Abstract
Objective: In this study, an injectable Sucrose Acetate Isobutyrate (SAIB) drug delivery system (SADS) was designed and fabricated for the sustained release of Ropivacaine (RP) to prolong the duration of local anesthesia.
Methods: By mixing SAIB, RP, and N-methyl-2-pyrrolidone, the SADS was prepared in a sol state with low viscosity before injection. After subcutaneous injection, the pre-gel solution underwent gelation in situ to form a drug-released depot.
Result: The in vitro release profiles and in vivo pharmacokinetic analysis indicated that RP-SADS had suitable controlled release properties. Particularly, the RP-SADS significantly reduced the initial burst release after subcutaneous injection in rats.
Conclusion: In a pharmacodynamic analysis of rats, the duration of nerve blockade was prolonged by over 3-fold for the RP-SADS formulation compared to RP solution. Additionally, RP-SADS showed good biocompatibility in vitro and in vivo. Thus, the SADS-based depot technology is a safe drug delivery strategy for the sustained release of local anesthetics with long-term analgesia effects.
Keywords: In situ-forming implant, sucrose acetate isobutyrate, ropivacaine, sustained release, biocompatibility, drug.
Graphical Abstract
[2]
Rakel, B.A.; Blodgett, N.P.; Zimmerman, M.B.; Logsden-Sackett, N.; Clark, C.; Noiseux, N.; Callaghan, J.; Herr, K.; Geasland, K.; Yang, X.; Sluka, K.A. Predictors of postoperative movement and resting pain following total knee replacement. Pain, 2012, 153, 2192-2203.
[3]
Bjornholdt, K.T.; Brandsborg, B.; Soballe, K.; Nikolajsen, L. Persistent pain is common 1-2 years after shoulder replacement. Acta Orthop., 2015, 86, 71-77.
[4]
Ronconi, E.; Sagrinati, C.; Angelotti, M.L.; Lazzeri, E.; Mazzinghi, B.; Ballerini, L.; Parente, E.; Becherucci, F.; Gacci, M.; Carini, M.; Maggi, E.; Serio, M.; Vannelli, G.B.; Lasagni, L.; Romagnani, S.; Romagnani, P. Regeneration of glomerular podocytes by human renal progenitors. J. Am. Soc. Nephrol., 2009, 20(2), 322-332.
[5]
Rawal, N. Current issues in postoperative pain management. Eur. J. Anaesthesiol., 2015, 33, 160.
[6]
Stone, A.L.; Wilson, A.C. Transmission of risk from parents with chronic pain to offspring: An integrative conceptual model. Pain, 2016, 157, 2628-2639.
[7]
Higgins, K.S.; Birnie, K.A.; Chambers, C.T.; Wilson, A.C.; Caes, L.; Clark, A.J.; Lynch, M.; Stinson, J.; Campbell-Yeo, M. Offspring of parents with chronic pain: A systematic review and meta-analysis of pain, health, psychological, and family outcomes. Pain, 2015, 156, 2256-2266.
[8]
Xin, Y.; Hong, Y.; Yong, L.Z. Efficacy of postoperative continuous wound infiltration with local anesthesia after open hepatectomy. Clin. J. Pain, 2014, 30, 571-576.
[9]
Beaussier, M.; El’Ayoubi, H.; Schiffer, E.; Rollin, M.; Parc, Y.; Mazoit, J.X.; Azizi, L.; Gervaz, P.; Rohr, S.; Biermann, C.; Lienhart, A.; Eledjam, J.J. Continuous preperitoneal infusion of ropivacaine provides effective analgesia and accelerates recovery after colorectal surgery: A randomized, double-blind, placebo-controlled study. Anesthesiology, 2007, 107, 461-468.
[10]
Barreveld, A.; Witte, J.; Chahal, H.; Durieux, M.E.; Strichartz, G. Preventive analgesia by local anesthetics: The reduction of postoperative pain by peripheral nerve blocks and intravenous drugs. Anesth. Analg., 2013, 116, 1141.
[11]
Raines, S.; Hedlund, C.; Franzon, M.; Lillieborg, S.; Kelleher, G.; Ahlen, K. Ropivacaine for continuous wound infusion for postoperative pain management: A systematic review and meta-analysis of randomized controlled trials. Eur. Surg. Res., 2014, 53, 43-60.
[12]
Kong, T.W.; Park, H.; Cheong, J.Y.; Min, S.K.; Ryu, H.S. Efficacy of continuous wound infiltration of local anesthetic for pain relief after gynecologic laparoscopy. Int. J. Gynaecol. Obstet., 2014, 124, 212-215.
[13]
Eroglu, A. A comparison of patient-controlled subacromial and i.v. analgesia after open acromioplasty surgery. Br. J. Anaesth., 2006, 96, 497-501.
[14]
Goldstein, A.; Grimault, P.; Henique, A.; Keller, M.; Fortin, A.; Darai, E. Preventing postoperative pain by local anesthetic instillation after laparoscopic gynecologic surgery: A placebo-controlled comparison of bupivacaine and ropivacaine. Anesth. Analg., 2000, 91, 403-407.
[15]
Helms, O.; Mariano, J.; Hentz, J.G.; Santelmo, N.; Falcoz, P.E.; Massard, G.; Steib, A. Intra-operative paravertebral block for postoperative analgesia in thoracotomy patients: A randomized, double-blind, placebo-controlled study. Eur. J. Cardiothorac. Surg., 2011, 40, 902-906.
[16]
Norrington, A.C.; Flood, L.M.; Meek, T.; Tremlett, M.R. Does day case pediatric tonsillectomy increase postoperative pain compared to overnight stay pediatric tonsillectomy? A prospective comparative audit. Paediatr. Anaesth., 2013, 23, 697-701.
[17]
Weiniger, C.F.; Golovanevski, M.; Sokolskypapkov, M.; Domb, A.J. Review of prolonged local anesthetic action. Expert Opin. Drug Deliv., 2010, 7, 737-752.
[18]
Sari, E.; Simsek, G. Comparison of the effects of total nasal block and central facial block on acute postoperative pain, edema, and ecchymosis after septorhinoplasty. Aesthetic Plast. Surg., 2015, 39, 877-880.
[19]
Roberti del Vecchio, P.M.; Christen, T.; Raffoul, W.; Erba, P. Ulnar nerve transposition at the elbow under local anesthesia: A patient satisfaction study. J. Reconstr. Microsurg., 2015, 31, 187-190.
[20]
Bowyer, A.; Royse, C.F. The future of postoperative quality of recovery assessment: Multidimensional, dichotomous, and directed to individualize care to patients after surgery. Curr. Opin. Anaesthesiol., 2016, 29, 683-690.
[21]
Bowyer, A.; Royse, C. The importance of postoperative quality of recovery: Influences, assessment, and clinical and prognostic implications. Can. J. Anaesth., 2016, 63, 176-183.
[22]
Igarashi, T.; Hirabayashi, Y.; Saitoh, K.; Fukuda, H.; Shimizu, R.; Mitsuhata, H. Dose-related cardiovascular effects of amrinone and epinephrine in reversing bupivacaine-induced cardiovascular depression. Acta Anaesthesiol. Scand., 1998, 42, 698-706.
[23]
Hassani, V.; Movassaghi, G.; Safaian, R.; Safari, S.; Zamani, M.M.; Hajiashrafi, M.; Sedaghat, M. Bupivacaine-sufentanil versus bupivacaine-fentanyl in spinal anesthesia of patients undergoing lower extremity surgery. Anesth. Pain Med., 2014, 4, e12091.
[24]
Schwemmer, U.; Schleppers, A.; Markus, C.; Kredel, M.; Kirschner, S.; Roewer, N. Operative management in axillary brachial plexus blocks: Comparison of ultrasound and nerve stimulation. Anaesthesist, 2006, 55, 451-456.
[25]
Farzi, F.; Mirmansouri, A.; Nabi, B.N.; Roushan, Z.A.; Tehran, S.G.; Sani, M.N.; Azad, S.M.; Nemati, M. Comparing the effect of adding fentanyl, sufentanil, and placebo with intrathecal bupivacaine on duration of analgesia and complications of spinal anesthesia in patients undergoing cesarean section. Anesth. Pain Med., 2017, 7, e12738.
[26]
Kohane, D.S.; Yieh, J.; Lu, N.T.; Langer, R.; Strichartz, G.R.; Berde, C.B. A re-examination of tetrodotoxin for prolonged duration local anesthesia. Anesthesiology, 1998, 89, 119-131.
[27]
Zhang, R.X.; Li, J.; Zhang, T.; Amini, M.A.; He, C.; Lu, B. Importance of integrating nanotechnology with pharmacology and physiology for innovative drug delivery and therapy - an illustration with firsthand examples. Acta Pharmacol. Sin., 2018, 39, 825-844.
[28]
Komiyama, M.; Yoshimoto, K.; Sisido, M.; Ariga, K. Chemistry can make strict and fuzzy controls for bio-systems: DNA nanoarchitectonics and cell-macromolecular nanoarchitectonics. Bull. Chem. Soc. Jpn., 2017, 90, 967-1004.
[29]
Lu, Y.; Aimetti, A.A.; Langer, R.; Gu, Z. Bioresponsive materials. Nat. Rev. Mater., 2016, 2, 16075.
[30]
Hare, J.I.; Lammers, T.; Ashford, M.B.; Puri, S.; Storm, G.; Barry, S.T. Challenges and strategies in anti-cancer nanomedicine development: An industry perspective. Adv. Drug Deliv. Rev., 2017, 108, 25-38.
[31]
Wang, Z.; Huang, H.; Yang, S.; Huang, S.; Guo, J.; Tang, Q.; Qi, F. Long-term effect of ropivacaine nanoparticles for sciatic nerve block on postoperative pain in rats. Int. J. Nanomedicine, 2016, 11, 2081-2090.
[32]
Ni, Q.; Chen, W.; Lei, T.; Cao, J.; Ji, C. Preparation of novel biodegradable ropivacaine microspheres and evaluation of their efficacy in sciatic nerve block in mice. Drug Des. Devel. Ther., 2016, 10, 2499.
[33]
da Silva, C.M.; Fraceto, L.F.; Franz-Montan, M.; Couto, V.M.; Casadei, B.R.; Cereda, C.M.; de Paula, E. Development of egg PC/cholesterol/α-tocopherol liposomes with ionic gradients to deliver ropivacaine. J. Liposome Res., 2015, 26, 1-10.
[34]
Bagshaw, K.R.; Hanenbaum, C.L.; Carbone, E.J.; Lo, K.W.; Laurencin, C.T.; Walker, J.; Nair, L.S. Pain management via local anesthetics and responsive hydrogels. Ther. Deliv., 2015, 6, 165-176.
[35]
Golembiewski, J.; Dasta, J. Evolving role of local anesthetics in managing postsurgical analgesia. Clin. Ther., 2015, 37, 1354-1371.
[36]
Candiotti, K. Liposomal bupivacaine: An innovative nonopioid local analgesic for the management of postsurgical pain. Pharmacotherapy, 2012, 32, 19S-26S.
[37]
Ickowicz, D.E.; Golovanevski, L.; Domb, A.J.; Weiniger, C.F. Extended duration local anesthetic agent in a rat paw model. Int. J. Pharm., 2014, 468, 152-157.
[38]
Sokolsky-Papkov, M.; Golovanevski, L.; Domb, A.J.; Weiniger, C.F. Prolonged local anesthetic action through slow release from poly (lactic acid co castor oil). Pharm. Res., 2009, 26, 32-39.
[39]
Sokolsky-Papkov, M.; Golovanevski, L.; Domb, A.J.; Weiniger, C.F. Long-acting poly(DL:lactic acid-castor oil) 3:7-bupivacaine formulation: Effect of hydrophobic additives. Pharm. Res., 2011, 28, 3265-3273.
[40]
Zhang, X.; Hu, M.; Wei, G.; Jia, M.; Gong, T.; Liu, J. An injectable in situ lipid phase transition system for sustained delivery of dabigatran etexilate with low burst release. Rsc. Adv, 2017, 7, 56594-56601.
[41]
Sheng, Y.; Hu, J.; Shi, J.; Lee, L.J. Stimuli-responsive carriers for controlled intracellular drug release. Curr. Med. Chem., 2017.
[http://dx.doi.org/10.2174/0929867324666170830102409]
[http://dx.doi.org/10.2174/0929867324666170830102409]
[42]
Hu, J.; Sheng, Y.; Shi, J.; Yu, B.; Yu, Z.; Liao, G. Long circulating polymeric nanoparticles for gene/drug delivery. Curr. Drug Metab., 2018, 19, 723-738.
[43]
Agarwal, P.; Rupenthal, I.D. Injectable implants for the sustained release of protein and peptide drugs. Drug Discov. Today, 2013, 18, 337.
[44]
Kempe, S.; Mäder, K. In situ forming implants - an attractive formulation principle for parenteral depot formulations. J. Control. Release, 2012, 161, 668-679.
[45]
Solorio, L.; Exner, A.A. Effect of the subcutaneous environment on phase-sensitive in situ-forming implant drug release, degradation, and microstructure. J. Pharm. Sci., 2015, 104, 4322-4328.
[46]
Solorio, L.; Olear, A.M.; Hamilton, J.I.; Patel, R.B.; Beiswenger, A.C.; Wallace, J.E. Noninvasive characterization of the effect of varying PLGA molecular weight blends on in situ forming implant behavior using ultrasound imaging. Theranostics, 2012, 2, 1064-1077.
[47]
Patel, R.B.; Carlson, A.N.; Solorio, L.; Exner, A.A. Characterization of formulation parameters affecting low molecular weight drug release from in situ forming drug delivery systems. J. Biomed. Mater. Res. A, 2010, 94, 476-484.
[48]
Patel, R.B.; Solorio, L.; Wu, H.; Krupka, T.; Exner, A.A. Effect of injection site on in situ implant formation and drug release in vivo. J. Control. Release, 2010, 147, 350-358.
[49]
Kim, J.H.; Taluja, A.; Knutson, K.; Han Bae, Y. Stability of bovine serum albumin complexed with PEG-poly(L-histidine) diblock copolymer in PLGA microspheres. J. Control. Release, 2005, 109, 86-100.
[50]
Oh, J.E.; Nam, Y.S.; Lee, K.H.; Park, T.G. Conjugation of drug to poly(D,L-lactic-co-glycolic acid) for controlled release from biodegradable microspheres. J. Control. Release, 1999, 57, 269-280.
[51]
Schadlich, A.; Kempe, S.; Mader, K. Non-invasive in vivo characterization of microclimate pH inside in situ forming PLGA implants using multispectral fluorescence imaging. J. Control. Release, 2014, 179, 52-62.
[52]
Liu, Y.; Ghassemi, A.H.; Hennink, W.E.; Schwendeman, S.P. The microclimate pH in poly(D,L-lactide-co-hydroxymethyl glycolide) microspheres during biodegradation. Biomaterials, 2012, 33, 7584-7593.
[53]
Yehia, S.A.; Halim, S.A.A.; Aziz, M.Y. Polymeric and non polymeric injectable in-situ forming implant systems for sustained delivery of lornoxicam: In vitro and in vivo evaluation. Curr. Drug Deliv., 2018, 15(8), 1193-1203.
[54]
Shapourgan, M.; Mobedi, H.; Sheikh, N.; Behnamghader, A.; Mashak, A. Leuprolide acetate release study from gamma-irradiated plga-based in situ forming system. Curr. Drug Deliv., 2017, 14, 1170-1177.
[55]
Zhang, G.; Hu, J.; Meng, Q.; Wang, T.; Yang, X.; Gao, L.; Quan, D. Release characteristics in vitro and in vivo of in situ gels for a novel peptide compared with low-molecular-weight hydrophilic drug. Curr. Drug Deliv., 2017, 14, 47-53.
[56]
Rafienia, M.; Emami, S.H.; Mirzadeh, H.; Mobedi, H.; Karbasi, S. Influence of poly (lactide-co-glycolide) type and gamma irradiation on the betamethasone acetate release from the in situ forming systems. Curr. Drug Deliv., 2009, 6, 184-191.
[57]
Li, H.; Liu, T.; Zhu, Y.; Fu, Q.; Wu, W.; Deng, J.; Lan, L.; Shi, S. An in situ-forming phospholipid-based phase transition gel prolongs the duration of local anesthesia for ropivacaine with minimal toxicity. Acta Biomater., 2017, 58, 136.
[58]
Geng, Z.; Luo, X.; Zhang, Z.; Li, H.; Tian, J.; Yu, Z. Study of an injectable in situ forming gel for sustained-release of Ivermectin in vitro and in vivo. Int. J. Biol. Macromol., 2016, 85, 271.
[59]
Cheng, T.L.; Schindeler, A.; Little, D.G. BMP-2 delivered via sucrose acetate isobutyrate (SAIB) improves bone repair in a rat open fracture model. J. Orthop. Res., 2016, 34, 1168-1176.
[60]
Lin, X.; Xu, Y.; Tang, X.; Zhang, Y.; Chen, J.; Zhang, Y. A uniform ultra-small microsphere/SAIB hybrid depot with low burst release for long-term continuous drug release. Pharm. Res., 2015, 32, 3708-3721.
[61]
Guo, J.; Wang, J.; Cai, C.; Xu, J.; Yu, H.; Xu, H.; Xing, T. The anti-melanoma efficiency of the intratumoral injection of cucurbitacin-loaded sustained release carriers: In situ-forming implants. AAPS PharmSciTech, 2015, 16, 973-985.
[62]
Cheng, T.L.; Murphy, C.M.; Roya, R.; Fariba, D.; Little, D.G.; Aaron, S. Bisphosphonate-adsorbed ceramic nanoparticles increase bone formation in an injectable carrier for bone tissue engineering. J. Tissue Eng., 2015, 6, 2041731415609448.
[63]
Jolck, R.I.; Binderup, T.; Hansen, A.E.; Scherman, J.B.; Munch, A.F.; Rosenschold, P.; Kjaer, A.; Andresen, T.L. Injectable colloidal gold in a sucrose acetate isobutyrate gelating matrix with potential use in radiation therapy. Adv. Healthc. Mater., 2014, 3, 1680-1687.
[64]
Lin, X.; Tang, X.; Xu, Y.H.; Zhang, Y.; He, H.B. Preparation and evaluation of risperidone-loaded microsphere/sucrose acetate isobutyrate in situ forming complex depot with double diffusion barriers. Yao Xue Xue Bao, 2015, 50, 775-782.
[65]
Cheng, T.L.; Murphy, C.M.; Cantrill, L.C.; Mikulec, K.; Carpenter, C.; Schindeler, A.; Little, D.G. Local delivery of recombinant human bone morphogenetic proteins and bisphosphonate via sucrose acetate isobutyrate can prevent femoral head collapse in Legg-Calve-Perthes disease: A pilot study in pigs. Int. Orthop., 2014, 38, 1527-1533.
[66]
Shamma, R.N.; Elkasabgy, N.A.; Mahmoud, A.A.; Gawdat, S.I.; Kataia, M.M.; Abdel Hamid, M.A. Design of novel injectable in-situ forming scaffolds for non-surgical treatment of periapical lesions: In-vitro and in-vivo evaluation. Int. J. Pharm., 2017, 521, 306-317.
[67]
Lin, X.; Wang, J.; Xu, Y.; Tang, X.; Chen, J.; Zhang, Y.; Yang, Z. Tracking the effect of microspheres size on the drug release from a microsphere/sucrose acetate isobutyrate (SAIB) hybrid depot in vitro and in vivo. Drug Dev. Ind. Pharm., 2016, 42, 1455-1465.
[68]
Xiang, N.; Zhou, X.; He, X.; Zhang, Y.; Zhang, J.; Zhang, Z.R. An injectable gel platform for the prolonged therapeutic effect of pitavastatin in the management of hyperlipidemia. J. Pharm. Sci., 2016, 105, 1148-1155.
[69]
Costa, P.; Sousa, Lobo J.M. Modeling and comparison of dissolution profiles. Eur. J. Pharm. Sci., 2001, 13, 123-133.
[70]
Higuchi, T. Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J. Pharm. Sci., 1963, 52, 1145-1149.
[71]
Peppas, N.A. Analysis of Fickian and non-Fickian drug release from polymers. Pharm. Acta Helv., 1985, 60, 110-111.
[72]
Thakur, R.R.; Mcmillan, H.L.; Jones, D.S. Solvent induced phase inversion-based in situ forming controlled release drug delivery implants. J. Control. Release, 2014, 176, 8.
[73]
Ohri, R.; Wang, J.C.; Blaskovich, P.D.; Pham, L.N.; Costa, D.S.; Nichols, G.A. Inhibition by local bupivacaine-releasing microspheres of acute postoperative pain from hairy skin incision. Anesth. Analg., 2013, 117, 717-730.
[74]
Mackenzie, K.M.; Henwood, S.M.; Tisdel, P.J.; Boysen, B.G.; Palmer, T.E.; Schardein, J.L. Sucrose acetate isobutyrate (SAIB): three-generation reproduction study in the rat and teratology studies in the rat and rabbit. Food Chem. Toxicol., 1998, 36, 135-140.
[75]
Mackenzie, K.M.; Tisdel, P.J.; Hall, R.L.; Boysen, B.G.; Field, W.E.; Chappel, C.I. Oral toxicity and carcinogenicity studies of sucrose acetate isobutyrate (SAIB) in the Fischer 344 rat and B6C3F1 mouse. Food Chem. Toxicol., 1998, 36, 111-120.
[76]
Procter, B.G.; Chappel, C.I. Subchronic toxicity studies of sucrose acetate isobutyrate (SAIB) in the rat and dog. Food Chem. Toxicol., 1998, 36, 101-110.
[77]
Reynolds, R.C. Metabolism and pharmacokinetics of sucrose acetate isobutyrate (SAIB) and sucrose octaisobutyrate (SOIB) in rats, dogs, monkeys or humans: A review. Food Chem. Toxicol., 1998, 36, 95-99.
[78]
Chanamai, R.; McClements, D.J. Impact of weighting agents and sucrose on gravitational separation of beverage emulsions. J. Agric. Food Chem., 2000, 48, 5561-5565.
[79]
Wang, J.W.; Xu, J.H.; Li, J.; Zhao, M.H.; Zhang, H.F.; Liu, D.C. Improvement of the antitumor efficacy of intratumoral administration of cucurbitacin Poly(Lactic-co-Glycolic Acid) microspheres incorporated in in situ-forming sucrose acetate isobutyrate depots. J. Pharm. Sci., 2016, 105, 205-211.
[80]
Lu, Y.; Yu, Y.; Tang, X. Sucrose acetate isobutyrate as an in situ forming system for sustained risperidone release. J. Pharm. Sci., 2007, 96, 3252-3262.
[81]
Reynolds, R.C.; Chappel, C.I. Sucrose acetate isobutyrate (SAIB): historical aspects of its use in beverages and a review of toxicity studies prior to 1988. Food Chem. Toxicol., 1998, 36, 81-93.
[82]
Lin, X.; Xu, Y.; Tang, X.; Zhang, Y.; Chen, J.; He, H. A uniform ultra-small microsphere/SAIB hybrid depot with low burst release for long-term continuous drug release. Pharm. Res., 2015, 32, 3708-3721.
[83]
Moore, A.; Ling, M.; Bucko, A.; Manna, V.; Rueda, M.J. Efficacy and safety of subantimicrobial dose, modified-release Doxycycline 40 mg versus Doxycycline 100 mg versus placebo for the treatment of inflammatory lesions in moderate and severe acne: A randomized, double-blinded, controlled study. J. Drugs Dermatol., 2015, 14, 581-586.
[84]
Yadava, S.K.; Khana, G.; Mishraa, B. Advances in patents related to intrapocket technology for the management of periodontitis. Recent Pat. Drug Deliv. Formul., 2015, 9, 129-145.
[85]
Braeckman, J.; Michielsen, D. Efficacy and tolerability of 1- and 3-month leuprorelin acetate depot formulations (Eligard(®)/Depo-Eligard(®)) for advanced prostate cancer in daily practice: A Belgian prospective non-interventional study. Arch. Med. Sci., 2014, 10, 477.
[86]
Smelov, V.; Novikov, A.; Brown, L.J.; Eklund, C.; Strokova, L.; Ouburg, S. False-positive prostate cancer markers in a man with symptomatic urethral Chlamydia trachomatis infection. Int. J. STD AIDS, 2013, 24, 501-502.
[87]
Karabakan, M.; Akdemir, S.; Akdemir, A.O.; Erkmen, A.E.; Kayabas, U. A rare case of prostatic brucellosis mimicking prostate cancer. Urol. J., 2014, 11, 1987-1988.
[88]
Fredeking, T.M.; Zavala-Castro, J.E.; Gonzalez-Martinez, P.; Moguel-Rodriguez, W.; Sanchez, E.C.; Foster, M.J.; Diaz-Quijano, F.A. Dengue patients treated with doxycycline showed lower mortality associated to a reduction in IL-6 and TNF levels. Recent Pat. Antiinfect. Drug Discov, 2015, 10, 51-58.
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