in 119 (29.2%) PWE. The seizure recurrence was not significantly different in-between mono and polytherapy groups; however, among monotherapy groups seizure recurrence was significantly higher (P = .023) in valproate (35.5%) followed by levetiracetam (28.8%) group. Parameters having significant association with seizure recurrence were duration of epilepsy (P = .03), frequency of seizures before control (P = .002), history of previously failed tapering (P = .04), and history of smoking/alcoholic/tobacco intake (P = .003). CONCLUSIONS: There is a wide variation in AEDs tapering pattern and seizure recurrence risk can be minimized by considering the risk factors like history of smoking/alcoholic/tobacco, longer duration of epilepsy, frequency of seizures before control, and previously failed tapering.

Impact of increased focus on pharmacovigilance on knowledge and attitude towards adverse drug reaction reporting among medical students in India.

BACKGROUND: Recent years have seen a surge in pharmacovigilance (PV) related activities in India. In the present study the impact of these initiatives on medical students from across the country was evaluated to identify their effectiveness, lacunae and arrive at remedial measures. METHODS: A cross-sectional, questionnaire based study was conducted. The survey questionnaire consisted of 28 multiple response items. The areas covered included subject knowledge (theoretical and practical), attitude and awareness towards pharmacovigilance. RESULTS: The survey participants (n = 253) were from 71 medical colleges and 17 states across India. While 60% of the participants were familiar with the term 'Pharmacovigilance', many could not distinguish side effect and adverse drug reaction. The majority was unaware that 'Periodic Safety Update Report' (PSURs) is a mandatory pharmacovigilance activity by the industry. 91% felt reporting is a useful practice and causes for under-reporting are a lack of awareness followed by attitude, misconceptions about what to report, fear of litigation and interestingly the least important is lack of time. However, most were reluctant to have reporting as mandatory tool; they would rather use it voluntary. CONCLUSION: In spite of collaborative and synchronized efforts by various agencies there is a need to further improve the PV milieu in India by confidence building exercises, imparting training on PV programme, updating of the current knowledge on PV and also sustaining motivation.

Aluminium utensils: Is it a concern?

Aluminium utensils are ubiquitous in Indian households and other developing countries. Concerns have recently been raised on the pathological effects of aluminium on the human body, due to its leaching from utensils with long-term use, which has been associated with certain clinical conditions such as anaemia, dementia and osteo-malacia. While some studies suggest that cooking in utensils or aluminium foils is safe, others suggest that it may lead to toxic levels of aluminium in the body. However, studies have shown that leaching of aluminium from cooking utensils depends on many factors such as pH, temperature and cooking medium. In healthy controls, 0.01 %-1 % of orally ingested aluminium is absorbed from the gastrointestinal tract and is eliminated by the kidney. Although the metal has a tendency to accumulate in tissues and may result in their dysfunction, the literature suggests that the apprehension is more apt in patients with chronic renal insufficiency. This article offers solutions to mitigate the risk of aluminium toxicity.

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.

Issues, challenges, and the way forward in conducting clinical trials among neonates: investigators' perspective.

Clinical trials are essential to test the safety and efficacy of new treatments in any population. The paucity of drug trials especially in the neonatal population has led to the widespread use of unlicensed or off-label medications, exposing them to the risks of drug toxicity and ineffective treatment. Ethical and operational challenges are no longer considered valid excuses for not conducting drug trials in neonates. We recently participated in a combined phase-2 and phase-3 trial investigating a new indigenous goat lung surfactant extract (GLSE) for the treatment of respiratory distress syndrome (RDS) in preterm neonates. In this article, we share pertinent challenges faced by us during the trial to better inform and foster-positive discussion among drug developers, administrators, regulatory authorities, patient advocacy groups, and researchers. Also, we provide many tools developed for the GLSE trial that can be modified and used by prospective trialists.