Identification of Potential Antitubulin Agents with Anticancer Assets from a Series of Imidazo[1,2-a]quinoxaline Derivatives: In Silico and In Vitro Approaches.

Computer-aided drug design is a powerful and promising tool for drug design and development, with a reduced cost and time. In the current study, we rationally selected a library of 34 fused imidazo[1,2-a]quinoxaline derivatives and performed virtual screening, molecular docking, and molecular mechanics for a lead identification against tubulin as an anticancer molecule. The computational analysis and pharmacophoric features were represented as 1A2; this was a potential lead against tubulin, with a maximized affinity and binding score at the colchicine-binding site of tubulin. The efficiency of this lead molecule was further identified using an in vitro assay on a tubulin enzyme and the anticancer potential was established using an MTT assay. Compound 1A2 (IC50 = 4.33-6.11 µM against MCF-7, MDA-MB-231, HCT-116, and A549 cell lines) displayed encouraging results similar to the standard drug colchicine in these in vitro studies, which further confirmed the effectiveness of CADD in new drug developments. Thus, we successfully applied the utility of in silico techniques to identify the best plausible leads from the fused azaheterocycles.

Efficacy of Cicuta virosa medicinal preparations against pentylenetetrazole-induced seizures.

Epileptic seizures are characterized by imbalanced inhibition-excitation cycle that triggers biochemical alterations responsible for jeopardized neuronal integrity. Conventional antiepileptic drugs (AEDs) have been the mainstay option for treatment and control; however, symptomatic control and potential to exacerbate the seizure condition calls for viable alternative to these chemical agents. In this context, natural product-based therapies have accrued great interest in recent years due to competent disease management potential and lower associated adversities. Cicuta virosa (CV) is one such herbal remedy that is used in traditional system of medicine against myriad of disorders including epilepsy. Homeopathic medicinal preparations (HMPs) of CV were assessed for their efficacy in pentylenetetrazole (PTZ)-induced acute and kindling models of epilepsy. CV HMPs increased the latency and reduced the duration of tonic-clonic phase in acute model while lowering the kindling score in the kindling model that signified their role in modulating GABAergic neurotransmission and potassium conductance. Kindling-induced impairment of cognition, memory, and motor coordination was ameliorated by the CV HMPs that substantiated their efficacy in imparting sustained neuronal fortification. Furthermore, biochemical evaluation showed attenuated oxidative stress load through reduced lipid peroxidation and strengthened free radical scavenging mechanism. Taken together, CV HMPs exhibited promising results in acute and kindling models and must be further assessed through molecular and epigenomic studies.

Antidiabetic Evaluation of Kigelia pinnata Root Bark Extract in Streptozotocin-Induced Type-2 Diabetes Model of Rats.

Diabetes mellitus (DM) is the most common endocrine disorder characterized by increased blood glucose levels resulting from defective insulin secretion, resistance to insulin action, or both. DM is often associated with severe complications, and there is an increasing appreciation that cognitive function declines in DM. The aim of this research work was to evaluate Kigelia pinnata root bark extract in Streptozotocin (STZ)-induced type-2 diabetes. Experimental diabetes was induced by a single administration of STZ (60 mg/kg, intraperitoneal [i.p.]), immediately after the STZ administration, and all animals were fed with normal food and water. Nicotinamide was administered (120 mg/kg, i.p.) 15 min before STZ. The development of hyperglycemia was confirmed by the elevated blood glucose levels determined at fixed intervals, which was confirmed by measuring fasting blood glucose levels in rats' blood taken from the tail vein. Supplementation with ethanolic extract of K. pinnata root bark (EEKP) significantly reduced the elevated blood glucose in STZ-induced hyperglycemia in rats. EEKP significantly restored the biochemical and antioxidant defense system. On the final day of the protocol, the extract also reduced inflammatory cytokines in the blood serum.

Incredible Combination of Lifestyle Modification and Herbal Remedies for Polycystic Ovarian Syndrome Management.

A relatively frequent endocrine-metabolic illness called polycystic ovarian syndrome (PCOS) is characterized by polycystic ovaries, persistent anovulation, and hyperandrogenism, which cause symptoms such as irregular menstruation, infertility, and hirsutism. PCOS is linked to obesity, insulin resistance, and increased amounts of androgens, or male hormones. The sedentary lifestyle, dietary fluctuations, inactivity, and stress are other contributing variables. According to estimates from India in 2021, around 22.5% of women, or one in five Indian women, suffer from PCOS. Evidence-based medical care for PCOS places a strong focus on a multidisciplinary approach, as standard pharmacological treatment frequently targets a single symptom, may be contraindicated, has adverse effects, and is ineffective in certain circumstances. However, long-term treatments have drawbacks and are likely to be ineffective, making complementary and alternative therapies a worthwhile choice. Yoga science is a thorough treatment plan for a healthy body and mind that may eradicate PCOS's primary causes, stress and obesity. Some common herbal remedies, including Foeniculum vulgare, Tinospora cordifolia, Asparagus racemosus, Ocimum tenuiflorum, Areca catechu, and Lepidium meyenii, have been highly regarded sources that have the benefits of lowering PCOS as well as having hypoglycemic and antiobesity effects. In light of existing literature, women with PCOS experienced symptomatic relief, improvement in hormonal balance, and the quality of life by utilizing yoga practices as well as herbal remedies. In conclusion, combining lifestyle modifications with herbal remedies can be used in the management of PCOS as a holistic approach. Therefore, this review opens a new window for researchers all across the world to validate such findings.

Cognition and memory impairment attenuation via reduction of oxidative stress in acute and chronic mice models of epilepsy using antiepileptogenic Nux vomica.

Ethnopharmacological relevance Processed Nux vomica seed extracts and homeopathic medicinal preparations (HMPs) are widely used in traditional Indian and Chinese medicine for respiratory, digestive, neurological and behavioral disorders. Antioxidant property of Nux vomica is well known and recent investigation has highlighted the anticonvulsant potential of its homeopathic formulation. AIM OF THE STUDY: To explore the anticonvulsant and antiepileptogenic potential of Nux vomica HMPs (6CH, 12CH and 30CH potency) in pentylenetetrazole (PTZ) induced acute and chronic experimental seizure models in mice and investigate their effects on cognition, memory, motor activity and oxidative stress markers in kindled animals. MATERIALS AND METHODS: Acute seizures were induced in the animals through 70 mg/kg (i.p.) administration of PTZ followed by the evaluation of latency and duration of Generalized tonic-clonic seizures (GTCS). Subconvulsive PTZ doses (35 mg/kg, i.p.) induced kindling in 29 days, which was followed by assessment of cognition, memory and motor impairment through validated behavioral techniques. The status of oxidative stress was estimated through measurement of MDA, GSH and SOD. RESULTS: HMPs delayed the latency and reduced the duration of GTCS in acute model signifying possible regulation of GABAergic neurotransmission. Kindling was significantly hindered by the HMPs that justified the ameliorated cognition, memory and motor activity impairment. The HMPs attenuated lipid peroxidation by reducing MDA level and strengthened the antioxidant mechanism by enhancing the GSH and SOD levels in the kindled animals. CONCLUSIONS: Nux vomica HMPs showed anticonvulsant and antiepileptogenic potency in acute and chronic models of epilepsy. The test drugs attenuated behavioral impairment and reduced the oxidative stress against PTZ induced kindling owing to which they can be further explored for their cellular and molecular mechanism(s).

SIRT1 Promotes Neuronal Fortification in Neurodegenerative Diseases through Attenuation of Pathological Hallmarks and Enhancement of Cellular Lifespan.

Neurodegeneration is a complex neurological phenomenon characterized by disturbed coherence in neuronal efflux. Progressive neuronal loss and brain damage due to various age-related pathological hallmarks perturb the behavioral balance and quality of life. Sirtuins have been widely investigated for their neuroprotective role, with SIRT1 being the most contemplated member of the family. SIRT1 exhibits significant capabilities to enhance neurogenesis and cellular lifespan by regulating various pathways, which makes it an exciting therapeutic target to inhibit neurodegenerative disease progression. SIRT1 mediated neuronal fortification involves modulation of molecular co-factors and biochemical pathways responsible for the induction and sustenance of pro-inflammatory and pro-oxidative environment in the cellular milieu. In this review, we present the major role played by SIRT1 in maintaining cellular strength through the regulation of genomic stability, neuronal growth, energy metabolism, oxidative stress, inhibiting mechanisms and anti-inflammatory responses. The therapeutic significance of SIRT1 has been put into perspective through a comprehensive discussion about its ameliorating potential against neurodegenerative stimuli in a variety of diseases that characteristically impair cognition, memory and motor coordination. This review enhances the acquaintance concerned with the neuroprotective potential of SIRT1 and thus promotes the development of novel SIRT1 regulating therapeutic agents and strategies.

Perspective, perceptions, and promulgation of biosimilars: A questionnaire-based study to assess and understand the current challenges of biosimilars to the potential and intended users.

INTRODUCTION: Biosimiliar, a copy of reference biological product, is making a buzz across the globe for its upper edge therapeutic usage. According to the market research report published by P&S Intelligence, biosimilars market is expected to generate $26.7 billion revenue by 2024, advancing at a CAGR of 29.6% during the forecast period. The first biosimilar to medicine Omnitrope, was approved in Europe by EMA (European Medicines Agency) in year 2006. Till date countries like US, China, Japan, India and many more have generated regulatory guidelines for biosimilars. AIM: Current study addresses the issues and challenges faced by Industry and regulators with their potential solutions and recommendations. MATERIALS AND METHODS: The questionnaire having 21 important questions/comments was given to participants after explaining the purpose of the study. The response in terms of responders V/s non-responders, agree V/s disagree, yes V/s no was recorded and analyzed by descriptive statistics. RESULTS AND DISCUSSION: The study shows the limitation regarding the qualified personnel involved in biosimilars, as approx. 91% people believe that there is lack of expertise in this field. The same can be achieved through government initiatives for bridge courses which is also strongly felt by the major (83.6%) stakeholders participated in the study.

Terror of 10 MB, a cross-sectional study investigates the regulation to the prospective of medical device.

An instrument, apparatus, implement, machine, implant, in vitro reagent, a component part or accessory which Intended for use in diagnosis of disease or other condition, or in the cure, mitigation and treatment or prevention of disease is called medical devices. Medical devices under new rule classified as Class A (low risk), Class B (low moderate risk), Class C (moderate high risk), and Class D (high risk) commemorating the notification of January 31, 2017 of Ministry of Health and Family Welfare which is conformity with Global Harmonisation Task Force framework. As per make in India program, the industry of medical devices is USD 5.2 billion and is contributing 4%-5% to the USD 96.7 billion Indian health-care industry. A total of 750-800 medical device manufacturers in India, an average investment of Rs 170-200 million and an average turnover of Rs 450-500 million. An online licensing portal of the Central Drugs Standard Control Organization (CDSCO) called "Sugam portal" has been launched on November 14, 2015, to file application and grant permission of registration exclusively for Medical Device CDSCO MD Online portal. By making the document submission easier, there are lot of challenges also present in "Sugam-online Portal." One of the main challenges in Sugam Portal is that there is no provision to upload files greater than 10MB file size. The current study addresses the issues and challenges faced by medical device industry and regulators with their potential solutions and recommendations.

Polymeric worm-like nanomicellar system for accelerated wound healing.

Self-assembly is an unparalleled step in designing macromolecular analogs of nature's simple amphiphiles. Tailoring hydrogel systems - a material with ample potential for wound healing applications - to simultaneously alleviate infection and prompt wound closure is vastly appealing. The poly (DEAEMA-co-AAc) (PDEA) is examined with a cutaneous excisional wound model alterations in wound size, and histological assessments revealed a higher wound healing rate, including dermis proliferation, re-epithelialization, reduced scar formation, and anti-inflammatory properties. Moreover, a mechanism for the formation of spherical and worm-like micelles (WLMs) is delineated using a suite of characterizations. The excellent porosity and ability to absorb exudates impart the PDEA with reliable wound healing. Altogether, this system demonstrates exceptional promise as an infection-mitigating, cell-stimulating, homeostasis-maintaining dressing for accelerated wound healing. The aim and objective of this study is to understand the mechanism of self-assembly in synthesized WLMs from PDEA and their application in wound healing.

Antiepileptic potential and behavioral profile of L-pGlu-(2-propyl)-L-His-L-ProNH2, a newer thyrotropin-releasing hormone analog.

Thyrotropin-releasing hormone (TRH) and its analogs have a number of neurobiological functions and therapeutic uses in disorders of the central nervous system. In this study, the newly synthesized TRH analogs were evaluated for central nervous system activity in pentobarbital-induced sleeping in mice. The most potent TRH analog (L-pGlu-(2-propyl)-L-His-L-ProNH(2) coded as NP-647) was evaluated for its antiepileptic potential in various seizure models in mice in comparison with TRH. Intravenous pretreatment with NP-647 (10 and 20 micromol/kg body wt) significantly delayed the onset and reduced the frequency of convulsions in the pentylenetetrazole model, but not in the maximum electroshock seizure model. Also, it was found to be protective against picrotoxin- and kainic acid-induced seizures. However, NP-647 did not significantly affect theophylline-induced seizures. Further study of the effect of NP-647 on locomotor activity and a functional observational battery revealed that it did not significantly exhibit any undesirable effects as compared with vehicle and TRH. NP-647 did not significantly affect cerebral blood flow, whereas the native peptide TRH markedly increased cerebral blood flow. Furthermore, NP-647 exerted antiepileptic activity without significantly altering plasma thyroid-stimulating hormone levels and mean arterial blood pressure. This suggests that NP-647 is more selective for central nervous system activity and devoid of hormonal and cerebrovascular system effects. In contrast, TRH exhibited cardiac and endocrine effects as marked by significant elevation in mean arterial blood pressure and plasma thyroid-stimulating hormone levels. This study demonstrates that NP-647 has potential antiepileptic activity devoid of undesirable effects and, thus, can be exploited for the prevention and treatment of epilepsy.

A questionnaire-based study to assess the status and perspective of fixed-dose combination among the various stakeholders including regulators, clinicians, researchers, and industry.

Fixed-dose combinations (FDCs) dominating the global market because of better compliance. However, irrational combination can lead to human-made menace in terms of development of resistance, tolerance, drug abuse, and economy encumbrance. The US Food and Drug Administration defines a combination product as "a product composed of any combination of a drug and a device or a biological product and a device or a drug and a biological product or a drug, device, and a biological product." Unfortunately, many FDC being introduced in India are usually irrational. The need for the present study arises as the Indian drug regulatory system has been oscillating between central drug authorities versus state drug regulatory authorities. To assess the same fifty-six regulators and 70 other stakeholders including researchers, clinician, and industry people have exposed to 14 questions, and the same are used to get the insights of FDC among producers and consumers. All data were analyzed using Sigma plot Software. Data was presented in the form of percentage of response (responders vs. nonresponders, agree vs. disagree, yes vs. no). Most of the stakeholders (99%) stressed on Rule 122 to be strictly followed and same should be disseminated among all the stakeholders. Similarly, it was emphasized by more than 95% stakeholders that FDC contents should be tested as per official pharmacopoeia.

Protective effects of L-pGlu-(2-propyl)-L-His-L-ProNH2, a newer thyrotropin releasing hormone analog in in vitro and in vivo models of cerebral ischemia.

In the present study, the newly synthesized TRH analog (L-pGlu-(2-propyl)-L-His-l-ProNH(2); NP-647) was evaluated for its effects in in vitro (oxygen glucose deprivation (OGD)-, glutamate- and H(2)O(2)-induced injury in PC-12 cells) and in vivo (transient global ischemia) models of cerebral ischemic injury. PC-12 cells were subjected to oxygen and glucose deprivation for 6h. Exposure of NP-647 was given before and during OGD. In glutamate and H(2)O(2) induced injury, exposure of NP-647 was given 1, 6 and 24h prior to exposure of glutamate and H(2)O(2) exposure. NP-647, per se found to be non-toxic in 1-100µM concentrations. NP-647 showed protection against OGD at the 1 and 10µM. The concentration-dependent protection was observed in H(2)O(2)- and glutamate-induced cellular injury. In in vivo studies, NP-647 treatment showed protection of hippocampal (CA1) neuronal damage in transient global ischemia in mice and subsequent improvement in memory retention was observed using passive avoidance retention test. Moreover, administration of NP-647 resulted in decrease in inflammatory cytokines TNF-α and IL-6 as well as lipid peroxidation. These results suggest potential of NP-647 in the treatment of cerebral ischemia and its neuroprotective effect may be attributed to reduction of excitotoxicity, oxidative stress and inflammation.

Neuropharmacological profile of L-pGlu-(1-benzyl)-L-His-L-ProNH2, a newer thyrotropin-releasing hormone analog: effects on seizure models, sodium current, cerebral blood flow and behavioral parameters.

In the present study, L-pGlu-(1-benzyl)-L-His-L-ProNH(2) (NP-355), a newer CNS active thyrotropin-releasing hormone (TRH) analog was evaluated for its antiepileptic potential. NP-355 (5, 10 and 20 micromol/kg; i.v.) pretreatment significantly delayed onset and reduced the frequency of convulsions in pentylenetetrazole-induced seizures. NP-355 was also found to be protective against picrotoxin- and kainic acid-induced seizures. Maximum electroshock-induced seizures were not protected even at 20 micromol/kg in mice. Effects of NP-355 on functional observation battery did not exhibit any undesirable effects. Moreover, the antiepileptic activity produced by NP-355 was observed without significantly altering mean arterial blood pressure. NP-355 significantly increases the CBF to 17+/-3% as compared to saline (6+/-2%). NP-355 (100, 300 and 1000 microM) produces a concentration-dependent depression (16%, 63% and 77%, respectively) of the peak sodium current. NP-355 did not alter neurobehavioral parameters. This study demonstrates that NP-355 has potential antiepileptic activity and devoid of undesirable effects.