11 research outputs found
In vitro anti-malarial interaction and gametocytocidal activity of cryptolepine
YesBackground: Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination
and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial
plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study
investigating the gametocytocidal activity of the plant and its major alkaloid, cryptolepine. This study also investigates
the anti-malarial interaction of cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations
continues.
Methods: The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta
and cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method
based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of cryptolepine
with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7.
Results: Cryptolepis sanguinolenta (
IC50 = 49.65 nM) and its major alkaloid, cryptolepine (
IC50 = 1965 nM), showed
high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual
stage, cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC50s of
1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant
concentration ratios showed a synergistic effect (mean ΣFIC50 = 0.287 ± 0.10) whereas an antagonistic activity (mean
ΣFIC50 = 4.182 ± 0.99) was seen with mefloquine.
Conclusions: The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and
cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages
of the parasite. Amodiaquine is a potential drug partner for cryptolepine in the development of novel fixed dose
combinations
Identification of cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of cryptolepine in Sprague Dawley rats
YesBackground: This study aims at characterizing the in vitro metabolism of cryptolepine using human and rat
hepatocytes, identifying metabolites in rat plasma and urine after a single cryptolepine dose, and evaluating the
single-dose oral and intravenous pharmacokinetics of cryptolepine in male Sprague Dawley (SD) rats.
Methods: The in vitro metabolic profiles of cryptolepine were determined by LC-MS/MS following incubation with
rat and human hepatocytes. The in vivo metabolic profile of cryptolepine was determined in plasma and urine
samples from Sprague Dawley rats following single-dose oral administration of cryptolepine. Pharmacokinetic
parameters of cryptolepine were determined in plasma and urine from Sprague Dawley rats after single-dose
intravenous and oral administration.
Results: Nine metabolites were identified in human and rat hepatocytes, resulting from metabolic pathways
involving oxidation (M2-M9) and glucuronidation (M1, M2, M4, M8, M9). All human metabolites were found in rat
hepatocyte incubations except glucuronide M1. Several metabolites (M2, M6, M9) were also identified in the urine
and plasma of rats following oral administration of cryptolepine. Unchanged cryptolepine detected in urine was
negligible. The Pharmacokinetic profile of cryptolepine showed a very high plasma clearance and volume of
distribution (Vss) resulting in a moderate average plasma half-life of 4.5 h. Oral absorption was fast and plasma
exposure and oral bioavailability were low.
Conclusions: Cryptolepine metabolism is similar in rat and human in vitro with the exception of direct glucuronidation
in human. Clearance in rat and human is likely to include a significant metabolic contribution, with proposed primary
human metabolism pathways hydroxylation, dihydrodiol formation and glucuronidation. Cryptolepine showed extensive
distribution with a moderate half-life.Funded by Novartis Pharma under the Next Generation Scientist Program
Facile Route to Targeted, Biodegradable Polymeric Prodrugs for the Delivery of Combination Therapy for Malaria
Isolation and development of a HPLC method for the detection and quantification of cryptolepine and its application in the determination of the total cryptolepine content in the root powder of cryptolepis sanguinolenta
Formulation And Evaluation of a Combined Chloroquine Phosphate and Chlorpheniramine Maleate Product
Chloroquine phosphate granules (B1) and chlorpheniramine maleate granules (B2) were separately formulated with maize starch and lactose with polyvinylpyrrolidone (10% w/v) as binder. B1 was coated with 5% w/v ethylcellulose to varying degrees by increasing the spray time of the coating solution by 2 minutes between successive batches to produce B1A, B1B, B1C, B1D, B1E, B1F, B1G, B1H and B1I of increasing coat thickness. B2 was not coated. The release profiles of the coated and uncoated granules were studied using the US Pharmacopoeia XXIV (2000) dissolution apparatus II. The release profiles showed a significant and progressive retardation of the release of chloroquine phosphate from B1A to B1I as the coating time was increased. Batch B1I which gave the most desired release profile was selected and combined with the chlorpheniramine maleate granules, encapsulated and the release profiles studied. Each capsule contained granules equivalent to 4mg chlorpheniramine maleate (uncoated) and 250mg chloroquine phosphate (coated). Almost all the chlorpheniramine (97.4%) in the combined product (capsule) was released in 35 min while only about a quarter (24.4%) of the chloroquine component was released in the same period. The combined formulation appears to possess the ability to protect susceptible patients from chloroquine-induced itching by releasing a greater amount of the antihistamine before the chloroquine is released. Journal of Science and Technology Vol. 26 (3) 2003: pp. 32-3