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Nirmal J.,All India Institute of Medical Sciences | Singh S.B.,All India Institute of Medical Sciences | Biswas N.R.,All India Institute of Medical Sciences | Thavaraj V.,Indian Council for Medical Research | And 2 more authors.
Eye (Basingstoke) | Year: 2013

PurposeWe hypothesize organic cation transporters (OCT) may have a potential role in determining the pharmacokinetics and toxicity of organic cation drugs applied topically. Hence, in the present in vivo study, we attempted to evaluate the role of OCT in modulating the transport of its substrates after topical application.MethodsNew Zealand albino rabbits of either sex were used. Transcorneal penetration of OCT substrates tetraethylammonium and metformin after single instillation was evaluated in the absence and presence of OCT blockers (quinidine and atropine). Aqueous humor (AH) samples were collected through paracentesis amounting to 70-100 μl under topical anesthesia at various time intervals. The samples were subjected for estimation of both substrate as well as blocker concentrations using liquid chromatography mass spectrometry.ResultsTopical pre-treatment (30 min before substrate) of OCT blockers significantly decreased the transcorneal penetration of OCT substrates after single topical administration. The levels of blockers reaching AH in the presence of substrates were also modulated at 60 min after its administration as compared with its control.ConclusionOCT are functionally active in the uptake of their substrates from tear to AH. Therefore, OCT in the corneal epithelium may be positioned from apical to basolateral. When administering their substrates/blockers topically, both may be competing for OCT for their uptake across the cornea, thereby decreasing the corneal penetration. Hence OCT can have a potential pharmacokinetic role in modulating the ocular bioavailability of their substrates administered topically, which are used as ocular therapeutics. © 2013 Macmillan Publishers Limited. All rights reserved.

Purohit P.,Veer Surendra Sai Medical College | Mashon R.S.,Veer Surendra Sai Medical College | Mashon R.S.,Indian Council for Medical Research | Patel S.,Veer Surendra Sai Medical College | And 8 more authors.
International Journal of Laboratory Hematology | Year: 2014

Introduction: Hb Hofu (HBB:c. 380T>A) is a rare inherited hemoglobin abnormality with few case reports in the world literature. Methods: Screening for the sickle cell gene mutation and other hemoglobinopathies was carried out using the sickle slide test, Hb electrophoresis, and HPLC under an ongoing central government project. Results: We detected twelve Hb Hofu heterozygotes and three sickle Hb Hofu compound heterozygotes. The heterozygotes were asymptomatic except for one individual who had chronic kidney disease and moderate anemia. Only one HbS-Hofu case was symptomatic and presented with intermittent attacks of painful crisis. In the carrier state, the Hb Hofu eluted as a hump at the beginning of the HbA0 window. But in HbS-Hofu cases, Hb Hofu eluted as a single peak in the HbA0 window, with the HbA2 levels being >4% consistently. Conclusion: HbS-Hofu has a variable clinical presentation. The retention time of Hb Hofu on HPLC is very close to that of HbA0 and often elutes in the A0 window. Thus, there is every possibility of the HbS-Hofu chromatogram to be misinterpreted as that of a sickle cell trait/transfused sickle cell-beta-thalassemia case. This is the first time where Hb Hofu has been detected by HPLC, which is the widely accepted screening technique for hemoglobinopathies around the world. © 2013 John Wiley & Sons Ltd.

Nirmal J.,All India Institute of Medical Sciences | Sirohiwal A.,All India Institute of Medical Sciences | Singh S.B.,All India Institute of Medical Sciences | Biswas N.R.,All India Institute of Medical Sciences | And 3 more authors.
Experimental Eye Research | Year: 2013

The present study was conducted to test the hypothesis; OCT may be active from blood-to-vitreous for the uptake of its substrates. Ocular uptake of Tetraethylammonium (TEA) across blood ocular barriers and the tissue distribution was evaluated invivo in New Zealand albino rabbits after intravenous administration. Quinidine (blocker) pretreatment resulted in a significant (p<0.05) reduction in the Area Under the Curve (AUC) of TEA in vitreous (4.2 fold) and aqueous humor (1.8 fold) as compared to the control group which supports the role of OCT in uptake transport of its substrate across Blood ocular barrier. The blockade of OCT also affected the elimination of its substrate resulting in increased plasma levels. In most of the tissues, OCT are functionally present from apical to basolateral. The gene expression studies also showed the presence of OCT1, OCTN1 and OCTN2 in various ocular tissues studied. The present findings suggest that OCT are functionally active in blood ocular barriers and involved in the transport of its substrate from blood-to-vitreous humor. © 2013 Elsevier Ltd.

Nirmal J.,All India Institute of Medical Sciences | Velpandian T.,All India Institute of Medical Sciences | Singh S.B.,All India Institute of Medical Sciences | Ranjan Biswas N.,All India Institute of Medical Sciences | And 5 more authors.
Current Eye Research | Year: 2012

Purpose: To evaluate the functional role of organic cation transporters (OCT) and ocular tissue distribution of intravitreally injected OCT substrate tetraethylammonium (TEA) in presence of OCT blocker (quinidine). Methods: New Zealand albino rabbits of either sex were used. Intravitreal quinidine pretreatment was made 30min before the administration of TEA. Modulation of vitreous and ocular tissue kinetics of OCT substrate was evaluated with or without blocker pretreatment. Gamma scintigraphy was also performed to visualize the vitreous residence of 99mTc-labelled TEA in the presence and absence of blocker. Results: Intravitreally injected quinidine did not significantly alter the ocular disposition of TEA. TEA showed less significant posterior elimination kinetics and slow anterior elimination which resulted in longer residence time of TEA in eye after intravitreal administration. Conclusions: Intravitreally injected OCT substrates may follow an anterior elimination pathway and prolonged residence time in vitreous humor. The present study shows that OCT may not be active from vitreous-to-blood route in the blood-retinal barrier. © 2012 Informa Healthcare USA, Inc.

Nirmal J.,All India Institute of Medical Sciences | Velpandian T.,All India Institute of Medical Sciences | Singh S.B.,All India Institute of Medical Sciences | Biswas N.R.,All India Institute of Medical Sciences | And 3 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2011

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 5. mM 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. © 2011 Elsevier B.V.

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