Posted by A recent paper in Cell Reports published an interesting finding: polymeric degradation products (compound X and Z, respectively) of antibiotics cefixime and ceftazidime were found to rescue mice in Alzheimer disease from synapse loss and memory deficits. [1]
Alzheimer disease is initiated by the interaction of cellular prion protein (PrPc) and oligomeric form of β-amyloid peptide (Aβo). This interaction is inhibited by compounds X and Z. While the fresh samples were ineffective, the inhibitory activity developed progressively from cefixime and ceftazidime incubated for several days. Other cephalosporins (cefdinir, cefotaxime, and ceftriaxone) exhibited zero activity either freshly used or after 6 days. Compound Z was isolated and fractionated and the fractions of various molecular weight effectively inhibited the binding of PrPc to Aβo.
Both cefixime and ceftazidime possess negatively charged carboxylic groups (Figure 1), while the other cephalosporins do not, suggesting that polymerization takes place through these carboxylic functions.
Fig. 1 Chemical formula of cefixime and ceftazidime
The memory deficit of transgenic mice was rescued by treating them with compound Z using intracerebroventricular minipump infusion.
It was also found that polyanionic structures with hydrophobic moieties, such as poly(styrene co-maleic acid) partial isobutyl ester also inhibit Aβo/PrPc binding to some extent.
The question arises if cyclodextrin formulation would improve the effect of cefixime and ceftazidime in Alzheimer disease, whether complexation has catalytic or inhibiting effect on polymerization.
What we know so far are the followings:
- Cefixime complexes with βCD and HPBCD show enhanced solubility (association constants: 164 M-1 and 131 M-1, resp.) [2], which can be further increased by using arginine [3], PVP or HPMC [4] as third component.
- The hydrolytic stability of cefixime is not improved by complexation with βCD [5], but the complexation can effectively mask the bitter taste of the drug. [6]
- The antibacterial effect of cefixime/HPBCD 1:3 complex (prepared by kneading) was higher than that of the pure drug. [7]
- Cefixime can be solubilized also by SBEBCD (Captisol) and the rate of drugs degradation is decreased. [8]
- Docking experiments resulted in conformation of the minimum energy for 1:1 complexation with HPBCD (Figure 2) [9], the carboxylic group remains outside of the cavity.
Fig. 2 Structure of cefixime/βCD complex
- The aqueous hydrolysis of ceftazidime is inhibited by complexation with HPBCD and subsequent micellization using poloxamer. [10]
- HPGCD can also solubilize ceftazimide, and the NMR studies showed that the thiazole ring with sulfur and nitrogen atoms with CO and CN bands of ceftazidime were included in the HPGCD cavity, [11] the carboxylic group remains outside of the cavity.
Fig. 3 Structure of ceftazidime/HPGCD complex
References:
[1] Gunther, E.C., Smith, L.M., Kostylev, M.A., Supattapone, S., Strittmatter, S.M. Rescue of Transgenic Alzheimer’s Pathophysiology by Polymeric Cellular Prion Protein Antagonists. Cell Reports, 2019, 26(1), 145–158. https://doi.org/10.1016/j.celrep.2018.12.021
[2] Varia, U., Patil, C., Kalyane, N., Agrawal, P. Effect of cyclodextrin inclusion complex on dissolution behaviour of cefixime. Journal of Pharmacy Research, 2010, 3(3), 570–557. https://www.researchgate.net/publication/41822972
[3] Jadhav, P., Petkar, B., Pore, Y., Kulkarni, A., Burade, K. Physicochemical and molecular modeling studies of cefixime-L-arginine-cyclodextrin ternary inclusion compounds. Carbohydrate Polymers, 2013, 98(2), 1317–1325. http://dx.doi.org/10.1016/j.carbpol.2013.07.070
[4] Mehta, P., More, A., Kulkarni, A. Effect of hydrophilic polymers on cefixime complexation with β-cyclodextrin. International Journal of Current Pharmaceutical Research, 2013, 5(3), 66–70. https://innovareacademics.in/journal/ijcpr/Issues/Vol5Issue3/719.pdf
[5] Pamudji, J.S., Mauludin, R. N. Influence of β-cyclodextrin on cefixime stability in liquid suspension dosage form. Procedia Chemistry 2014, 13, 119–127. https://doi.org/10.1016/j.proche.2014.12.015
[6] Madhavi, B.R., Murthy, V.S.N., Rani, A.P., Kumar, Y.M. Formulation and evaluation of taste masked oral disintegrating tablet of cefixime based on cyclodextrin binary systems. Journal of Global Trends in Pharmaceutical Sciences 2014, 5(2), 1738–1746. https://www.jgtps.com/admin/uploads/MgW6n2.pdf
[7] Mallick, S., Mondal, A., Sannigrahi, S. Kinetic measurements of the hydrolytic degradation of cefixime: effect of Captisol complexation and water-soluble polymers. Journal of Pharmacy and Pharmacology, 2008, 60(7), 833–841. https://doi.org/10.1211/jpp.60.7.0004
[8] Bushetti, S.S., Pandey, J.D., Divakar, K., Kotnal, R.B., Patil, R.G., Syed, S. Studies on cyclodextrin inclusion complexes of cefixime – An approach to improve the antibacterial activity of cefixime. Journal of Pharmacy Research 2010, https://www.researchgate.net/publication/290191791_Studies_on_cyclodextrin_inclusion_complexes_of_cefixime_-_An_approach_to_improve_the_antibacterial_activity_of_cefixime
[9] Mogal, P. Functionality advancement of poorly soluble drug by comparative study of solubilizing techniques with molecular simulation to in vivo evaluation. International Journal of PharmTech Research 2017, 10, 139–155. https://www.researchgate.net/publication/280020903 http://www.sphinxsai.com/2017/ph_vol10_no3/1/(139-155)V10N3PT.pdf
[10] Kharwade, Rohini S.; More, Sachin M.; Khan, Shagufta; Yeole, P. G. Stabilization of ceftazidime in liquid state using poloxamer and cyclodextrin. International Journal of Pharmacy and Pharmaceutical Sciences, 2010, 2(Suppl.3), 156-161. https://innovareacademics.in/journal/ijpps/Vol2Suppl3/706.pdf
[11] Misiuk, W. Investigation of inclusion complex of HP-γ-cyclodextrin with ceftazimide. Journal of Molecular Liquids 2016, 224, 387–392. https://doi.org/10.1016/j.molliq.2016.10.009