Jayabalan Nirmal
Nanyang Technological University
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Publication
Featured researches published by Jayabalan Nirmal.
The Journal of Urology | 2013
Jayabalan Nirmal; Pradeep Tyagi; Michael B. Chancellor; Jonathan Kaufman; Michele Anthony; David D. Chancellor; Yen-Ta Chen; Yao-Chi Chuang
PURPOSE The potent immunosuppressive effect of systemic tacrolimus is limited by the high incidence of severe adverse effects, including nephrotoxicity and hypertension. Intravesical application of tacrolimus is hindered by its poor aqueous solubility, justifying the search for novel delivery platforms such as liposomes. We evaluated the pharmacokinetics of tacrolimus encapsulated in liposomes (lipo-tacrolimus), which is being developed as a potential orphan drug indication for hemorrhagic cystitis. MATERIALS AND METHODS A single dose of lipo-tacrolimus was instilled in the bladder with the rat under anesthesia. Also, tacrolimus was instilled intravesically or injected intraperitoneally in other rat groups. The tacrolimus dose was constant in all formulations at 200 μg/ml. At different times blood, urine and bladder samples were collected and stored at -80C until analysis. Tacrolimus levels in samples were analyzed using microparticle enzyme immunoassay II. RESULTS The AUC of lipo-tacrolimus in serum at 0 to 24 hours was significantly lower than that of tacrolimus instillation or injection. Noncompartmental pharmacokinetic data analysis revealed maximum concentration of lipo-tacrolimus and tacrolimus in serum and urine at 1 and at 2 hours, respectively. Urine AUC(0-24) after intravesical administration was significantly higher than in the intraperitoneal group (p <0.05). Bladder tacrolimus AUC(0-24) did not differ significantly between the groups. CONCLUSIONS Single dose pharmacokinetics revealed that bladder instillation of liposome encapsulated tacrolimus significantly decreased systemic exposure to instilled tacrolimus as well as vehicle related toxicity. Intravesical liposomal tacrolimus may be a promising approach as an orphan drug indication for hemorrhagic cystitis.
PLOS ONE | 2015
Bharathi Raja Rajaganapathy; Michael B. Chancellor; Jayabalan Nirmal; Loan Dang; Pradeep Tyagi
Liposomes have been used therapeutically and as a local drug delivery system in the bladder. However, the exact mechanism for the uptake of liposomes by bladder cells is unclear. In the present study, we investigated the role of endocytosis in the uptake of liposomes by cultured human UROtsa cells of urothelium and rat bladder. UROtsa cells were incubated in serum-free media with liposomes containing colloidal gold particles for 2 h either at 37°C or at 4°C. Transmission Electron Microscopy (TEM) images of cells incubated at 37°C found endocytic vesicles containing gold inside the cells. In contrast, only extracellular binding was noticed in cells incubated with liposomes at 4°C. Absence of liposome internalization at 4°C indicates the need of energy dependent endocytosis as the primary mechanism of entry of liposomes into the urothelium. Flow cytometry analysis revealed that the uptake of liposomes at 37°C occurs via clathrin mediated endocytosis. Based on these observations, we propose that clathrin mediated endocytosis is the main route of entry for liposomes into the urothelial layer of the bladder and the findings here support the usefulness of liposomes in intravesical drug delivery.
PLOS ONE | 2014
Jayabalan Nirmal; Pradeep Tyagi; Yao-Chi Chuang; Wei-Chia Lee; Naoki Yoshimura; Chao-Cheng Huang; Bharathi Raja Rajaganapathy; Michael B. Chancellor
Background The functional and molecular alterations of nerve growth factor (NGF) and Prostaglandin E2 (PGE2) and its receptors were studied in bladder and urine in streptozotocin (STZ)-induced diabetic rats. Methodology/Principal Findings Diabetes mellitus was induced with a single dose of 45 mg/kg STZ Intraperitoneally (i.p) in female Sprague-Dawley rats. Continuous cystometrogram were performed on control rats and STZ treated rats at week 4 or 12 under urethane anesthesia. Bladder was then harvested for histology, expression of EP receptors and NGF by western blotting, PGE2 levels by ELISA, and detection of apoptosis by TUNEL staining. In addition, 4-hr urine was collected from all groups for urine levels of PGE2, and NGF assay. DM induced progressive increase of bladder weight, urine production, intercontraction interval (ICI) and residual urine in a time dependent fashion. Upregulation of Prostaglandin E receptor (EP)1 and EP3 receptors and downregulation of NGF expression, increase in urine NGF and decrease levels of urine PGE2 at week 12 was observed. The decrease in ICI by intravesical instillation of PGE2 was by 51% in control rats and 31.4% in DM group at week 12. Conclusions/Significance DM induced hyposensitive underactive bladder which is characterized by increased inflammatory reaction, apoptosis, urine NGF levels, upregulation of EP1 and EP3 receptors and decreased bladder NGF and urine PGE2. The data suggest that EP3 receptor are potential targets in the treatment of diabetes induced underactive bladder.
Drug Discovery Today | 2012
Gaurav K. Jain; Musarrat H. Warsi; Jayabalan Nirmal; Vaidehi Garg; Shadab A. Pathan; Farhan Jalees Ahmad; Roop K. Khar
In this review we discuss insights into therapeutic stratagems that can selectively target the choroid, retinal cells and vitreoretinal space for the treatment of vision-threatening vascular degenerative disorders of the posterior eye. Despite the relative success of these novel drugs, new problems related to its delivery remain. Systems carrying drugs to the target site, such as nanoparticles, liposomes, vectosomes, spanlastics, micelles, dendrimers and implants are also discussed. Further, we also consider drug penetration enhancement approaches along with cutting-edge strategies for regaining vision during vision-threatening vascular degenerative disorders of the eye. Finally, challenges, such as ocular or even systemic complications associated with use of prolonged therapies and future prospects, such as combination of approaches with multidisciplinary integration to optimize delivery to the posterior eye are also addressed.
Journal of Chromatography B | 2011
Jayabalan Nirmal; Thirumurthy Velpandian; Sundararajan Baskar Singh; Nihar Ranjan Biswas; Vasantha Thavaraj; Rajvardhan Azad; Supriyo Ghose
Tetraethylammonium is widely used as a probe in organic cation transporters studies. A simple, highly sensitive, and specific method using direct protein precipitation was developed using Hydrophilic Interaction Liquid Chromatography coupled with positive electrospray ionization tandem mass spectrometry for the determination of tetraethylammonium (TEA) in rabbit plasma. Isocratic separation was achieved using a ZIC-HILIC column with acetonitrile and 5mM ammonium acetate in the ratio of 8:2 containing 0.1% formic acid. Acquisition was performed in multiple reaction monitoring mode with the transitions: m/z 130→100 and 130→86 for TEA and m/z 276.1→142.2 for internal standard (homatropine). This method was validated to determine selectivity, linearity, sensitivity, precision, accuracy, recovery and stability. A good linearity was found within a range of 1.53-784.6 ng/mL. The above method has been demonstrated for its capability to estimate the plasma levels of TEA after its topical instillation in rabbit eyes. This method provides an accurate, precise and sensitive tool for determining TEA levels for transporter studies.
Journal of Chromatography B | 2014
Beauty Arora; Angayarkanni Narayanasamy; Jayabalan Nirmal; Nabanita Halder; Santosh Patnaik; Alok Kumar Ravi; Thirumurthy Velpandian
The present study demonstrates the development and validation of a sensitive method for the quantification of homocysteine thiolactone (HCTL) in human plasma using the technique of LC-MS/MS. The gradient elution of HCTL was achieved within 5min using ZIC HILIC column having acetonitrile with 0.1% formic acid and water with 0.1% formic acid. The method was validated for the linearity, sensitivity, accuracy, precision, recovery, matrix effect and stability. A good linearity was found within a range of 0.5-32.5nmol/ml. Quantification was performed using multiple reaction monitoring (MRM) mode based on the molecular/fragment ion transitions for HCTL (118/56) and homatropine (276.1/142.2) as internal standard. Generally, HCTL levels in plasma were found to be highly unstable. In order to verify the stability of the HCTL levels in plasma for a longer period, the samples were extracted immediately and stored at -86°C. Using the above method it was found to be stable for a period of 1 month. The method was well applied for quantification of HCTL in plasma of healthy human volunteers.
Pharmaceutica Analytica Acta | 2011
Nanjappan Satheesh Kumar; Narayanan Nisha; Jayabalan Nirmal; Narayanan Sonali; J Bagyalakshmi
A simple, sensitive, reliable and rapid reversed-phase high-performance liquid chromatographic (RP-HPLC) method has been developed and validated for the determination of pitavastatin calcium using paracetamol as internal standard. The chromatographic system consisted of Shimadzu LC-10ATVP Pump, SPD-M10 AVP with PDA detector. Separation was achieved on the phenomenex C 18 (250 x 4.60), 5 μ particle size column in isocratic mode at room temperature. The sample was introduced through an injector valve with a 20 μl, sample loop. 0.5% Acetic acid: Acetonitrile 35:65 (%, v/v), was used as mobile phase with flow rate of 1 ml/min. UV detection was performed at 245 nm. A calibration graph was plotted which showed a linearity range between 1-5 μg/ml with the correlation coefficient of 0.9986. The LOD was 5 ng/ ml, while the LOQ was 20 ng/ml. Validation studies revealed the method is specific, rapid, reliable, and reproducible. To study the validity of the method, recovery studies and repeatability studies were carried out using the same optimum conditions. The system suitability studies were also calculated which includes column efficiency, resolution, capacity factor and peak asymmetrical factor. Therefore the proposed method is reliable, rapid, precise and selective so may be used for the quantitative analysis of pitavastatin calcium.
Drug Discovery Today | 2017
Krishna Radhakrishnan; Nirmal Sonali; Miguel Moreno; Jayabalan Nirmal; Alexandra Alvarez Fernandez; Subbu S. Venkatraman; Rupesh Agrawal
Utilization of the full clinical potential of many novel therapeutic proteins designed for diseases affecting the posterior segment of the eye has often been limited because of their inherent instability and the difficulty in overcoming various ocular barriers. Intravitreal injection is currently the only approved mode of administration, although it is suboptimal because it is painful and has to be done every 1-2 months as a result of high protein clearance rates from the vitreous humor. In this review, we discuss the status of protein drug delivery to back of the eye in terms of novel protein drugs developed, physiological barriers encountered, strategies for carrier design to overcome these limitations, and protein stability. We focus on the most promising approaches as well as on current shortcomings.
European Journal of Pharmaceutics and Biopharmaceutics | 2016
Miguel Moreno; T.S. Tabitha; Jayabalan Nirmal; Krishna Radhakrishnan; C.H. Yee; Soo Ghim Lim; Subbu S. Venkatraman; Rupesh Agrawal
The anti-vascular endothelial growth factor (VEGF) agents such as ranibizumab (Lucentis®) and aflibercept (EyLea®) are currently used as monthly or bimonthly intravitreal injections to treat potentially retinal diseases such as wet age-related macular degeneration (AMD) or diabetic macular edema (DME). Because of the complications associated with repeated intra-vitreal injections, there is considerable interest in developing a sustained delivery system. The purpose of this study was to examine the stability of both therapeutic proteins under physiological conditions as well as when incorporated into drug delivery systems (DDS). First, thermotropic properties in physiological conditions and at different pH values were evaluated by differential scanning calorimetry (DSC) to determine the protein denaturation temperature. Second, the effects of pH and incubation time on conformational changes and aggregation were evaluated by circular dichroism (CD), steady-state tryptophan fluorescence spectroscopy, and size-exclusion chromatography (SEC). Also, the ability of both proteins to bind to VEGF was tested in the aforementioned experimental conditions for up to 30 days. Finally, we investigated the stability of both proteins after a rapid screening method that simulates the first homogenizing step during the protein microencapsulation process. This method allowed the development of stable ranibizumab and aflibercept formulations that may be useful to entrap these proteins into microparticles selecting the most convenient organic solvent and protein stabilizers.
Medical Hypotheses | 2013
Vaidehi Garg; Gaurav K. Jain; Jayabalan Nirmal; Kanchan Kohli
Uveitis is a sight threatening inflammatory disorder that affects all ages and remains a significant cause of visual loss. Inflammatory activity plays an important role in the whole pathogenesis of uveitis. Treatment of uveitis is mainly driven by corticosteroids that have potential side effects. Recent investigations demonstrated that tacrolimus inhibits T-cell proliferation and suppresses release of inflammatory cytokines. Since tacrolimus is a definite immunosuppressive agent, and since inflammatory process has been involved in uveitis, the compound must have effect on the progression of uveitis through reduction in inflammatory activity. Even results of the clinical trials demonstrate that tacrolimus have useful role in treatment of sight threatening uveitis that is refractory to other therapy. Studies also indicate that long term use of tacrolimus is well tolerated. However, its use in uveitis is limited because of its poor physico-chemical properties including poor aqueous solubility and high molecular weight (822 Da). Therefore, we have proposed that tacrolimus nanoemulsion administered topically is a promising therapeutic approach to treat uveitis. Based on previous evidences, we have hypothesized that nanoemulsion formulation of tacrolimus can improve efficacy and safety profile of tacrolimus.