Etiopathology, Epidemiology, Diagnosis, and Treatment of Fungal Keratitis.

Fungal keratitis (FK) is a severe ocular condition resulting from corneal infection that is prevalent in tropical countries, particularly in developing regions of Asia and Africa. Factors like corneal lens misuse, inappropriate steroid use, and diagnostic challenges have provoked the epidemic. FK causes significant vision impairment, scarring, and ocular deformities. Accurate pathological diagnosis is crucial for effective therapeutic intervention. Topical antifungal therapy with surface healing medications proves effective in preventing fungal-borne ulcers. Managing FK requires a comprehensive understanding of fungal pathogenesis, guiding formulation strategies and preventive measures to curb global ocular blindness. This review provides in-depth insights into FK, covering etiology, epidemiology, pathogenesis, therapeutic interventions, antifungal resistance, limitations, prevention, and future perspectives on ocular surface disease management.

Nanocarrier - Mediated Salinomycin Delivery Induces Apoptosis and Alters EMT Phenomenon in Prostate Adenocarcinoma.

Salinomycin (Sal) has been recently discovered as a novel chemotherapeutic agent against various cancers including prostate cancer which is one of the most commonly diagnosed cancers affecting male populations worldwide. Herein we designed salinomycin nanocarrier (Sal-NPs) to extend its systemic circulation and to increase its anticancer potential. Prepared nanoform showed high encapsulation and sustained release profile for salinomycin. The present study elucidated the cytotoxicity and mechanism of apoptotic cell death of Sal-NPs against prostate cancer both in vitro and in vivo. At all measured concentrations, Sal-NPs showed more significant cytotoxicity to DU145 and PC3 cells than Sal alone. This effect was mediated by apoptosis, as confirmed by ROS generation, loss of MMP and cell cycle arrest at the G1 phase in both cells. Sal-NPs efficiently inhibited migration of PC3 and DU145 cells via effectively downregulating the epithelial mesenchymal transition. Also, the results confirmed that Sal-NPs can effectively inhibit the induction of Prostate adenocarcinoma in male Wistar rats. Sal-NPs treatment exhibited a decrease in tumour sizes, a reduction in prostate weight, and an increase in body weight, which suggests that Sal-NPs is more effective than salinomycin alone. Our results suggest that the molecular mechanism underlying the Sal-NPs anticancer effect may lead to the development of a potential therapeutic strategy for treating prostate adenocarcinoma.

Codetermination of antimicrobial agents in rabbit tear fluid using LC-MS/MS assay: Insights into ocular pharmacokinetic study.

Managing ocular microbial infections typically requires pharmacotherapy using antibiotic eye drops, such as moxifloxacin hydrochloride (MFX), combined with an antifungal agent like amphotericin B (AB). We carried out and validated an LC-MS/MS assay to quantify these compounds in rabbit tear fluid in order to look into the pharmacokinetics of these two drugs. We employed a protein precipitation technique for the extraction of drugs under examination. A Waters Symmetry C18 column was used to separate the analytes and internal standard. The composition of the mobile phase was like (A) 0.1% v/v formic acid in water and (B) methanol. The detection of MFX and AB was accomplished through the utilization of positive ion electrospray ionization under multiple reaction monitoring mode. The linearity curves for both analytes exhibited an acceptable trendline across a concentration range of 2.34-300 ng/mL for MFX and 7.81-1000 ng/mL for AB in surrogate rabbit tear fluid. The lower limit of quantitation for MFX was 2.34 ng/mL, while for AB, it was 7.81 ng/mL. The approach was strictly validated, encompassing tests of selectivity, linearity (with r2 > 0.99), precision, accuracy, matrix effects, and stability. Consequently, we employed this method to evaluate the pharmacokinetics profiles of MFX and AB in rabbit tear fluid following single topical doses.

Pharmaceutical Emulsions: A Viable Approach for Ocular Drug Delivery.

Ocular disorders can lead to serious sight impairment and irreversible blindness. Generally simple topical and systemic treatments are recommended for treating these vision-threatening illnesses. The distinctive architecture of the eye complicates ocular drug delivery. The ophthalmic emulsion formulations have been found to increase bioavailability in the eye by prolonging residence time and improving permeability through the cornea. Therefore, this study highlights ophthalmic emulsions meant for both the anterior and posterior parts of the eye while examining a wide range of ocular disorders that affect individuals globally. This review presents, in brief, recent emulsion-based patented innovations, clinical trials, and marketed emulsion formulations for ocular drug delivery, which are strengthening development of the new ophthalmic drug products for managing different ocular diseases and disorders.

Solanum nigrum Toxicity and Its Neuroprotective Effect Against Retinal Ganglion Cell Death Through Modulation of Extracellular Matrix in a Glaucoma Rat Model.

Purpose: Glaucoma is a complex degenerative optic neuropathy characterized by loss of retinal ganglion cells (RGCs) leading to irreversible vision loss and blindness. Solanum nigrum has been used for decades in traditional medicine system. However, no extensive studies were reported on its antiglaucoma properties. Therefore, this study was designed to investigate the neuroprotective effects of S. nigrum extract on RGC against glaucoma rat model. Methods: High performance liquid chromatography and liquid chromatography tandem mass spectrometry was used to analyze the phytochemical profile of aqueous extract of S. nigrum (AESN). In vitro, {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide} (MTT) and H2DCFDA assays were used to determine cell viability and reactive oxygen species (ROS) production in Statens Seruminstitut Rabbit Cornea cells. In vivo, AESN was orally administered to carbomer-induced rats for 4 weeks. Intraocular pressure, antioxidant levels, and electrolytes were determined. Histopathological and immunohistochemical analysis was carried out to evaluate the neurodegeneration of RGC. Results: MTT assay showed AESN exhibited greater cell viability and minimal ROS production at 10 µg/mL. Slit lamp and funduscopy confirmed glaucomatous changes in carbomer-induced rats. Administration of AESN showed minimal peripheral corneal vascularization and restored histopathological alterations such as minimal loss of corneal epithelium and moderate narrowing of the iridocorneal angle. Immunohistochemistry analysis showed increased expression of positive BRN3A cells and decreased matrix metalloproteinase (MMP)-9 activation in retina and cornea, whereas western blot analysis revealed downregulation of extracellular matrix proteins (COL-1 and MMP-9) in AESN-treated rats compared with the diseased group rats. Conclusions: AESN protects RGC loss through remodeling of MMPs and, therefore, can be used for the development of novel neurotherapeutics for the treatment of glaucoma.

Polymers and their engineered analogues for ocular drug delivery: Enhancing therapeutic precision.

Ocular drug delivery is constrained by anatomical and physiological barriers, necessitating innovative solutions for effective therapy. Natural polymers like hyaluronic acid, chitosan, and gelatin, alongside synthetic counterparts such as PLGA and PEG, have gained prominence for their biocompatibility and controlled release profiles. Recent strides in polymer conjugation strategies have enabled targeted delivery through ligand integration, facilitating tissue specificity and cellular uptake. This versatility accommodates combined drug delivery, addressing diverse anterior (e.g., glaucoma, dry eye) and posterior segment (e.g., macular degeneration, diabetic retinopathy) afflictions. The review encompasses an in-depth exploration of each natural and synthetic polymer, detailing their individual advantages and disadvantages for ocular drug delivery. By transcending ocular barriers and refining therapeutic precision, these innovations promise to reshape the management of anterior and posterior segment eye diseases.

Pirfenidone: A Promising Drug in Ocular Therapeutics.

Pirfenidone, initially indicated for lung fibrosis, has gone beyond its original purpose, and shown promise in eye care. This detailed review tracks its evolution from lung treatment to aiding eye healing as evidenced by published literature. Pirfenidone's multifaceted attributes extend to mitigating corneal fibrosis, inflammation, and trauma. Through rigorous investigations, its efficacy emerges in diabetic retinopathy, macular degeneration, and postoperative glaucoma interventions. As an unheralded protagonist, pirfenidone reshapes ocular care paradigms, inviting renewed research opportunities.

Design, synthesis and biological evaluation of novel pyrimidine derivatives as bone anabolic agents promoting osteogenesis via the BMP2/SMAD1 signaling pathway.

Anti-resorptive inhibitors such as bisphosphonates are widely used but they have limited efficacy and serious side effects. Though subcutaneous injection of teriparatide [PTH (1-34)] is an effective anabolic therapy, long-term repeated subcutaneous administration is not recommended. Henceforth, orally bio-available small-molecule-based novel therapeutics are unmet medical needs to improve the treatment. In this study, we designed, synthesized, and carried out a biological evaluation of 31 pyrimidine derivatives as potent bone anabolic agents. A series of in vitro experiments confirmed N-(5-bromo-4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-yl)hexanamide (18a) as the most efficacious anabolic agent at 1 pM. It promoted osteogenesis by upregulating the expression of osteogenic genes (RUNX2 and type 1 col) via activation of the BMP2/SMAD1 signaling pathway. In vitro osteogenic potential was further validated using an in vivo fracture defect model where compound 18a promoted the bone formation rate at 5 mg kg-1. We also established the structure-activity relationship and pharmacokinetic studies of 18a.

Ocular bioanalysis of moxifloxacin and ketorolac tromethamine in rabbit lacrimal matrix using liquid chromatography-tandem mass spectrometry.

Aim: The fixed-dose combination of moxifloxacin (MOXI) and ketorolac tromethamine (KTR) is widely used for the treatment of bacterial keratitis. Thus, a new LC-MS/MS method was developed to determine MOXI and KTR in lacrimal fluid. Methods: Bioanalysis was performed using a Shimadzu 8050 LC-MS/MS in electrospray ionization-positive mode and the method was validated per US FDA guidelines. Isocratic separation was performed with a Waters Symmetry C18 column using methanol and 0.1% formic acid containing deionized water (85:15, v/v). Results & conclusion: An easy, quick and selective method was established and applied to assess the ocular pharmacokinetic profile of a commercially available formulation containing MOXI and KTR. Based on the pharmacokinetic data, this work describes pharmacokinetics-based dosage regimen calculations and their clinical significance.

Quantification of Arbortristoside-A isolated from Nyctanthes arbor-tristis using HPLC: Method development and pharmaceutical applications.

Arbortristoside-A (Arbor-A) is a naturally occurring iridoid glycoside and herbal-based lead molecule with proven medicinal potential. Aiming at the development of an efficient analytical tool for the quantification of Arbor-A in pharmaceutical dosage forms, in the presented work, we developed an economical, fast, and sensitive RP-HPLC-UV method and validated the procedure as per the ICH guidelines, Q2(R1). The chromatographic separation was accomplished under the optimised experimental conditions using an HPLC system with an LC-2010 autosampler, a PDA detector, and a Phenomenex C18 column with the mobile phase composed of a 70:30 (v/v) water-acetonitrile mixture eluting isocratically at a flow rate of 1 mL/min at ambient temperature, and UV detection at 310 nm. Arbor-A showed a sharp peak at the retention time of 5.60 min and exhibited linearity (R2 = 0.9988) with LOD and LOQ of 0.50 µg/mL and 1.50 µg/mL, respectively. The accuracy of the method was 98.33-101.36 % with acceptable intra-day and inter-day precisions as well as robustness (<2% RSD). To ratify the applicability of the presented approach in emerging pharmaceuticals, a nanoformulation loaded with Arbor-A was designed and analysed utilising the provided methodology. The method has also enabled to determine the degradation kinetics of Arbor-A under stress conditions, etcetera, employing forced degradation and short term stability studies.

Recent Insights into the Etiopathogenesis of Diabetic Retinopathy and Its Management.

Purpose: Diabetic retinopathy (DR) is a microvascular retinal disease associated with chronic diabetes mellitus, characterized by the damage of blood vessels in the eye. It is projected to become the leading cause of blindness, given the increasing burden of the diabetic population worldwide. The diagnosis and management of DR pose significant challenges for physicians because of the involvement of multiple biochemical pathways and the complexity of ocular tissues. This review aims to provide a comprehensive understanding of the molecular pathways implicated in the pathogenesis of DR, including the polyo pathway, hexosamine pathway, protein kinase C (PKC), JAK/STAT signaling pathways, and the renin-angiotensin system (RAS). Methods: Academic databases such as PubMed, Scopus, Google Scholar and Web of Science was systematically searched using a carefully constructed search strategy incorporating keywords like "Diabetic Retinopathy," "Molecular Pathways," "Pharmacological Treatments," and "Clinical Trials" to identify relevant literature for the comprehensive review. Results: In addition to activating other inflammatory cascades, these pathways contribute to the generation of oxidative stress within the retina. Furthermore, it aims to explore the existing pharmacotherapy options available for the treatment of DR. In addition to conventional pharmacological therapies such as corticosteroids, antivascular endothelial growth factors, and nonsteroidal anti-inflammatory drugs (NSAIDs), this review highlights the potential of repurposed drugs, phyto-pharmaceuticals, and novel pipeline drugs currently undergoing various stages of clinical trials. Conclusion: Overall, this review serves as a technical exploration of the complex nature of DR, highlighting both established and emerging molecular pathways implicated in its pathogenesis. Furthermore, it delves into the available pharmacological treatments, as well as the promising repurposed drugs, phyto-pharmaceuticals, and novel drugs currently being evaluated in clinical trials, with a focus on their specific mechanisms of action.

Concurrent determination of anti-microbial and anti-inflammatory drugs in lachrymal fluid and tissue by LC-MS/MS: A potential treatment for microbial keratitis and its PK-PD evaluation.

Unforeseen surfacing of microbial keratitis (MKT) over the years has led to a requisite for promising treatment strategy involving combination of antifungal and antibacterial agents. Subsequently, symptoms associated with MKT including inflammation and watery eyes require treatment with anti-inflammatory agents. Thus, a requirement of functional clinical treatment strategy involving combination of anti-inflammatory corticosteroids (Betamethasone) with antifungal polyene (Amphotericin B, AmB) and antibacterials macrolide (Azithromycin, AZT) and aminoglycoside (Neomycin, NEO). In the ensuing pursuit, a sensitive and fast simultaneous LC-MS/MS method of four drastically different analytes in rabbit tear fluid and cornea was developed and validated as per US-FDA guidelines. The gradient LC set-up was used with C18 column and flow rate of 0.55 mL/min along with short run time of 7 min. The calibration curves showed good linearity over the concentration range of 0.07-300 ng/mL, 1.00-400 ng/mL, 3.00-600 ng/mL and 8.00-900 ng/mL for AZT, AmB, NEO and BEM respectively. The bioanalytical method requires only 10 µL of ocular sample and analytes were extracted with fast protein precipitation with acidic methanol. Finally, the developed method was validated for selectivity, linearity (r2 > 0.99), precision, accuracy, matrix effects, and stability. PK-PD indices and dosing frequency was predicted using Phoenix WinNonlin Software, based on single dose ocular pharmacokinetics and MIC values of AmB, AZT and NEO. According to the PK-PD simulation, S. aureus and E. coli required 6 and 12 instillations of AZT per 24 h, respectively whereas 12 instillation of NEO requires per 24 h for S. aureus. The result suggests that to minimize antimicrobial resistance; drug, dose and dosing schedule depend upon the pathogen as well as the strain.

Preclinical pharmacokinetic exploration of a novel osteoporotic quinazolinone-benzopyran-indole hybrid (S019-0385) using LC-MS/MS.

1. The current investigation was to develop and validate the LC-MS/MS method in order to analyse the various pharmacokinetic parameters of S019-0385. A sensitive, selective, and robust LC-MS/MS approach was established and validated for measuring S019-0385 in female mice plasma and tissue, using optimal multiple reaction monitoring (MRM) transition m/z 488.25/329.12 on positive mode. On a Waters Symmetry Shield C18 column, the analyte was separated using acetonitrile and deionised water with formic acid within 6 min at 0.7 mL/min. Linearity (R2 ≥ 0.99) was observed across 0.195-100 ng/mL concentration range using linear least-squares regression.2. Blood-to-plasma ratio and plasma protein drug binding (%) in mice and human was assessed and found to be less than 1 and >83%, respectively. Absolute bioavailability (%F) of S019-0385 in female Swiss mice was exhibited to be 6.90%. Percent dose excreted S019-0385 in unchanged form through urine and faecal was found to be less than 2% and 0.5%, respectively.3. Following oral administration at 5 mg/kg, the concentration of S019-0385 in tissue distribution was found to be in the order of C small intestine > C bone > C lung > C spleen > C kidney > C liver > C heart > C brain.

Combining donepezil and memantine via mannosylated PLGA nanoparticles for intranasal delivery: Characterization and preclinical studies.

The current work is focused on developing mannose-coated PLGA nanoparticles for delivering Donepezil and Memantine in one dosage form. The formulated nanoparticles were prepared using a simple emulsification technique. The final coated NPs exhibited 179.4 nm size and - 33.1 mV zeta potential and spherical shape. The concentration of IN-administrated MEM and DPZ mannose coated NPs in brain was ~573 and 207 ng/mL respectively. This amount accounts for 3 times more in comparison to uncoated NPs administered via intranasal and peroral routes. The plasma concentration of coated NPs administered via the intranasal route was various times less in comparison to other groups. In the field of pharmacodynamics, the administration of coated NPs via the IN route has shown superior efficacy in comparison to other groups in various investigations involving neurobehavioral assessments, gene expression analyses and biochemical estimations. The findings indicate that the IN route may be a potential avenue for delivering therapeutic agents using nanoparticles to treat neurological illnesses. This approach shows promise as a viable alternative to traditional dose forms and administration methods.

Trends in Formulation Approaches for Sustained Drug Delivery to the Posterior Segment of the Eye.

The eye, an intricate organ comprising physical and physiological barriers, poses a significant challenge for ophthalmic physicians seeking to treat serious ocular diseases affecting the posterior segment, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Despite extensive efforts, the delivery of therapeutic drugs to the rear part of the eye remains an unresolved issue. This comprehensive review delves into conventional and innovative formulation strategies for drug delivery to the posterior segment of the eye. By utilizing alternative nanoformulation approaches such as liposomes, nanoparticles, and microneedle patches, researchers and clinicians can overcome the limitations of conventional eye drops and achieve more effective drug delivery to the posterior segment of the eye. These innovative strategies offer improved drug penetration, prolonged residence time, and controlled release, enhancing therapeutic outcomes for ocular diseases. Moreover, this article explores recently approved delivery systems that leverage diverse polymer technologies, such as chitosan and hyaluronic acid, to regulate drug-controlled release over an extended period. By offering a comprehensive understanding of the available formulation strategies, this review aims to empower researchers and clinicians in their pursuit of developing highly effective treatments for posterior-segment ocular diseases.

Design, synthesis, and biological evaluation of quinoline-piperazine/pyrrolidine derivatives as possible antileishmanial agents.

In pursuance of our efforts to expand the scope of novel antileishmanial entities, a series of thirty-five quinoline-piperazine/pyrrolidine, and other heterocyclic amine derivatives were synthesized via a molecular hybridization approach and examined against intracellular amastigotes of luciferase-expressing Leishmania donovani. The preliminary in vitro screening suggests that twelve compounds in the series exhibited better inhibition against amastigote form with good IC50 values ranging from 2.09 to 8.89 µM and lesser cytotoxicity in contrast to the standard drug miltefosine (IC50 9.25 ± 0.17 µM). Based on the satisfactory selectivity index (SI), two compounds were tested for in vivo leishmanicidal efficacy against Leishmania donovani/golden hamster model. Compounds 33 and 46 have shown significant inhibition of 56.32%, and 49.29%, respectively, in vivo screening at a daily dose of 50 mg/kg for 5 days. The pharmacokinetic results confirmed that 33 and 46 have satisfactory IP exposure with adequate parameters. Collectively, Compound 33 was identified as the most significant potential lead that could be employed as a prototype for future optimizations.

Hesperidin: Enrichment, forced degradation, and structural elucidation of potential degradation products using spectral techniques.

RATIONALE: Hesperidin (HES) is a well-known citrus bioflavonoid phyto-nutraceutical agent with polypharmacological properties. After 2019, HES was widely used for prophylaxis and COVID-19 treatment. Moreover, it is commonly prescribed for treating varicose veins and other diseases in routine clinical practice. Pharmaceutical impurities and degradation products (DP) impact the drug's quality and safety and thus its effectiveness. Therefore, forced degradation studies help study drug stability, degradation mechanisms, and their DPs. This study was performed because stress stability studies using detailed structural characterization of hesperidin are currently unavailable in the literature. METHODS: In the HES enrichment method crude HES was converted to its pure form (98% purity) using column chromatography and then subjected to forced degradation under acid, base, and neutral hydrolyses followed by oxidative, reductive, photolytic, and thermal stress testing (International Conference on Harmonization guidelines). The stability-indicating analytical method (SIAM) was developed to determine DPs using reversed-phase high-performance liquid chromatography (C18 column with methanol and 0.1% v/v acetic acid in deionized water [70:30, v/v] at 284 nm). Further, structural characterization of DPs was performed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and nuclear magnetic resonance (NMR) spectroscopy. In addition, in silico toxicity predictions were performed using pKCSM and DataWarior freeware. RESULTS: HES was found to be susceptible to acidic and basic hydrolytic conditions and yielded three DPs in each, which were detected using designed SIAM. Of six DPs, three were pseudo-DPs (short lived), and the remaining were characterized using LC-MS/MS and NMR spectroscopy. The tentative mechanism of the formation of proposed DPs was explained. The proposed DPs were found inactive from in silico toxicity predictions. CONCLUSIONS: Hesperidin was labile under acidic and basic stress conditions. The potential DPs were characterized using LC-ESI-MS/MS and NMR spectral techniques. The proposed mechanism of formation was hypothesized. In addition, to identify and characterize the DPs, a SIAM, which has broad biomedical applications, was successfully developed.

Ophthalmic nano-bioconjugates: critical challenges and technological advances.

Ophthalmic disease can cause permanent loss of vision and blindness. Easy-to-administer topical and systemic treatments are preferred for treating sight-threatening disorders. Typical ocular anatomy makes topical and systemic ophthalmic drug delivery challenging. Various novel nano-drug delivery approaches are developed to attain the desired bioavailability in the eye by increasing residence time and improved permeability across the cornea. The review focuses on novel methods that are biocompatible, safe and highly therapeutic. Novelty in nanocarrier design and modification can overcome their drawbacks and make them potential drug carriers for eye disorders in both the anterior and posterior eye segments. This review briefly discussed technologies, patented developments, and clinical trial data to support nanocarriers' use in ocular drug delivery.

Preclinical Pharmacokinetics and CYP Modulation Activity of Chebulinic Acid: A Potent Molecule Against Metabolic Disease.

BACKGROUND: Chebulinic acid (CA) is an active constituent of Terminalia chebula fruits with therapeutic potential against multiple metabolic diseases, including dementia, benign prostate hyperplasia, and osteoporosis. OBJECTIVE: The present work intends to explore the preclinical pharmacokinetics, including the absolute bioavailability of CA and its influence on the gene expression of cytochrome P450 enzymes in the liver. METHODS: Quantifying CA and probe drugs in vitro samples and preclinical serum samples of male SD rats were performed using LC-MS/MS. The influence of CA on the hepatic CYPs and their gene expression was analyzed in rat liver by quantitative real-time polymerase chain reaction. RESULTS: The plasma protein binding was found to be 84.81 ± 7.70 and 96.34 ± 3.12, blood-to-plasma ratio of 0.62 ± 0.16 and 0.80 ± 0.23 at 1 µM and 10 µM concentrations, respectively. Again, the absolute oral bioavailability of CA at 100 mg/kg was found to be 37.56 ± 7.3%. The in-vivo pharmacokinetic profile of probe drugs revealed CA to have significant inducing effects on CYP1A2, 2C11, 2D2, and 2E1 after 14 days, which correlates to both in-vitro rat microsomal data and gene expression results. CONCLUSION: Altogether, pharmacokinetic parameters reveal CA to have an affinity to distribute across different extravascular tissues and induce rat liver CYP enzymes.

Recent Update on Pharmacokinetics and Drug Metabolism in CNS-based Drug Discovery.

Despite significant advancements in CNS research, CNS illnesses are the most important and serious cause of mental disability worldwide. These facts show a tremendous unmet demand for effective CNS medications and pharmacotherapy since it accounts for more hospitalizations and extended care than practically all other disorders combined. The site-targeted kinetics of the brain and, pharmacodynamics of CNS effects are determined/regulated by various mechanisms after the dose, including blood-brain barrier (BBB) transport and many other processes. These processes are condition-dependent in terms of their rate and extent because they are dynamically controlled. For effective therapy, drugs should access the CNS "at the right place, time, and concentration". Details on inter-species and inter-condition variances are required to translate target site pharmacokinetics and associated CNS effects between species and illness states, improving CNS therapeutics and drug development. The present review encircles a short discussion about the barriers that affect effective CNS treatment and precisely focuses on the pharmacokinetics aspects of efficient CNS therapeutics.