Codrug: An efficient approach for drug optimization

European Journal of Pharmaceutical Sciences

Volumn 41, Issue 5, 2010, Pages 571-588

  Das, N ^a   Dhanawat, M ^a   Dash, B ^a   Nagarwal, R C ^a   Shrivastava, S K ^a  

^a BANARAS HINDU UNIVERSITY   (India)

Author keywords

Codrug; Drug delivery; Mutual prodrug

Indexed keywords

ANTIPARKINSON AGENT; ASCORBIC ACID DERIVATIVE; ATENOLOL; CAPTOPRIL; CODRUG; DRUG; ENTACAPONE; ETACRYNIC ACID; ETACRYNIC ACID ATENOLOL CODRUG; ETACRYNIC ACID TIMOLOL CODRUG; GABAPENTIN; GABAPENTIN PREGABALIN CODRUG; HYBRID DRUG; LEVODOPA; LEVODOPA ENTACAPONE CODRUG; LEVODOPA THIOCTIC ACID CODRUG; MORPHINE DERIVATIVE; MORPHOLINE DERIVATIVE; NALTREXOL; PACLITAXEL CAPTOPRIL CODRUG; PACLITAXEL DERIVATIVE; PREGABALIN; PRODRUG; RADAFAXINE; RADAFAXINE NALTREXOL CODRUG; RETINOIC ACID DERIVATIVE; RETINYL ASCORBATE CODRUG; THIOCTIC ACID; TIMOLOL; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ALZHEIMER DISEASE; CARDIOVASCULAR DISEASE; COVALENT BOND; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CONJUGATION; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG HALF LIFE; DRUG PENETRATION; DRUG POTENTIATION; DRUG RELEASE; DRUG STABILITY; DRUG SYNTHESIS; DRUG TARGETING; GLAUCOMA; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; NEUROPATHIC PAIN; NONHUMAN; PARKINSON DISEASE; PHARMACOPHORE; PRIORITY JOURNAL; RETINA NEOVASCULARIZATION; REVIEW; STRUCTURE ACTIVITY RELATION; VITREORETINOPATHY;

ADMINISTRATION, TOPICAL; ANIMALS; DELAYED-ACTION PREPARATIONS; DOGS; DRUG COMBINATIONS; DRUG DELIVERY SYSTEMS; DRUG DESIGN; DRUG SYNERGISM; GUINEA PIGS; HUMANS; MICE; PRODRUGS; RABBITS; RATS;

EID: 78349307784     PISSN: 09280987     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ejps.2010.09.014     Document Type: Review

References (93)

1. Abdel-Azeem A.Z., Abdel-Hafez A.A., El-Karamany G.S., Farag H.H. Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: design, synthesis, pharmacological investigations and docking studies. Bioorg. Med. Chem. 2009, 17:3665-3670.
2. Abdulmajed K., Heard C.M. Topical delivery of retinyl ascorbate co-drug. 1. Synthesis, penetration into and permeation across human skin. Int. J. Pharm. 2004, 280:113-124.
3. Ahmad S., Tester R.F., Corbett A., Karkalas J. Dextran and 5-aminosalicylic acid (5-ASA) conjugates: synthesis, characterisation and enzymic hydrolysis. Carbohydr. Res. 2006, 341:2694-2701.
4. Al-Ghananeem A.M., Crooks P.A. Phase I and phase II ocular metabolic activities and the role of metabolism in ophthalmic prodrug and codrug design and delivery. Molecules 2007, 12:373-388.
5. Appel L., Geffen Y., Heurling K., Eriksson C., Antoni G., Kapur S. BL-1020, a novel antipsychotic candidate with GABA-enhancing effects: D2 receptor occupancy study in humans. Eur. Neuropsychopharmacol. 2009, 19:841-850.
6. Batta A.K., Tint G.S., Xu G., Shefer S., Salen G. Synthesis and intestinal metabolism of ursodeoxycholic acid conjugate with an antiinflammatory agent, 5-aminosalicylic acid. J. Lipid Res. 1998, 39:1641-1646.
7. Ben-Shabat S., Benisty R., Wormser U., Sintov A.C. Vitamin D3-based conjugates for topical treatment of psoriasis: synthesis, antiproliferative activity, and cutaneous penetration studies. Pharm. Res. 2005, 22:50-57.
8. Berger A.S., Cheng C.K., Pearson P.A., Ashton P., Crooks P.A., Cynkowski T., Cynkowska G., Jaffe G.J. Intravitreal sustained release of corticosteroid-5-fluoruracil conjugate in the treatment of experimental proliferative vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 1996, 37:2318-2325.
9. Betrosian A.P., Douzinas E.E. Ampicillin-sulbactam: an update on the use of parenteral and oral forms in bacterial infections. Expert Opin. Drug Metab. Toxicol. 2009, 5:1099-1112.
10. Bhosle D., Bharambe S., Gairola N., Dhaneshwar S.S. Mutual prodrug concept: fundamentals and applications. Indian J. Pharm. Sci. 2006, 68:286-294.
11. Bodor N. Retrometabolic drug design concepts in ophthalmic target specific drug delivery. Adv. Drug Deliv. Rev. 1995, 16:21-38.
12. Brown G.R., Clarke D.S., Faull A.W., Foubister A.J., Smithers M.J. Design of dual-acting thromboxane antagonist-synthase inhibitors by a mutual prodrug approach. Bioorg. Med. Chem. Lett. 1996, 6:273-278.
13. Bryskier A. Dual beta-lactam-fluoroquinolone compounds: a novel approach to antibacterial treatment. Expert Opin. Invest. Drugs 1997, 6:1479-1499.
14. Cai T.B., Tang X., Nagorski J., Brauschweiger P.G., Wang P.G. Synthesis and cytotoxicity of 5-fluorouracil/diazeniumdiolate conjugates. Bioorg. Med. Chem. 2003, 11:4971-4975.
15. Cardillo J.A., Farah M.E., Mitre J., Morales P.H., Costa R.A., Melo L.A.S., Kuppermann B., Jorge R., Ashton P. An intravitreal biodegradable sustained release naproxen and 5-fluorouracil system for the treatment of experimental post-traumatic proliferative vitreoretinopathy. Br. J. Ophthalmol. 2004, 88:1201-1205.
16. Casagrande R., Georgetti S.R., Verri W.A., Borin M.F., Lopez R.F., Fonseca M.J. In vitro evaluation of quercetin cutaneous absorption from topical formulations and its functional stability by antioxidant activity. Int. J. Pharm. 2007, 328:183-190.
17. Cavalli A., Bolognesi M.L., Minarini A., Rosini M., Tumiatti V., Recanatini M., Melchiorre C. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 2008, 51:347-372.
18. Centonze D., Calabresi P., Giacomini P., Bernardi G. Neurophysiology of Parkinson's disease: from basic research to clinical correlates. Clin. Neurophysiol. 1999, 110:2006-2013.
19. Charteris D.G., Aylward G.W., Wong D., Groenewald C., Asaria R.H., Bunce C. A randomized controlled trial of combined 5-fluorouracil and low-molecular-weight heparin in management of established proliferative vitreoretinopathy. Ophthalmology 2004, 111:2240-2245.
20. Cheema R.A., Peyman G.A., Fang T., Jones A., Lukaris A.D., Lim K. Triamcinolone acetonide as an adjuvant in the surgical treatment of retinal detachment with proliferative vitreoretinopathy. Ophthalmic Surg. Lasers Imaging 2007, 38:365-370.
21. Christenson J.G., Chan K.K., Cleeland R., Dix-Holzknecht B., Farrish H.H., Patel I.H., Specian A. Pharmacokinetics of Ro 23-9424, a dual-action cephalosporin, in animals. Antimicrob. Agents Chemother. 1990, 34:1895-1900.
22. Croft D.N., Cuddigan J.H., Sweetland C. Gastric bleeding and benorylate, a new aspirin. Br. Med. J. 1972, 3:545-547.
23. Cynkowska G., Cynkowski T., Al-Ghananeem A.M., Guo H., Ashton P., Crooks P.A. Novel antiglaucoma prodrugs and codrugs of ethacrynic acid. Bioorg. Med. Chem. Lett. 2005, 15:3524-3527.
24. Dhaneshwar S.S., Chail M., Patil M., Naqvi S., Vadnerkar G. Colon-specific mutual amide prodrugs of 4-aminosalicylic acid for their mitigating effect on experimental colitis in rats. Eur. J. Med. Chem. 2009, 44:131-142.
25. Dhaneshwar S.S., Gairola N., Kandpal M., Vadnerkar G., Bhatt L., Rathi B., Kadam S.S. Synthesis, kinetic studies and pharmacological evaluation of mutual azo prodrugs of 5-aminosalicylic acid for colon-specific drug delivery in inflammatory bowel disease. Eur. J. Med. Chem. 2009, 44:3922-3929.
26. Di Stefano A., Sozio P., Cocco A., Iannitelli A., Santucci E., Costa M., Pecci L., Nasuti C., Cantalamessa F., Pinnen F. l-Dopa- and dopamine-(R)-alpha-lipoic acid conjugates as multifunctional codrugs with antioxidant properties. J. Med. Chem. 2006, 49:1486-1493.
27. Di Stefano A., Sozio P., Iannitelli A., Cerasa L.S. New drug delivery strategies for improved Parkinson's disease therapy. Expert Opin. Drug Deliv. 2009, 6:389-404.
28. Foo J., Michor F. Evolution of resistance to targeted anti-cancer therapies during continuous and pulsed administration strategies. PLoS Comput. Biol. 2009, 5:e1000557.
29. Francois H., Makhanova N., Ruiz P., Ellison J., Mao L., Rockman H.A., Coffman T.M. A role for the thromboxane receptor in l-NAME hypertension. Am. J. Physiol. Renal. Physiol. 2008, 295:F1096-F1102.
30. Friedel H.A., Campoli-Richards D.M., Goa K.L. Sultamicillin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1989, 37:491-522.
31. Fukuhara A., Imai T., Otagiri M. Stereoselective disposition of flurbiprofen from a histamine H2 antagonist to reduce gastrointestinal lesions in the rat. Chirality 1996, 8:494-502.
32. Gabriel S.E., Jaakkimainen L., Bombardier C. Risk for serious gastrointestinal complications related to use of non-steroidal anti-inflammatory drugs. A meta analysis. Ann. Int. Med. 1991, 115:787-796.
33. Gediya L.K., Khandelwal A., Patel J., Belosay A., Sabnis G., Mehta J., Purushottamachar P., Njar V.C. Design, synthesis, and evaluation of novel mutual prodrugs (hybrid drugs) of all-trans-retinoic acid and histone deacetylase inhibitors with enhanced anticancer activities in breast and prostate cancer cells in vitro. J. Med. Chem. 2008, 51:3895-3904.
34. Geffen Y., Nudelman A., Gil-Ad I., Rephaeli A., Huang M., Savitsky K., Klapper L., Winkler I., Meltzer H.Y., Weizman A. BL-1020: a novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia. Eur. Neuropsychopharmacol. 2009, 19:1-13.
35. Goldfarb J., Aronoff S.C., Jaffe A., Reed M.D., Blumer J.L. Sultamicillin in the treatment of superficial skin and soft tissue infections in children. Antimicrob. Agents Chemother. 1987, 31:663-664.
36. Goto M., Okamoto Y., Yamamoto M., Aki H. Anti-inflammatory effects of 5-aminosalicylic acid conjugates with chenodeoxycholic acid and ursodeoxycholic acid on carrageenan-induced colitis in guinea-pigs. J. Pharm. Pharmacol. 2001, 53:1711-1720.
37. Gottesman M.M. Mechanisms of cancer drug resistance. Annu. Rev. Med. 2002, 53:615-627.
38. Grimpen F., Pavli P. Advances in the management of inflammatory bowel disease. Intern. Med. J. 2010, 40:258-264.
39. Gupta S.P.B.N., Moorthy N.S.H.N. Synthesis and physicochemical characterization of mutual prodrug of indomethacin. Trends Appl. Sci. Res. 2007, 2:165-169.
40. Hamad M.O., Kiptoo P.K., Stinchcomb A.L., Crooks P.A. Synthesis and hydrolytic behavior of two novel tripartate codrugs of naltrexone and 6 β-naltrexol with hydroxybupropion as potential alcohol abuse and smoking cessation agents. Bioorg. Med. Chem. 2006, 14:7051-7061.
41. Hasibi M., Mohraz M., Haji-Abdolbaghi M., Rasoolinejad M., Rashidi A., Abouzari M. Low-dose sultamicillin versus amoxicillin-clavulanic acid in the treatment of acute bacterial sinusitis in adults: a randomized clinical trial. Infect. Dis. Clin. Pract. 2007, 15:104-105.
42. Howard-Sparks M., Al-Ghananeem A.M., Crooks P.A., Pearson A.P. A novel chemical delivery system comprising an ocular sustained release formulation of a 3α,17α,21-trihydroxy-5β-pregnan-20-one-BIS-5-fluorouracil codrug. Drug Dev. Ind. Pharm. 2007, 33:677-682.
43. Husain A., Khan M.S.Y. Studies on a mutual prodrug of sulfamethoxazole and nalidixic acid. Understanding Biology Using Peptides 2005, American Peptide Society, pp. 477-478.
44. Jolimaitre P., Malet-Martino M., Martino R. Fluorouracil prodrugs for the treatment of proliferative vitreoretinopathy: formulation in silicone oil and in vitro release of fluorouracil. Int. J. Pharm. 2003, 259:181-192.
45. Jones R.N. In vitro activity of Ro 24-6392, a novel ester-linked co-drug combining ciprofloxacin and desacetylcefotaxime. Eur. J. Clin. Microbiol. Infect. Dis. 1990, 9:435-438.
46. Kaur I.P., Garg A., Singla A.K., Aggarwal D. Vesicular systems in ocular drug delivery: an overview. Int. J. Pharm. 2004, 269:1-14.
47. Kaur I.P., Kanwar M. Ocular preparations: the formulation approach. Drug Dev. Ind. Pharm. 2002, 28:473-493.
48. Kiptoo P.K., Hamad M.O., Crooks P.A., Stinchcomb A.L. Enhancement of transdermal delivery of 6-β-naltrexol via a codrug linked to hydroxybupropion. J. Control. Release 2006, 113:137-145.
49. Kiptoo P.K., Paudel K.S., Hammell D.C., Hamad M.O., Crooks P.A., Stinchcomb A.L. In vivo evaluation of a transdermal codrug of 6-β-naltrexol linked to hydroxybupropion in hairless guinea pigs. Eur. J. Pharm. Sci. 2008, 33:371-379.
50. Kostrzewa R.M., Kostrzewa J.P., Brus R. Neuroprotective and neurotoxic roles of levodopa (l-DOPA) in neurodegenerative disorders relating to Parkinson's disease. Amino Acids 2002, 23:57-63.
51. Kouznetsov V.V., Gomez-Barrio A. Recent developments in the design and synthesis of hybrid molecules based on aminoquinoline ring and their antiplasmodial evaluation. Eur. J. Med. Chem. 2009, 44:3091-3113.
52. Lau W.M., White A.W., Gallagher S.J., Donaldson M., McNaughton G., Heard C.M. Scope and limitations of the co-drug approach to topical drug delivery. Curr. Pharm. Des. 2008, 14:794-802.
53. Lee J.J., Park J.K., Kim Y.T., Kwon B.M., Kang S.G., Yoo Y.D., Yu Y.S., Chung H. Effect of 2′-benzoyl-oxycinnamaldehyde on RPE cells in vitro and in an experimental proliferative vitreoretinopathy model. Invest. Ophthalmol. Vis. Sci. 2002, 43:3117-3124.
54. Leppanen J., Huuskonen J., Nevalainen T., Gynther J., Taipale H., Jarvinen T. Design and synthesis of a novel l-Dopa-entacapone codrug. J. Med. Chem. 2002, 45:1379-1382.
55. Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001, 46:3-26.
56. Lode H.M. Rational antibiotic therapy and the position of ampicillin/sulbactam. Int. J. Antimicrob. Agents 2008, 32:10-28.
57. Lode H. Role of sultamicillin and ampicillin/sulbactam in the treatment of upper and lower bacterial respiratory tract infections. Int. J. Antimicrob. Agents 2001, 18:199-209.
58. Luscher T.F., Noll G. The pathogenesis of cardiovascular disease: role of the endothelium as a target and mediator. Atherosclerosis 1995, 118:S81-S90.
59. Machemer R. Proliferative vitreoretinopathy (PVR): a personal account of its pathogenesis and treatment. Invest. Ophthalmol. Vis. Sci. 1988, 29:1771-1783.
60. Macky T.A., Oelkers C., Rix U., Heredia M.L., Kunzel E., Wimberly M., Rohrer B., Crosson C.E., Rohr J. Synthesis, pharmacokinetics, efficacy, and rat retinal toxicity of a novel mitomycin C-triamcinolone acetonide conjugate. J. Med. Chem. 2002, 45:1122-1127.
61. Manon B., Sharma P.D. Design, synthesis and evaluation of diclofenac-antioxidant mutual prodrugs as safer NSAIDS. Indian J. Chem. 2009, 48B:1279-1287.
62. Menger F.M., Rourk M.J. Synthesis and reactivity of 5-fluorouracil/cytarabine mutual prodrugs. J. Org. Chem. 1997, 62:9083-9088.
63. Meunier B. Hybrid molecules with a dual mode of action: dream or reality?. Acc. Chem. Res. 2008, 41:69-77.
64. Mishra A., Veerasamy R., Jain P.K., Dixit V.K., Agrawal R.K. Synthesis, characterization and pharmacological evaluation of amide prodrug of ketorolac. Eur. J. Med. Chem. 2008, 43:2464-2472.
65. Morphy R., Kay C., Rankovic Z. From magic bullets to designed multiple ligands. Drug Discov. Today 2004, 9:641-651.
66. Narisawa T., Fukaura Y., Takeba N., Nakai K. Chemoprevention of N-methylnitrosourea-induced colon carcinogenesis by ursodeoxycholic acid-5-aminosalicylic acid conjugate in F344 rats. Jpn. J. Cancer Res. 2002, 93:143-150.
67. Nudelman A., Gil-Ad I., Shpaisman N., Terasenko I., Ron H., Savitsky K., Geffen Y., Weizman A., Rephaeli A. A mutual prodrug ester of GABA and perphenazine exhibits antischizophrenic efficacy with diminished extrapyramidal effect. J. Med. Chem. 2008, 51:2858-2862.
68. Nudelman A., Kelner R. Approaches to mutual prodrugs: calcium channel blockers. Arch. Pharm. 1993, 326:907-909.
69. Nudelman A., Rephaeli A. Novel mutual prodrug of retinoic and butyric acids with enhanced anticancer activity. J. Med. Chem. 2000, 43:2962-2966.
70. Otagiri M., Imai T., Fukuhara A. Improving the pharmacokinetic and pharmacodynamic properties of a drug by chemical conversion to a chimera drug. J. Control. Release 1999, 62:223-229.
71. Pena F., Gutierrez-Lerma A., Quiroz-Baez R., Arias C. The role of beta-amyloid protein in synaptic function: implications for Alzheimer's disease therapy. Curr. Neuropharmacol. 2006, 4:149-163.
72. Pinnen F., Cacciatore I., Cornacchia C., Sozio P., Cerasa L.S., Iannitelli A., Nasuti C., Cantalamessa F., Sekar D., Gabbianelli R., Falcioni M.L., Di Stefano A. Codrugs linking l-Dopa and sulfur-containing antioxidants: new pharmacological tools against Parkinson's disease. J. Med. Chem. 2009, 52:559-563.
73. Pinnen F., Cacciatore I., Cornacchia C., Sozio P., Iannitelli A., Costa M., Pecci L., Nasuti C., Cantalamessa F., Di Stefano A. Synthesis and study of l-Dopa-glutathione codrugs as new anti-parkinson agents with free radical scavenging properties. J. Med. Chem. 2007, 50:2506-2515.
74. Prateek J.R., Jaim K., Ravichandran V., Agrawal R.K. Synthesis and evaluation of mutual prodrugs of isoniazid, p-amino salicylic acid and ethambutol. Arkivoc 2007, 1:105-118.
75. Rephaeli A., Zhuk R., Nudelman A. Prodrugs of butyric acid from bench to bedside: synthetic design, mechanism of action, and clinical applications. Drug Dev. Res. 2000, 50:379-391.
76. Sheha M., Khedr A., Elsherief H. Biological and metabolic study of naproxen-propyphenazone mutual prodrug. Eur. J. Pharm. Sci. 2002, 17:121-130.
77. Shi W., Liu H., Zhang Y., Zhong B., Yang H. Design, synthesis, and preliminary evaluation of gabapentin-pregabalin mutual prodrugs in relieving neuropathic pain. Arch. Pharm. 2005, 338:358-364.
78. Shimazaki A., Ichikawa M., Rao P.V., Kirihara T., Konomi K., Epstein D.L., Hara H. Effects of the new ethacrynic acid derivative SA 9000 on intraocular pressure in cats and monkeys. Biol. Pharm. Bull. 2004, 27:1019-1024.
79. Sozio P., D'Aurizio E., Iannitelli A., Cataldi A., Zara S., Cantalamessa F., Nasuti C., Di Stefano A. Ibuprofen and lipoic acid diamides as potential codrugs with neuroprotective activity. Arch. Pharm. (Weinheim) 2010, 343:133-142.
80. Sozio P., Iannitelli A., Cerasa L.S., Cacciatore I., Cornacchia C., Giorgioni G., Ricciutelli M., Nasuti C., Cantalamessa F., Di Stefano A. New l-Dopa codrugs as potential antiparkinson agents. Arch. Pharm. (Weinheim) 2008, 341:412-417.
81. Strasinger C.L., Scheff N.N., Stinchcomb A.L. Prodrugs and codrugs as strategies for improving percutaneous absorption. Expert Rev. Dermatol. 2008, 3:221-233.
82. Sun S.Y., Wan H., Yue P., Hong W.K., Lotan R. Evidence that retinoic acid receptor beta induction by retinoids is important for tumor cell growth inhibition. J. Biol. Chem. 2000, 275:17149-17153.
83. Sun X.F., Wu Q., Wang N., Cai Y., Lin X.F. Novel mutual prodrugs of 2′,3′-dideoxyinosine with 3-octadecyloxy-propane-1,2-diol by straightforward enzymatic regioselective synthesis in acetone. Biotechnol. Lett. 2005, 27:113-117.
84. Svartz N. Salazopyrin a new sulfanilamide preparation. A. Therapeutic results in rheumatic polyarthritis. B. Therapeutic results in ulcerative colitis. C. Toxic manifestations in treatment with sulfanilamide preparations. Acta Med. Scand. 1942, 110:577-598.
85. Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv. Drug Deliv. Rev. 2006, 58:1131-1135.
86. 2-(acetoxymethyl)-1-(2-carboxypyrrolidin-1-yl) diazenium-1,2-diolate nitric oxide donor moiety: design, synthesis, biological evaluation, and nitric oxide release studies. J. Med. Chem. 2008, 51:1954-1961.
87. Vigroux A., Bergon M. Synthesis of prodrugs and a mutual prodrug of chlorzoxazone and acetaminophen based on a masked benzoxazolone. Bioorg. Med. Chem. Lett. 1995, 5:427-430.
88. Vigroux A., Bergon M., Zedde C. Cyclization-activated prodrugs: N-(substituted 2-hydroxyphenyl and 2-hydroxypropyl) carbamates based on ring-opened derivatives of active benzoxazolones and oxazolidinones as mutual prodrugs of acetaminophen. J. Med. Chem. 1995, 38:3983-3994.
89. Viles-Gonzalez J.F., Fuster V., Corti R., Valdiviezo C., Hutter R., Corda S., Anand S.X., Badimon J.J. Atherosclerosis regression and TP receptor inhibition: effect of S18886 on plaque size and composition-a magnetic resonance imaging study. Eur. Heart. J. 2005, 26:1557-1561.
90. Vlieghe P., Clerc T., Pannecouque C., Witvrouw M., De Clercq E., Salles J.P., Kraus J.L. Synthesis of new covalently bound kappa-carrageenan-AZT conjugates with improved anti-HIV activities. J. Med. Chem. 2002, 45:1275-1283.
91. Vrudhula V.M., MacMaster J.F., Li Z., Kerr D.E., Senter P.D. Reductively activated disulfide prodrugs of paclitaxel. Bioorg. Med. Chem. Lett. 2002, 12:3591-3594.
92. Yadav M.R., Nimekar D.M., Ananthakrishnan A., Brahmkshatriya P.S., Shirude S.T., Giridhar R., Parmar A., Balaraman R. Synthesis of new chemical entities from paracetamol and NSAIDs with improved pharmacodynamic profile. Bioorg. Med. Chem. 2006, 14:8701-8706.
93. Yang C.S., Khawly J.A., Hainsworth D.P., Chen S.N., Ashton P., Guo H., Jaffe G.J. An intravitreal sustained-release triamcinolone and 5-fluorouracil codrug in the treatment of experimental proliferative vitreoretinopathy. Arch. Ophthalmol. 1998, 116:69-77.