Pre-referral intranasal artesunate powder for cerebral malaria: a proof-of-concept study

Abstract

Background Malaria still kills young children in rural endemic areas because early treatment is not available. Thus, the World Health Organization recommends the administration of artesunate suppositories as pre-referral treatment before transportation to the hospital in case of severe symptoms with an unavailable parenteral and oral treatment. However, negative cultural perception of the rectal route, and limited access to artesunate suppositories, could limit the use of artesunate suppositories. There is, therefore, a need for an alternative route for malaria pre-referral treatment. The aim of this study was to assess the potential of intranasal route for malaria pre-referral treatment. Methods The permeability of artesunate through human nasal mucosa was tested in vitro. The Transepithelial Electrical Resistance (TEER) of the nasal mucosa was followed during the permeation tests. Beside, regional deposition of artesunate powder was assessed with an unidose drug delivery device in each nostril of a nasal cast. Artesunate quantification was performed using Liquid Chromatography coupled to tandem Mass Spectrometry. Results The experimental model of human nasal mucosa was successfully implemented. Using this model, artesunate powder showed a much better passage rate through human nasal mucosa than solution (26.8 ± 6.6% versus 2.1 ± 0.3%). More than half (62.3%) of the artesunate dose sprayed in the nostrils of the nasal cast was recovered in the olfactory areas (44.7 ± 8.6%) and turbinates (17.6 ± 3.3%) allowing nose-to-brain and systemic drug diffusion, respectively. Conclusion Artesunate powder showed a good permeation efficiency on human nasal mucosa. Moreover it can be efficiently sprayed in the nostrils using unidose device to reach the olfactory area leading to a fast nose-to-brain delivery as well as a systemic effect. Taken together, those results are part of the proof-of-concept for the use of intranasal artesunate as a malaria pre-referral treatment.

Artesunate Exerts Organ- and Tissue-Protective Effects by Regulating Oxidative Stress, Inflammation, Autophagy, Apoptosis, and Fibrosis: A Review of Evidence and Mechanisms

“…Hence, the therapeutic efficacy of AS administration routes ranks as intramuscular > rectal > oral. In another study [ 22 ], intranasal administration of AS in a female CBA/J mouse model with cerebral malaria improved survival rates, led to the degradation of AS to dihydroartemisinin (DHA) within 15-h post-administration, and reduced blood parasitemia after 24 h. This suggests that the intranasal route represents the most expedient means to deliver the drug to the brain promptly [ 23 ]. Regardless of the administration route, AS undergoes rapid metabolism to DHA ( Figure 1 ) in the body and is excreted within a short timeframe.…”

Cerebral Malaria

“…Daerah pedesaan di mana pengobatan intravena tidak tersedia, WHO merekomendasikan artesunat pra-rujukan, yaitu pemberian artesunat dosis tunggal secara intrarektal kepada anak kecil (<6 tahun) yang berisiko terkena malaria berat ketika rute oral tidak tersedia (Kouakou et 2022). Artesunat juga dapat diberikan melalui nasal.…”

“…Artesunat juga dapat diberikan melalui nasal. Menurut (Kouakou et al, 2022), pemberian melalui jalur nasal lebih baik diterima dibandingkan melalui rektal dan dapat terhindar dari metabolisme di hepar. Jalur nasal memungkinkan obat untuk melewati sawar darah otak dan memfasilitasi difusi obat langsung di dalam mikrovaskular otak.…”