OCULAR DISPOSITION OF ACYCLOGUANOSINE ANALOGUES

Summary

Principal Investigator: Ashim Mitra
Affiliation: University of Missouri-Kansas City
Country: USA
Abstract: The broad overall objective of this research is to enhance drug delivery to the anterior segment of the eye. More specifically the goal of this research is to develop acycloguanosine analogues of greater efficacy and reduced toxicities in the treatment of necrotising herpes simplex and cytomegalovirus macular and peripheral iritis, uveitis and retinitis in AIDS patients. Acycloguanosine analogues have low thermodynamic activity or escaping tendency from the aqueous phase into the lipid biophase. The specific aim will be achieved via the synthesis of a series of lipophilic bioreversible analogues. A series of 3', 5'-diesters of ganciclovir and 3'- monoesters of acyclovirwill be synthesized comprising of 1) a homologous series of aliphatic esters: propionate, butyrate and valerate, 2) branched chain aliphatic esters: pivaloate, isobutyrate, 3) aromatic esters: benzoate, p methoxy, p-nitro benzoates and 4) alicyclic ester: 1-adamantoate. The compounds are purified by recrystallization from methanol-chloroform mixture and purity is checked by HPLC. TLC and by melting point on two successive crystallizations. Characterization of these compounds will be made with respect to their l.R., N.M.R., mass spec. melting points, aqueous solubilities and octanoliwater partition coefficients. The in-vitro kinetics of chemical and enzymatic regeneration of the parent drugs will be studied using appropriate media and tissue homogenates. Evaluation of the rates of permeation across the rabbit corena will be made. The transfer, disposition and bioconversion of these compounds from both topical and intravitreal delivery will also be defined. These novel prodrugs are expected to permeate more rapidly and to a greater extent into the ocular tissues and nerve cells than parent acyclovir or ganciclovir. The pharmacokinetic and disposition characteristic studies of the analogues will result in the identification of a compound with optimal therapeutic potential. the distribution of the esters, regenerated parent drug and any phosphate metabolite in the plasma, aqueous humor, cornea, lens, iris ciliary body, vitreous and retinal tissues will be measured at (1) at different time points following topical administration of 50 microL volume of the same molar concentration of each compound (2) at different time points following intravitreal injection of the same molar equivalent doses of all compounds. Preliminary experiments just performed in our laboratory revealed that 50 microL of a 1 mM topical dosing of acyclovir-3'-valerate produced an aqueous humor acyclovir level of 25.99 microM at 30 mins post instillation compared to 6.25 microM concentration from a molar equivalent dose of the parent drug acyclovir. The parent drug is the only chemical species observed in the ocular fluids at 30 mins following topical dosing of the 3'- valerate analogue. The antiviral efficacies of three pharmacokinetically optimized analogues in each series (acyclovir and ganciclovir) will be evaluated in virus infected rabbit acute epithelial keratitis models by Prof. James Hill at LSU Eye Center. LSU Medical Center, New Orleans, Louisiana. The unsacrified corneas will be inoculated with 25microl of a suspension of HSV-1 strain McKrae (Ixl0(5) Plaque Forming Unitslml. The lesions after infections and after topical dosing of 50 micro 1 solution of 1 mM derivative will be evaluated by Slit-Lamp Biomicroscopic Examination.
Funding Period: 1994-11-01 - 2001-11-30
more information: NIH RePORT

Top Publications

  1. pmc Recent developments in protein and peptide parenteral delivery approaches
    Ashaben Patel
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO 64108, USA
    Ther Deliv 5:337-65. 2014
  2. ncbi Design and evaluation of a novel nanoparticulate-based formulation encapsulating a HIP complex of lysozyme
    Ripal Gaudana
    Par Pharmaceutical Companies, Inc, One Ram Ridge Road, Spring Valley, NY, USA
    Pharm Dev Technol 18:752-9. 2013
  3. pmc Bioanalytical method validation of rapamycin in ocular matrix by QTRAP LC-MS/MS: application to rabbit anterior tissue distribution by topical administration of rapamycin nanomicellar formulation
    Ravinder Earla
    UMKC School of Pharmacy, Pharmaceutical Sciences, University of Missouri Kansas City, 2464 Charlotte Street, 5258 Health Sciences Building, MO 64108, United States
    J Chromatogr B Analyt Technol Biomed Life Sci 908:76-86. 2012
  4. pmc Mitochondrial localization of P-glycoprotein and peptide transporters in corneal epithelial cells--novel strategies for intracellular drug targeting
    Megha Barot
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
    Exp Eye Res 106:47-54. 2013
  5. pmc Functional and molecular aspects of biotin uptake via SMVT in human corneal epithelial (HCEC) and retinal pigment epithelial (D407) cells
    Aswani Dutt Vadlapudi
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, Missouri 64108 2718, USA
    AAPS J 14:832-42. 2012
  6. doi Ocular toxicity from systemically administered xenobiotics
    Mitan R Gokulgandhi
    University of Missouri Kansas City, School of Pharmacy, Division of Pharmaceutical Sciences, HSB 5258, 2464 Charlotte St, Kansas City, MO 64108, USA
    Expert Opin Drug Metab Toxicol 8:1277-91. 2012
  7. pmc Targeted lipid based drug conjugates: a novel strategy for drug delivery
    Aswani Dutt Vadlapudi
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Int J Pharm 434:315-24. 2012
  8. pmc Transfected MDCK cell line with enhanced expression of CYP3A4 and P-glycoprotein as a model to study their role in drug transport and metabolism
    Deep Kwatra
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, Missouri 64108, United States
    Mol Pharm 9:1877-86. 2012
  9. ncbi Prodrug strategies in ocular drug delivery
    Megha Barot
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO 64108, USA
    Med Chem 8:753-68. 2012
  10. ncbi Current and emerging antivirals for the treatment of cytomegalovirus (CMV) retinitis: an update on recent patents
    Aswani D Vadlapudi
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Recent Pat Antiinfect Drug Discov 7:8-18. 2012

Detail Information

Publications81

  1. pmc Recent developments in protein and peptide parenteral delivery approaches
    Ashaben Patel
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO 64108, USA
    Ther Deliv 5:337-65. 2014
    ..This review summarizes recent developments on some currently existing approaches to improve stability, bioavailability and bioactivity of peptide and protein therapeutics following parenteral administration. ..
  2. ncbi Design and evaluation of a novel nanoparticulate-based formulation encapsulating a HIP complex of lysozyme
    Ripal Gaudana
    Par Pharmaceutical Companies, Inc, One Ram Ridge Road, Spring Valley, NY, USA
    Pharm Dev Technol 18:752-9. 2013
    ..HIP complexation using a polymer may also be employed to formulate sustained release dosage forms of other macromolecules with enhanced encapsulation efficiency...
  3. pmc Bioanalytical method validation of rapamycin in ocular matrix by QTRAP LC-MS/MS: application to rabbit anterior tissue distribution by topical administration of rapamycin nanomicellar formulation
    Ravinder Earla
    UMKC School of Pharmacy, Pharmaceutical Sciences, University of Missouri Kansas City, 2464 Charlotte Street, 5258 Health Sciences Building, MO 64108, United States
    J Chromatogr B Analyt Technol Biomed Life Sci 908:76-86. 2012
    ..The method demonstrates that absorption of rapamycin by a topical application of 0.2% rapamycin nanomicellar formulation generates therapeutically effective concentrations in the anterior segment of the eye...
  4. pmc Mitochondrial localization of P-glycoprotein and peptide transporters in corneal epithelial cells--novel strategies for intracellular drug targeting
    Megha Barot
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
    Exp Eye Res 106:47-54. 2013
    ..This knowledge of mitochondrial existence of P-gp and peptide transporter will aid in the development of subcellular ocular drug delivery strategies...
  5. pmc Functional and molecular aspects of biotin uptake via SMVT in human corneal epithelial (HCEC) and retinal pigment epithelial (D407) cells
    Aswani Dutt Vadlapudi
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, Missouri 64108 2718, USA
    AAPS J 14:832-42. 2012
    ..This study shows for the first time the functional and molecular presence of SMVT in HCEC and D407 cells. Therefore, these cell lines may be utilized as in vitro models to study the cellular translocation of biotin-conjugated prodrugs...
  6. doi Ocular toxicity from systemically administered xenobiotics
    Mitan R Gokulgandhi
    University of Missouri Kansas City, School of Pharmacy, Division of Pharmaceutical Sciences, HSB 5258, 2464 Charlotte St, Kansas City, MO 64108, USA
    Expert Opin Drug Metab Toxicol 8:1277-91. 2012
    ..Hence, knowledge of most recent updates on ever-increasing reports of such toxicities has become imperative to develop better therapy while minimizing toxicities...
  7. pmc Targeted lipid based drug conjugates: a novel strategy for drug delivery
    Aswani Dutt Vadlapudi
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Int J Pharm 434:315-24. 2012
    ..Moreover, this novel prodrug design can result in higher cell permeability of hydrophilic therapeutics such as genes, siRNA, antisense RNA, DNA, oligonucleotides, peptides and proteins...
  8. pmc Transfected MDCK cell line with enhanced expression of CYP3A4 and P-glycoprotein as a model to study their role in drug transport and metabolism
    Deep Kwatra
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, Missouri 64108, United States
    Mol Pharm 9:1877-86. 2012
    ..This cell line can also be used to study the combined contribution of efflux transporter and metabolizing enzymes toward drug-drug interactions. ..
  9. ncbi Prodrug strategies in ocular drug delivery
    Megha Barot
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO 64108, USA
    Med Chem 8:753-68. 2012
    ..In addition, this review will highlight ongoing academic and industrial research and development in terms of ocular prodrug design and delivery...
  10. ncbi Current and emerging antivirals for the treatment of cytomegalovirus (CMV) retinitis: an update on recent patents
    Aswani D Vadlapudi
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Recent Pat Antiinfect Drug Discov 7:8-18. 2012
    ..This review provides an overview of disease etiology, existing anti-CMV drugs, advances in emerging therapeutics in clinical development and related recent patents for the treatment of CMV retinitis...
  11. pmc Novel strategies for anterior segment ocular drug delivery
    Kishore Cholkar
    Division of Pharmaceutical Sciences, University of Missouri Kansas City, Kansas City, MO 64108 2718, USA
    J Ocul Pharmacol Ther 29:106-23. 2013
    ....
  12. ncbi Update on emerging antivirals for the management of herpes simplex virus infections: a patenting perspective
    Aswani D Vadlapudi
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Recent Pat Antiinfect Drug Discov 8:55-67. 2013
    ....
  13. pmc Ritonavir inhibits HIF-1α-mediated VEGF expression in retinal pigment epithelial cells in vitro
    R K Vadlapatla
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO, USA
    Eye (Lond) 28:93-101. 2014
    ..Hence, the primary objective of this study was to examine the expression of HIF-1α and VEGF in human retinal pigment epithelial cells treated with ritonavir under hypoxic and normoxic conditions...
  14. pmc Aqueous nanomicellar formulation for topical delivery of biotinylated lipid prodrug of acyclovir: formulation development and ocular biocompatibility
    Aswani Dutt Vadlapudi
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri
    J Ocul Pharmacol Ther 30:49-58. 2014
    ....
  15. pmc In vitro moxifloxacin drug interaction with chemotherapeutics: implications for retinoblastoma management
    Megha Barot
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
    Exp Eye Res 118:61-71. 2014
    ..This study may be further extended to explore in vivo outcome of this finding. ..
  16. doi Monocarboxylate transporter mediated uptake of moxifloxacin on human retinal pigmented epithelium cells
    Megha Barot
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO, USA
    J Pharm Pharmacol 66:574-83. 2014
    ..This work was aim to determine in vitro interaction of moxifloxacin with monocarboxylate transporter (MCT) using a human retinal pigment epithelium cells (ARPE-19)...
  17. pmc Molecular expression and functional activity of efflux and influx transporters in hypoxia induced retinal pigment epithelial cells
    Ramya Krishna Vadlapatla
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Int J Pharm 454:444-52. 2013
    ..This study demonstrates for the first time that hypoxic conditions may alter expression of efflux and influx transporters in RPE cells. These findings suggest that hypoxia may further alter disposition of ophthalmic drugs. ..
  18. ncbi Hypoxia-inducible factor-1 (HIF-1): a potential target for intervention in ocular neovascular diseases
    Ramya Krishna Vadlapatla
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Curr Drug Targets 14:919-35. 2013
    ..Further, various inhibitors of HIF-1 pathway that may have a viable potential in the treatment of oxygen-dependent ocular diseases are also discussed...
  19. pmc Novel biotinylated lipid prodrugs of acyclovir for the treatment of herpetic keratitis (HK): transporter recognition, tissue stability and antiviral activity
    Aswani Dutt Vadlapudi
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, Missouri 64108, USA
    Pharm Res 30:2063-76. 2013
    ..Biotinylated lipid prodrugs of acyclovir (ACV) were designed to target the sodium dependent multivitamin transporter (SMVT) on the cornea to facilitate enhanced cellular absorption of ACV...
  20. pmc Microvascular complications and diabetic retinopathy: recent advances and future implications
    Megha Barot
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
    Future Med Chem 5:301-14. 2013
    ..In addition, current therapeutics and future directions for advancement of standard treatment for DR patients will be discussed...
  21. pmc Approaches for enhancing oral bioavailability of peptides and proteins
    Jwala Renukuntla
    Division of Pharmaceutical Sciences, South College School of Pharmacy, 400 Goody s Lane, Knoxville, TN 37931, USA
    Int J Pharm 447:75-93. 2013
    ..This review article intends to summarize the physiological barriers to oral delivery of peptides and proteins and novel pharmaceutical approaches to circumvent these barriers and enhance oral bioavailability of these macromolecules...
  22. pmc Ocular sustained release nanoparticles containing stereoisomeric dipeptide prodrugs of acyclovir
    Jwala Jwala
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
    J Ocul Pharmacol Ther 27:163-72. 2011
    ....
  23. pmc Recent patents and emerging therapeutics in the treatment of allergic conjunctivitis
    Gyan P Mishra
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, MO 64108 2718, USA
    Recent Pat Inflamm Allergy Drug Discov 5:26-36. 2011
    ..In recent years newer drug molecules have been introduced in the treatment of allergic conjunctivitis. This article reviews recent patents and emerging therapeutics in the treatment of allergic conjunctivitis...
  24. doi Development and characterization of nanoparticulate formulation of a water soluble prodrug of dexamethasone by HIP complexation
    Ripal Gaudana
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO 64108 2718, USA
    J Microencapsul 28:10-20. 2011
    ..Finally, a simple yet novel method was developed which can also be applicable to encapsulate other charged hydrophilic molecules, such as peptides and proteins...
  25. pmc In vitro evaluation of a targeted and sustained release system for retinoblastoma cells using Doxorubicin as a model drug
    Sai H S Boddu
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO 64108 2718, USA
    J Ocul Pharmacol Ther 26:459-68. 2010
    ..The objective of this study was to develop a novel folate receptor-targeted drug delivery system for retinoblastoma cells using doxorubicin (DOX) as a model drug...
  26. pmc Interaction of gatifloxacin with efflux transporters: a possible mechanism for drug resistance
    Deep Kwatra
    University of Missouri Kansas City, School of Pharmacy, 2464 Charlotte Street, Kansas City, MO 64108, USA
    Int J Pharm 395:114-21. 2010
    ..This information can be further extended to design prodrugs or formulations in order to prevent development of acquired resistance and improve therapeutic efficacy with its reduction in side effects...
  27. pmc Vitreal pharmacokinetics of peptide-transporter-targeted prodrugs of ganciclovir in conscious animals
    Kumar G Janoria
    Aptuit, Inc, Kansas City, Missouri, USA
    J Ocul Pharmacol Ther 26:265-71. 2010
    ..To delineate the vitreal pharmacokinetics of dipeptide monoester prodrugs of ganciclovir (GCV) with conscious rabbit model using ocular microdialysis and to compare with published results from anesthetized model...
  28. pmc Effect of short term and chronic administration of Sutherlandia frutescens on pharmacokinetics of nevirapine in rats
    Mukul Minocha
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Int J Pharm 413:44-50. 2011
    ..Taken together, these results suggest that a potential drug-herb interaction is possible when NVP is co-administered with S. frutescens, although this hypothesis still remains to be investigated in a clinical setting...
  29. pmc Effect of emergence of fluoroquinolone resistance on intrinsic expression of P-glycoprotein phenotype in corneal epithelial cells
    Megha Barot
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri, Kansas City, Missouri 64108, USA
    J Ocul Pharmacol Ther 27:553-9. 2011
    ..This article examines whether long-term FQ (levofloxacin, ofloxacin, and gatifloxacin) therapy can modify the MDR phenotype (P-glycoprotein [P-gp]) on corneal epithelial cells (Statens Seruminstitut Rabbit Cornea [SIRC])...
  30. pmc Differential effect of P-gp and MRP2 on cellular translocation of gemifloxacin
    Ramya Krishna Vadlapatla
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Int J Pharm 420:26-33. 2011
    ..Better understanding of these mechanistic interactions may aid in the development of newer strategies to achieve adequate therapeutic levels and higher bioavailability...
  31. doi Mitochondrial dysfunction in retinal diseases
    Megha Barot
    School of Pharmacy, University of Missouri Kansas City, Kansas City, MO 64108, USA
    Curr Eye Res 36:1069-77. 2011
    ..Mitochondria based drug targeting to diminish oxidative stress or promote repair of mtDNA damage may offer potential alternatives for the treatment of various retinal degenerative diseases...
  32. pmc Differential expression of folate receptor-alpha, sodium-dependent multivitamin transporter, and amino acid transporter (B (0, +)) in human retinoblastoma (Y-79) and retinal pigment epithelial (ARPE-19) cell lines
    Jwala Jwala
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri 64108, USA
    J Ocul Pharmacol Ther 28:237-44. 2012
    ....
  33. ncbi Sodium dependent multivitamin transporter (SMVT): a potential target for drug delivery
    Aswani Dutt Vadlapudi
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Curr Drug Targets 13:994-1003. 2012
    ..This review highlights studies employing SMVT transporter as a target for drug delivery to improve bioavailability and investigate the feasibility of developing SMVT targeted drug delivery systems...
  34. ncbi Recent overview of ocular patents
    Ripal J Gaudana
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 64108, USA
    Recent Pat Drug Deliv Formul 6:95-106. 2012
    ..Genebased therapeutics has opened a new avenue for vision threatening disorders. In all, the current developments in the entire field have been very exciting for finding out new strategies to treat vision threatening disorders...
  35. doi Transporter-targeted lipid prodrugs of cyclic cidofovir: a potential approach for the treatment of cytomegalovirus retinitis
    Mitan R Gokulgandhi
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri 64108, USA
    J Pharm Sci 101:3249-63. 2012
    ..These results indicate that transporter-targeted lipid analogue of cCDF exhibits improved cellular accumulation along with higher transporter affinity and hence could be a viable strategy for the treatment of CMV retinitis...
  36. pmc Ocular drug delivery
    Ripal Gaudana
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte St, Kansas City, Missouri 64108 2718, USA
    AAPS J 12:348-60. 2010
    ..Current developments in the field of ophthalmic drug delivery promise a significant improvement in overcoming the challenges posed by various anterior and posterior segment diseases...
  37. pmc Development and validation of a fast and sensitive bioanalytical method for the quantitative determination of glucocorticoids--quantitative measurement of dexamethasone in rabbit ocular matrices by liquid chromatography tandem mass spectrometry
    Ravinder Earla
    Division of Pharmaceutical Sciences, School of Pharmacy, 5258 Health Science Building, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    J Pharm Biomed Anal 52:525-33. 2010
    ..0, 1050.07, 529.6, 103.9 and 48.5ng/mg protein respectively. Absorption of DEX after topical administration from a novel aqueous mixed micellar formulation achieved therapeutic concentration levels in posterior segment of the rabbit eye...
  38. pmc Novel nanoparticulate gel formulations of steroids for the treatment of macular edema
    Sai H S Boddu
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri 64108 2718, USA
    J Ocul Pharmacol Ther 26:37-48. 2010
    ....
  39. pmc Polymeric vectors for ocular gene delivery
    Viral Tamboli
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Ther Deliv 2:523-36. 2011
    ..Chemical modification of these polymers allows for the generation of flexible delivery vectors with desirable properties. In this article several synthetic and natural polymeric systems utilized for ocular gene delivery are discussed...
  40. pmc Expression of multidrug resistance associated protein 5 (MRP5) on cornea and its role in drug efflux
    Pradeep K Karla
    University of Missouri at Kansas City, Pharmaceutical Sciences, Kansas City, Missouri 64112, USA
    J Ocul Pharmacol Ther 25:121-32. 2009
    ..The purpose of this manuscript is to investigate the presence of nucleoside/nucleotide efflux transporter in cornea and to evaluate the role in ocular drug efflux...
  41. ncbi Development of a novel formulation containing poly(d,l-lactide-co-glycolide) microspheres dispersed in PLGA-PEG-PLGA gel for sustained delivery of ganciclovir
    Sridhar Duvvuri
    Department of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005, Rockhill Road, Kansas City, MO 64110, USA
    J Control Release 108:282-93. 2005
    ..In conclusion, this study reports the development of PLGA microspheres with high payloads and their PLGA-PEG-PLGA gel based formulations. Drug release equations have been developed that effectively describe the triphasic GCV release...
  42. ncbi Molecular evidence and functional expression of multidrug resistance associated protein (MRP) in rabbit corneal epithelial cells
    Pradeep K Karla
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, MO 64110 2499, USA
    Exp Eye Res 84:53-60. 2007
    ..For the first time we have demonstrated high expression of MRP-2 in rabbit corneal epithelium and its functional activity causing drug efflux. RT-PCR, immunoprecipitation followed by Western blot analysis further confirms the result...
  43. ncbi Identification and functional expression of a carrier-mediated riboflavin transport system on rabbit corneal epithelium
    Sudharshan Hariharan
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri 64112 2499, USA
    Curr Eye Res 31:811-24. 2006
    ..The secondary objective was to understand the physiological significance behind the presence of such a transport system for riboflavin on the apical side of the corneal epithelium...
  44. ncbi Biotin uptake by rabbit corneal epithelial cells: role of sodium-dependent multivitamin transporter (SMVT)
    Kumar G Janoria
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri 64110 2499, USA
    Curr Eye Res 31:797-809. 2006
    ..The objective of this research was to investigate the presence of sodium-dependent multivitamin transporter (SMVT) on rabbit corneal epithelial cells...
  45. ncbi Vitreal pharmacokinetics of dipeptide monoester prodrugs of ganciclovir
    Soumyajit Majumdar
    Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, Oxford, MS, USA
    J Ocul Pharmacol Ther 22:231-41. 2006
    ..The aim of this study was to determine vitreal pharmacokinetics of a series of dipeptide monoester ganciclovir (GCV) prodrugs and to study their interaction with the retinal peptide transporter...
  46. ncbi In vivo ocular pharmacokinetics of acyclovir dipeptide ester prodrugs by microdialysis in rabbits
    Banmeet S Anand
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri 64110, USA
    Mol Pharm 3:431-40. 2006
    ..The dipeptide prodrug GVACV owing to its enhanced absorption of ACV seems to be a promising candidate for the treatment of ocular HSV infections...
  47. ncbi Mechanism of L-ascorbic acid uptake by rabbit corneal epithelial cells: evidence for the involvement of sodium-dependent vitamin C transporter 2
    Ravi S Talluri
    School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri 64110, USA
    Curr Eye Res 31:481-9. 2006
    ..To investigate the mechanism of L-ascorbic acid uptake by rabbit corneal epithelial cells and to functionally characterize the specific transporter involved in this translocation process...
  48. ncbi Modulation of P-glycoprotein-mediated efflux by prodrug derivatization: an approach involving peptide transporter-mediated influx across rabbit cornea
    Suresh Katragadda
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri, USA
    J Ocul Pharmacol Ther 22:110-20. 2006
    ..Enhanced permeabilities of the prodrugs indicate that drug derivatization can be a viable strategy for overcoming P-gp-mediated efflux...
  49. ncbi Simultaneous modulation of transport and metabolism of acyclovir prodrugs across rabbit cornea: An approach involving enzyme inhibitors
    Suresh Katragadda
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, MO 64110 2499, USA
    Int J Pharm 320:104-13. 2006
    ..In conclusion, utility of enzyme inhibitors to modulate transport and metabolism of prodrugs appears to be promising strategy for enhancing drug transport across cornea...
  50. ncbi Biotin uptake and cellular translocation in human derived retinoblastoma cell line (Y-79): a role of hSMVT system
    Viral Kansara
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, MO 64110 2499, USA
    Int J Pharm 312:43-52. 2006
    ..These studies demonstrated for the first time the existence of a human sodium dependant multivitamin transporter (hSMVT), a specialized carrier-mediated system for biotin uptake, in human derived retinoblastoma cells...
  51. ncbi Identification and functional characterization of riboflavin transporter in human-derived retinoblastoma cell line (Y-79): mechanisms of cellular uptake and translocation
    Viral Kansara
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO 64112 2499, USA
    J Ocul Pharmacol Ther 21:275-87. 2005
    ....
  52. ncbi Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations
    Soumyajit Majumdar
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, 64110 2499, USA
    J Ocul Pharmacol Ther 21:463-74. 2005
    ..The aim of this study was to evaluate a series of dipeptide monoester ganciclovir (GCV) prodrugs with the goal of improving ocular bioavailability of GCV from topical ophthalmic solutions...
  53. ncbi Effect of polymer blending on the release of ganciclovir from PLGA microspheres
    Sridhar Duvvuri
    Department of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005, Rockhill Road, Kansas City, Missouri 64110, USA
    Pharm Res 23:215-23. 2006
    ..The aim of the study is to investigate the effect of polymer blending on entrapment and release of ganciclovir (GCV) from poly(D,L-lactide-co-glycolide) (PLGA) microspheres using a set of empirical equations...
  54. ncbi Role of efflux pumps and metabolising enzymes in drug delivery
    Suresh Katragadda
    University of Missouri Kansas City, Division of Pharmaceutical Sciences, School of Pharmacy, 64110 2499, USA
    Expert Opin Drug Deliv 2:683-705. 2005
    ..In summary, this review emphasises the urgent need to make changes in drug discovery and drug delivery as efflux pumps and metabolising enzymes play an important role in drug delivery and disposition...
  55. ncbi Identification and characterization of a Na+-dependent neutral amino acid transporter, ASCT1, in rabbit corneal epithelial cell culture and rabbit cornea
    Suresh Katragadda
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri 64110 2499, USA
    Curr Eye Res 30:989-1002. 2005
    ..The aim of this study was to investigate the presence of a Na+-dependent neutral amino acid transporter, ASCT1, in rabbit primary corneal epithelial cell culture and rabbit cornea...
  56. ncbi Microdialysis assessment of drug delivery systems for vitreoretinal targets
    Sridhar Duvvuri
    Department of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO 64110, USA
    Adv Drug Deliv Rev 57:2080-91. 2005
    ..Special problems examined include anterior and posterior ocular clearance mechanisms, intraocular metabolism and active transport of drugs...
  57. ncbi Synthesis, physicochemical properties and antiviral activities of ester prodrugs of ganciclovir
    Kunal Patel
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, MO 64110 2499, USA
    Int J Pharm 305:75-89. 2005
    ..In conclusion, the diester GCV prodrugs demonstrated excellent chemical stability, high aqueous solubility and markedly enhanced antiviral potency against the herpes viruses without any increase in cytotoxicity...
  58. pmc Functional characterization of peptide transporters in MDCKII-MDR1 cell line as a model for oral absorption studies
    Sheetal Agarwal
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, MO 64110 2499, USA
    Int J Pharm 332:147-52. 2007
    ..Results from these studies suggest the application of MDCKII-MDR1 cell line as a rapid effective tool to study peptide mediated influx of compounds that may be substrates for both P-gp and peptide transporters...
  59. pmc Molecular evidence and functional expression of a novel drug efflux pump (ABCC2) in human corneal epithelium and rabbit cornea and its role in ocular drug efflux
    Pradeep K Karla
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri, Kansas City, MO 64110, United States
    Int J Pharm 336:12-21. 2007
    ..A-->B transport of [(3)H]-cyclosporine-A was elevated in the presence of MK-571 in freshly excised rabbit cornea indicating potential role of this efflux transporter and high clinical significance of this finding...
  60. pmc Interaction of ocular hypotensive agents (PGF2 alpha analogs-bimatoprost, latanoprost, and travoprost) with MDR efflux pumps on the rabbit cornea
    Sudharshan Hariharan
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri 64110, USA
    J Ocul Pharmacol Ther 25:487-98. 2009
    ....
  61. pmc Vitreal pharmacokinetics of biotinylated ganciclovir: role of sodium-dependent multivitamin transporter expressed on retina
    Kumar G Janoria
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri 64110 2499, USA
    J Ocul Pharmacol Ther 25:39-49. 2009
    ..Study also aims to delineate the vitreal pharmacokinetics of biotin-GCV...
  62. doi Molecular expression and functional evidence of a drug efflux pump (BCRP) in human corneal epithelial cells
    Pradeep K Karla
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri 64110 2499, USA
    Curr Eye Res 34:1-9. 2009
    ..The objective of this study was to explore physical barriers for ocular drug absorption and to verify the presence and possible role of BCRP as a barrier for ocular drug resistance...
  63. ncbi Recent patents and advances in ophthalmic drug delivery
    Kumar G Janoria
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO 64110 2499, USA
    Recent Pat Drug Deliv Formul 1:161-70. 2007
    ..As a whole, this article is intended to provide a valuable insight into current trends in the field of ocular drug delivery and highlights advances made in patent literature...
  64. doi Enhanced corneal absorption of erythromycin by modulating P-glycoprotein and MRP mediated efflux with corticosteroids
    Sudharshan Hariharan
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, MO 64110, USA
    Pharm Res 26:1270-82. 2009
    ..The objectives were (i) to test in vivo functional activity of MRP2 on rabbit corneal epithelium and (ii) to evaluate modulation of P-gp and MRP2 mediated efflux of erythromycin when co-administered with corticosteroids...
  65. doi Recent perspectives in ocular drug delivery
    Ripal Gaudana
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, Missouri 64110 2499, USA
    Pharm Res 26:1197-216. 2009
    ..Current momentum in the invention of new drug delivery systems hold a promise towards much improved therapies for the treatment of vision threatening disorders...
  66. pmc Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: interaction with the transporters on Caco-2 cells
    Suresh Katragadda
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, MO 64110 2499, USA
    Int J Pharm 362:93-101. 2008
    ..The amino acid ester prodrug SACV owing to its enhanced stability, higher AUC and better concentration at last time point seems to be a promising candidate for the oral treatment of herpes infections...
  67. pmc Synthesis, metabolism and cellular permeability of enzymatically stable dipeptide prodrugs of acyclovir
    Ravi S Talluri
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road Kansas City, Missouri 64110 2499, USA
    Int J Pharm 361:118-24. 2008
    ..This strategy improved both the cellular permeability and the amount of intact prodrug transported which would enable targeting the nutrient transporters at blood ocular barrier (BOB)...
  68. pmc Ocular pharmacokinetics of acyclovir amino acid ester prodrugs in the anterior chamber: evaluation of their utility in treating ocular HSV infections
    Suresh Katragadda
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO, United States
    Int J Pharm 359:15-24. 2008
    ..To evaluate in vivo corneal absorption of the amino acid prodrugs of acyclovir (ACV) using a topical well model and microdialysis in rabbits...
  69. doi Folic acid transport via high affinity carrier-mediated system in human retinoblastoma cells
    Viral Kansara
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, MO 64110 2499, USA
    Int J Pharm 355:210-9. 2008
    ..This research work demonstrated, for the first time, the functional and molecular existence of a specialized high affinity carrier-mediated system for folic acid uptake, in human retinoblastoma cells...
  70. ncbi MDR- and CYP3A4-mediated drug-drug interactions
    Dhananjay Pal
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, MO 64110 2499, USA
    J Neuroimmune Pharmacol 1:323-39. 2006
    ..This article provides an insight into low and variable oral bioavailability and related complications leading to loss of therapeutic activity of MDR and CYP 450 substrates...
  71. ncbi Dipeptide monoester ganciclovir prodrugs for transscleral drug delivery: targeting the oligopeptide transporter on rabbit retina
    Viral Kansara
    Department of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO, USA
    J Ocul Pharmacol Ther 23:321-34. 2007
    ..The overall aim of this research work was to evaluate a series of dipeptide monoester prodrugs of an antiviral agent, ganciclovir (GCV), for oligopeptide transporter-targeted transscleral drug delivery to rabbit retina...
  72. ncbi Functional activity of a large neutral amino acid transporter (LAT) in rabbit retina: a study involving the in vivo retinal uptake and vitreal pharmacokinetics of L-phenyl alanine
    Harisha Atluri
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, MO 64110 2499, USA
    Int J Pharm 347:23-30. 2008
    ..The purpose of this study is to elucidate the functional activity of large neutral amino acid transporter (LAT) in rabbit retina and to delineate its role in the retinal uptake and intravitreal pharmacokinetics of L-phenylalanine (L-Phe)...
  73. ncbi Novel approaches to retinal drug delivery
    Kumar G Janoria
    University of Missouri Kansas City, Department of Pharmaceutical Sciences, School of Pharmacy, 5005 Rockhill Road, Kansas City, MO 64110, USA
    Expert Opin Drug Deliv 4:371-88. 2007
    ..In this review article, the authors discuss various drug delivery strategies, devices and challenges associated with drug delivery to the retina...
  74. ncbi Controlled delivery of ganciclovir to the retina with drug-loaded Poly(d,L-lactide-co-glycolide) (PLGA) microspheres dispersed in PLGA-PEG-PLGA Gel: a novel intravitreal delivery system for the treatment of cytomegalovirus retinitis
    Sridhar Duvvuri
    Bioanalytical R and D, Wyeth Research, Pearl River, NY
    J Ocul Pharmacol Ther 23:264-74. 2007
    ....
  75. ncbi Effect of lactide/glycolide ratio on the in vitro release of ganciclovir and its lipophilic prodrug (GCV-monobutyrate) from PLGA microspheres
    Kumar G Janoria
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, KPB, Kansas City, MO 64110 2499, USA
    Int J Pharm 338:133-41. 2007
    ....
  76. ncbi Corneal absorption and anterior chamber pharmacokinetics of dipeptide monoester prodrugs of ganciclovir (GCV): in vivo comparative evaluation of these prodrugs with Val-GCV and GCV in rabbits
    Sriram Gunda
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, Kansas City, MO 64110 2499, USA
    J Ocul Pharmacol Ther 22:465-76. 2006
    ..Another aim was to evaluate the pharmacokinetics of these prodrugs in aqueous humor...
  77. ncbi Functional activity of a monocarboxylate transporter, MCT1, in the human retinal pigmented epithelium cell line, ARPE-19
    Soumyajit Majumdar
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 5005 Rockhill Road, Kansas City, MO 64110, USA
    Mol Pharm 2:109-17. 2005
    ..This cell line may thus be used as an effective screening tool for intravitreally administered drugs/prodrugs targeted toward MCT1 expressed on the RPE...