The difficulty of developing an efficient
malaria vaccine along
with increasing spread of multidrug resistant strain of Plasmodium falciparum to the available antimalarial
drugs poses the need to discover safe and efficacious antimalarial
drugs to control malaria. An alternative strategy is to synthesize
compounds possessing structures similar to the active natural products
or marketed drugs. Several biologically active natural products and
drugs contain β-carboline moiety. In the present study, few
selected β-carboline derivatives have been synthesized and tested
for their in vitro and in vivo antiplasmodial activity against the
rodent malaria parasite Plasmodium berghei (NK-65). The designed analogs exhibited considerable in vitro antimalarial
activity. Two compounds (1R,3S)-methyl
1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (9a) and (1R,3S)-methyl 1-(pyridin-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (9b) were further selected for in vivo studies. Both the lead
compounds (9a and 9b) were observed to be
safe for oral administration. The therapeutic effective dose (ED50) for 9a and 9b were determined
and in the animal model, 9a (at 50 mg/kg dose) exhibited
better activity in terms of parasite clearance and enhancement of
host survival. Biochemical investigations also point toward the safety
of the compound to the hepatic and renal functions of the rodent host.
Further studies are underway to explore its activity alone as well
as in combination therapy with artesunate against the human malaria
parasite P. falciparum.
Increasing resistance to presently
available antimalarial drugs
urges the need to look for new promising compounds. The β-carboline
moiety, present in several biologically active natural products and
drugs, is an important scaffold for antimalarial drug discovery. The
present study explores the antimalarial activity of a β-carboline
derivative (1
R
,3
S
)-methyl 1-(benzo[
d
][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1
H
-pyrido[3,4-
b
]indole-3-carboxylate (
9a
) alone
in vitro
against
Plasmodium
falciparum
and
in vivo
in combination
therapy with the standard drug artesunate against
Plasmodium
berghei
. Compound
9a
inhibited both 3D7
and RKL-9 strains of
P. falciparum
with
half-maximal inhibitory concentration (IC
50
) < 1 μg/mL,
respectively. The compound was nontoxic (50% cytotoxic concentration
(CC
50
) > 640 μg/mL) to normal dermal fibroblasts.
Selectivity index was >10 against both the strains. The compound
exhibited
considerable
in vivo
antimalarial activity (median
effective dose (ED
50
) = 27.74 mg/kg) in monotherapy. The
combination of
9a
(100 mg/kg) and artesunate (50 mg/kg)
resulted in 99.69% chemosuppression on day 5 along with a mean survival
time of 25.8 ± 4.91 days with complete parasite clearance. Biochemical
studies indicated the safety of the HIT compound to hepatic and renal
functions of mice. Molecular docking also highlighted the suitability
of
9a
as a potential antimalarial candidate.
Background
Incidence of pulmonary aspergillosis is rising worldwide, owing to an increased population of immunocompromised patients. Notable potential of the pulmonary route has been witnessed in antifungal delivery due to distinct advantages of direct lung targeting and first-pass evasion. The current research reports biomimetic surface-active lipid-polymer hybrid (LPH) nanoparticles (NPs) of voriconazole, employing lung-specific lipid, i.e., dipalmitoylphosphatidylcholine and natural biodegradable polymer, i.e., chitosan, to augment its pulmonary deposition and retention, following nebulization.
Results
The developed nanosystem exhibited a particle size in the range of 228–255 nm and drug entrapment of 45–54.8%. Nebulized microdroplet characterization of NPs dispersion revealed a mean diameter of ≤ 5 μm, corroborating its deep lung deposition potential as determined by next-generation impactor studies. Biophysical interaction of LPH NPs with lipid-monolayers indicated their surface-active potential and ease of intercalation into the pulmonary surfactant membrane at the air-lung interface. Cellular viability and uptake studies demonstrated their cytocompatibility and time-and concentration-dependent uptake in lung-epithelial A549 and Calu-3 cells with clathrin-mediated internalization. Transepithelial electrical resistance experiments established their ability to penetrate tight airway Calu-3 monolayers. Antifungal studies on laboratory strains and clinical isolates depicted their superior efficacy against Aspergillus species. Pharmacokinetic studies revealed nearly 5-, 4- and threefolds enhancement in lung AUC, Tmax, and MRT values, construing significant drug access and retention in lungs.
Conclusions
Nebulized LPH NPs were observed as a promising solution to provide effective and safe therapy for the management of pulmonary aspergillosis infection with improved patient compliance and avoidance of systemic side-effects.
Background Resistance to artemisinin and its partner drugs has threatened the sustainability of continuing the global efforts to curb malaria, which urges the need to look for newer therapies to control the disease without any adverse side effects. In the present study, novel homeopathic nosodes were prepared from Plasmodium falciparum and also assessed for their in vitro and in vivo anti-plasmodial activity.
Methods Three nosodes were prepared from P. falciparum (chloroquine [CQ]-sensitive [3D7] and CQ-resistant [RKL-9] strains) as per the Homeopathic Pharmacopoeia of India, viz. cell-free parasite nosode, infected RBCs nosode, mixture nosode. In vitro anti-malarial activity was assessed by schizont maturation inhibition assay. The in vitro cytotoxicity was evaluated by MTT assay. Knight and Peter's method was used to determine in vivo suppressive activity. Mice were inoculated with P. berghei-infected erythrocytes on day 1 and treatment was initiated on the same day. Biochemical, cytokine and histopathological analyses were carried out using standard methods.
Results In vitro: the nosodes exhibited considerable activity against P. falciparum with maximum 71.42% (3D7) and 68.57% (RKL-9) inhibition by mixture nosode followed by cell-free parasite nosode (62.85% 3D7 and 60% RKL-9) and infected RBCs nosode (60.61% 3D7 and 57.14% RKL-9). The nosodes were non-toxic to RAW macrophage cell line with >70% cell viability. In vivo: Considerable suppressive efficacy was observed in mixture nosode-treated mice, with 0.005 ± 0.001% parasitemia on day 35. Levels of liver and kidney function biomarkers were within the normal range in the mixture nosode-treated groups. Cytokine analysis revealed increased levels of IL-4 and IL-10, whilst a decline in IL-17 and IFN-γ was evident in the mixture nosode-treated mice.
Conclusion The mixture nosode exhibited promising anti-malarial activity against P. falciparum and P. berghei. Biochemical and histopathological studies also highlighted the safety of the nosode for the rodent host. The study provides valuable insight into a novel medicament that has potential for use in the treatment of malaria.
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