Development and characterization of formulations based on combinatorial potential of antivirals against genital herpes.
Antivirals
Combination therapy
Formulations
Genital herpes
Good health and well-being
Local drug delivery
Journal
Naunyn-Schmiedeberg's archives of pharmacology
ISSN: 1432-1912
Titre abrégé: Naunyn Schmiedebergs Arch Pharmacol
Pays: Germany
ID NLM: 0326264
Informations de publication
Date de publication:
30 Sep 2024
30 Sep 2024
Historique:
received:
27
07
2024
accepted:
17
09
2024
medline:
30
9
2024
pubmed:
30
9
2024
entrez:
30
9
2024
Statut:
aheadofprint
Résumé
Herpes simplex virus type 2 (HSV-2) treatment faces challenges due to antiviral resistance and systemic side effects of oral therapies. Local delivery of antiviral agents, such as tenofovir (TDF) and zinc acetate dihydrate (ZAD), may offer improved efficacy and reduced systemic toxicity. This study's objective is to develop and evaluate local unit dose formulations of TDF and ZAD combination for local treatment of HSV-2 infection and exploring their individual and combinatory effects in vitro. The study involved the development of immediate-release film and pessary formulations containing TDF and ZAD. These formulations were characterized for physicochemical properties and in vitro drug release profiles. Cytotoxicity and antiviral activity assays were conducted to evaluate the individual and combinatory effects of TDF and ZAD. Film formulations released over 90% of the drugs within 1 h, and pessary formulations within 90 min, ensuring effective local drug delivery. ZAD showed moderate antiviral activity while TDF exhibited significant antiviral activity at non-cytotoxic concentrations. The combination of TDF and ZAD demonstrated synergistic effects in co-infection treatments, reducing the concentration required for 50% inhibition of HSV-2. Developed film and pessary formulations offer consistent and predictable local drug delivery, enhancing antiviral efficacy while minimizing systemic side effects. The combination of TDF and ZAD showed potential synergy against HSV-2, particularly in co-infection treatments. Further preclinical studies on pharmacokinetics, safety, and efficacy are necessary to advance these formulations toward clinical application.
Identifiants
pubmed: 39347802
doi: 10.1007/s00210-024-03468-y
pii: 10.1007/s00210-024-03468-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Akil A, Parniak MA, Dezzuitti CS et al (2011) Development and characterization of a vaginal film containing dapivirine, a non- nucleoside reverse transcriptase inhibitor (NNRTI), for prevention of HIV-1 sexual transmission. Drug Deliv Transl Res 1:209–222. https://doi.org/10.1007/s13346-011-0022-6
doi: 10.1007/s13346-011-0022-6
Akil A, Agashe H, Dezzutti CS et al (2015) Formulation and characterization of polymeric films containing combinations of antiretrovirals (ARVs) for HIV prevention. Pharm Res 32:458–468. https://doi.org/10.1007/s11095-014-1474-4
doi: 10.1007/s11095-014-1474-4
Apriliyani MW, Purwadi Manab A, Ikhwan AD (2020) Characteristics of moisture content, swelling, opacity and transparency with addition chitosan as edible films/coating base on casein. Adv J Food Sci Technol 18:9–14. https://doi.org/10.19026/ajfst.18.6041
doi: 10.19026/ajfst.18.6041
Avlani D, Kumar A, HN S (2023) Development of dispersible vaginal tablets of tenofovir loaded mucoadhesive chitosan microparticles for anti-HIV pre-exposure prophylaxis. Mol Pharmaceutics 20:5006–5018. https://doi.org/10.1021/acs.molpharmaceut.3c00288
doi: 10.1021/acs.molpharmaceut.3c00288
Avlani D, Shivakumar HN, Kumar A et al (2024) Pre-exposure prophylactic mucoadhesive sodium alginate microsphere laden pessaries for intravaginal delivery of tenofovir disoproxil fumarate. Int J Biol Macromol 258:128816. https://doi.org/10.1016/j.ijbiomac.2023.128816
doi: 10.1016/j.ijbiomac.2023.128816
Bender Ignacio RA, Perti T, Magaret AS et al (2015) Oral and vaginal tenofovir for genital herpes simplex virus type 2 shedding in immunocompetent women: a double-blind, randomized, cross-over trial. J Infect Dis 212:1949–1956. https://doi.org/10.1093/infdis/jiv317
doi: 10.1093/infdis/jiv317
Bourne N, Stegall R, Montano R et al (2005) Efficacy and toxicity of zinc salts as candidate topical microbicides against vaginal herpes simplex virus type 2 infection. Antimicrob Agents Chemother 49:1181–1183. https://doi.org/10.1128/AAC.49.3.1181-1183.2005
doi: 10.1128/AAC.49.3.1181-1183.2005
Brandariz-Nuñez D, Correas-Sanahuja M, Maya-Gallego S, Martín Herranz I (2021) Neurotoxicity associated with acyclovir and valacyclovir: a systematic review of cases. J Clin Pharm Ther 46:918–926. https://doi.org/10.1111/jcpt.13464
doi: 10.1111/jcpt.13464
Cautela MP, Moshe H, Sosnik A et al (2019) Composite films for vaginal delivery of tenofovir disoproxil fumarate and emtricitabine. Eur J Pharm Biopharm 138:3–10. https://doi.org/10.1016/j.ejpb.2018.02.001
doi: 10.1016/j.ejpb.2018.02.001
Chou T-C, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55. https://doi.org/10.1016/0065-2571(84)90007-4
doi: 10.1016/0065-2571(84)90007-4
Cohen JI (2020) Herpesvirus latency. J Clin Invest 130:3361–3369. https://doi.org/10.1172/JCI136225
doi: 10.1172/JCI136225
Cunha AR, Machado RM, Palmeira-de-Oliveira A et al (2014) Characterization of commercially available vaginal lubricants: a safety perspective. Pharmaceutics 6:530. https://doi.org/10.3390/pharmaceutics6030530
doi: 10.3390/pharmaceutics6030530
Fernández-Romero JA, Abraham CJ, Rodriguez A et al (2012) Zinc acetate/carrageenan gels exhibit potent activity in vivo against high-dose herpes simplex virus 2 vaginal and rectal challenge. Antimicrob Agents Chemother 56:358–368. https://doi.org/10.1128/AAC.05461-11
doi: 10.1128/AAC.05461-11
Fleischer R, Johnson M (2010) Acyclovir nephrotoxicity: a case report highlighting the importance of prevention, detection, and treatment of acyclovir-induced nephropathy. Case Rep Med 2010:602783. https://doi.org/10.1155/2010/602783
doi: 10.1155/2010/602783
Friedland BA, Hoesley CJ, Plagianos M et al (1999) (2016) First-in-human trial of MIV-150 and zinc acetate coformulated in a carrageenan gel: safety, pharmacokinetics, acceptability, adherence, and pharmacodynamics. J Acquir Immune Defic Syndr 73:489. https://doi.org/10.1097/QAI.0000000000001136
doi: 10.1097/QAI.0000000000001136
Geddawy A, Ibrahim YF, Elbahie NM, Ibrahim MA (2017) Direct acting anti-hepatitis c virus drugs: clinical pharmacology and future direction. J Transl Int Med 5:8–17. https://doi.org/10.1515/jtim-2017-0007
doi: 10.1515/jtim-2017-0007
Gershengorn HB, Blower SM (2000) Impact of antivirals and emergence of drug resistance: HSV-2 epidemic control. AIDS Patient Care STDS 14:133–142. https://doi.org/10.1089/108729100317911
doi: 10.1089/108729100317911
Gibas KM, Kelly SG, Arribas JR et al (2022) Two-drug regimens for HIV treatment. Lancet HIV 9:e868–e883. https://doi.org/10.1016/S2352-3018(22)00249-1
doi: 10.1016/S2352-3018(22)00249-1
Giorgi J, Simon B, Destras G et al (2023) Novel UL23 and UL30 substitutions in HSV1 and HSV2 viruses related to polymorphism or drug resistance. Antiviral Res 216:105672. https://doi.org/10.1016/j.antiviral.2023.105672
doi: 10.1016/j.antiviral.2023.105672
Gong T, Zhang W, Parniak MA et al (2017) Preformulation and vaginal film formulation development of microbicide drug candidate CSIC for HIV prevention. J Pharm Innov 12:142–154. https://doi.org/10.1007/s12247-017-9274-0
doi: 10.1007/s12247-017-9274-0
Goulding LV, Kiss E, Goatley L et al (2022) In vitro and in vivo antiviral activity of nucleoside analogue cHPMPC against African swine fever virus replication. Antiviral Res 208:105433. https://doi.org/10.1016/j.antiviral.2022.105433
doi: 10.1016/j.antiviral.2022.105433
Greeley ZW, Giannasca NJ, Porter MJ, Margulies BJ (2020) Acyclovir, cidofovir, and amenamevir have additive antiviral effects on herpes simplex virus TYPE 1. Antiviral Res 176:104754. https://doi.org/10.1016/j.antiviral.2020.104754
doi: 10.1016/j.antiviral.2020.104754
Ham AS, Robert W, Buckheit J (2017) Designing and developing suppository formulations for anti-HIV drug delivery. Ther Deliv 8:805. https://doi.org/10.4155/tde-2017-0056
doi: 10.4155/tde-2017-0056
Hammond SP, Rangaraju M, Sumner M et al (2024) A multicenter assessment of the outcomes and toxicities of foscarnet for treatment of acyclovir-resistant mucocutaneous herpes simplex in immunocompromised patients. Open Forum Infect Dis 11:ofae046. https://doi.org/10.1093/ofid/ofae046
doi: 10.1093/ofid/ofae046
Hoang T, Date AA, Ortiz JO et al (2019) Development of rectal enema as microbicide (DREAM): preclinical progressive selection of a tenofovir prodrug enema. Eur J Pharm Biopharm 138:23–29. https://doi.org/10.1016/j.ejpb.2018.05.030
doi: 10.1016/j.ejpb.2018.05.030
Ianevski A, Yao R, Simonsen RM et al (2022) Mono- and combinational drug therapies for global viral pandemic preparedness. iScience 25:104112. https://doi.org/10.1016/j.isci.2022.104112
doi: 10.1016/j.isci.2022.104112
Jiang Y-C, Feng H, Lin Y-C, Guo X-R (2016) New strategies against drug resistance to herpes simplex virus. Int J Oral Sci 8:1–6. https://doi.org/10.1038/ijos.2016.3
doi: 10.1038/ijos.2016.3
Kandagal PB, Manjunatha DH, Seetharamappa J, Kalanur SS (2008) RP-HPLC method for the determination of tenofovir in pharmaceutical formulations and spiked human plasma. Anal Lett 41:561–570. https://doi.org/10.1080/00032710801910742
doi: 10.1080/00032710801910742
Kenzaka T, Sugimoto K, Goda K, Akita H (2021) Acute kidney injury and acyclovir-associated encephalopathy after administration of valacyclovir in an elderly person with normal renal function: a case report and literature review. Medicine 100:e26147. https://doi.org/10.1097/MD.0000000000026147
doi: 10.1097/MD.0000000000026147
Kimberlin DW, Whitley RJ (2007) Antiviral therapy of HSV-1 and -2. In: Arvin A, Campadelli-Fiume G, Mocarski E et al (eds) Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge University Press, Cambridge
Kumar L, Reddy MS, Shirodkar RK et al (2013) Preparation and characterisation of fluconazole vaginal films for the treatment of vaginal candidiasis. Indian J Pharm Sci 75:585–590
Kümel G, Schrader S, Zentgraf H et al (1990) The mechanism of the antiherpetic activity of zinc sulphate. J Gen Virol 71:2989–2997. https://doi.org/10.1099/0022-1317-71-12-2989
doi: 10.1099/0022-1317-71-12-2989
Machado A, Cunha-Reis C, Araújo F et al (2016) Development and in vivo safety assessment of tenofovir-loaded nanoparticles-in-film as a novel vaginal microbicide delivery system. Acta Biomater 44:332–340. https://doi.org/10.1016/j.actbio.2016.08.018
doi: 10.1016/j.actbio.2016.08.018
Marrazzo JM, Rabe L, Kelly C et al (2019) Tenofovir gel for prevention of herpes simplex virus type 2 acquisition: findings from the VOICE trial. J Infect Dis 219:1940–1947. https://doi.org/10.1093/infdis/jiz045
doi: 10.1093/infdis/jiz045
Marreiro D do N, Cruz KJC, de Oliveira ARS, et al (2021) Antiviral and immunological activity of zinc and possible role in COVID-19. Br J Nutr 1–8. https://doi.org/10.1017/S0007114521002099
Mesquita PMM, Rastogi R, Segarra TJ et al (2012) Intravaginal ring delivery of tenofovir disoproxil fumarate for prevention of HIV and herpes simplex virus infection. J Antimicrob Chemother 67:1730. https://doi.org/10.1093/jac/dks097
doi: 10.1093/jac/dks097
Mishra R, Joshi P, Mehta T (2016) Formulation, development and characterization of mucoadhesive film for treatment of vaginal candidiasis. Int J Pharm Investig 6:47–55. https://doi.org/10.4103/2230-973X.176487
doi: 10.4103/2230-973X.176487
Moss JA, Srinivasan P, Smith TJ et al (2014) Pharmacokinetics and preliminary safety study of pod-intravaginal rings delivering antiretroviral combinations for HIV prophylaxis in a macaque model. Antimicrob Agents Chemother 58:5125–5135. https://doi.org/10.1128/aac.02871-14
doi: 10.1128/aac.02871-14
Nixon B, Jandl T, Teller RS et al (2014) Vaginally delivered tenofovir disoproxil fumarate provides greater protection than tenofovir against genital herpes in a murine model of efficacy and safety. Antimicrob Agents Chemother 58:1153–1160. https://doi.org/10.1128/AAC.01818-13
doi: 10.1128/AAC.01818-13
Notario-Pérez F, Cazorla-Luna R, Martín-Illana A et al (2020) Design, fabrication and characterisation of drug-loaded vaginal films: state-of-the-art. J Control Release 327:477–499. https://doi.org/10.1016/j.jconrel.2020.08.032
doi: 10.1016/j.jconrel.2020.08.032
Patel SK, Agashe H, Patton DL et al (2023) Tenofovir vaginal film as a potential MPT product against HIV-1 and HSV-2 acquisition: formulation development and preclinical assessment in non-human primates. Front Reprod Health 5:1217835. https://doi.org/10.3389/frph.2023.1217835
doi: 10.3389/frph.2023.1217835
Robinson JA, Marzinke MA, Fuchs EJ et al (2018) Comparison of the pharmacokinetics and pharmacodynamics of single-dose tenofovir vaginal film and gel formulation (FAME-05). Journal of acquired immune deficiency syndromes 77(1999):175. https://doi.org/10.1097/QAI.0000000000001587
doi: 10.1097/QAI.0000000000001587
Sauerbrei A (2016) Herpes genitalis: diagnosis, treatment and prevention. Geburtshilfe Frauenheilkd 76:1310–1317. https://doi.org/10.1055/s-0042-116494
doi: 10.1055/s-0042-116494
Sehrawat S, Kumar D, Rouse BT (2018) Herpesviruses: harmonious pathogens but relevant cofactors in other diseases? Front Cell Infect Microbiol 8. https://doi.org/10.3389/fcimb.2018.00177
Shankar GN, Alt C (2014) Prophylactic treatment with a novel bioadhesive gel formulation containing aciclovir and tenofovir protects from HSV-2 infection. J Antimicrob Chemother 69:3282–3293. https://doi.org/10.1093/jac/dku318
doi: 10.1093/jac/dku318
Shapiro RL, DeLong K, Zulfiqar F et al (2022) In vitro and ex vivo models for evaluating vaginal drug delivery systems. Adv Drug Deliv Rev 191:114543. https://doi.org/10.1016/j.addr.2022.114543
Shyr ZA, Cheng Y-S, Lo DC, Zheng W (2021) Drug combination therapy for emerging viral diseases. Drug Discov Today 26:2367–2376. https://doi.org/10.1016/j.drudis.2021.05.008
doi: 10.1016/j.drudis.2021.05.008
Srinivasan P, Moss JA, Gunawardana M et al (2016) Topical delivery of tenofovir disoproxil fumarate and emtricitabine from Pod-intravaginal rings protects macaques from multiple SHIV exposures. PLoS ONE 11:e0157061. https://doi.org/10.1371/journal.pone.0157061
doi: 10.1371/journal.pone.0157061
Stern A, Alonso CD, Garcia-Vidal C et al (2021) Safety and efficacy of intravenously administered cidofovir in adult haematopoietic cell transplant recipients: a retrospective multicentre cohort study. J Antimicrob Chemother 76:3020–3028. https://doi.org/10.1093/jac/dkab259
doi: 10.1093/jac/dkab259
Takeuchi Y, Ikeda N, Tahara K, Takeuchi H (2020) Mechanical characteristics of orally disintegrating films: Comparison of folding endurance and tensile properties. Int J Pharm 589:119876. https://doi.org/10.1016/j.ijpharm.2020.119876
doi: 10.1016/j.ijpharm.2020.119876
Tsioptsias C, Fardis D, Ntampou X et al (2023) Thermal behavior of poly(vinyl alcohol) in the form of physically crosslinked film. Polymers 15:1843. https://doi.org/10.3390/polym15081843
doi: 10.3390/polym15081843
Tyo KM, Vuong HR, Malik DA et al (2017) Multipurpose tenofovir disoproxil fumarate electrospun fibers for the prevention of HIV-1 and HSV-2 infections in vitro. Int J Pharm 531:118–133. https://doi.org/10.1016/j.ijpharm.2017.08.061
doi: 10.1016/j.ijpharm.2017.08.061
Weinberg A, Bate BJ, Masters HB et al (1992) In vitro activities of penciclovir and acyclovir against herpes simplex virus types 1 and 2. Antimicrob Agents Chemother 36:2037–2038. https://doi.org/10.1128/aac.36.9.2037
doi: 10.1128/aac.36.9.2037
Yadavalli T, Mallick S, Patel P et al (2020) Pharmaceutically acceptable carboxylic acid-terminated polymers show activity and selectivity against HSV-1 and HSV-2 and synergy with antiviral drugs. ACS Infect Dis 6:2926–2937. https://doi.org/10.1021/acsinfecdis.0c00368
doi: 10.1021/acsinfecdis.0c00368