Showing papers by "William N. Charman published in 2004"
TL;DR: Here it is described how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.
Abstract: The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem and proteins (enzymes), one of which--the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)--may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chemical (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.
617 citations
TL;DR: In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations, and Digestion of microemulsion preconcentrate formulations based on medium- Chain lipids may limit in vivo utility whenCompared with similar formulations based with long chain lipids.
Abstract: Purpose. To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly water-soluble drug.
Methods. Three lipid-based danazol formulations [a long-chain triglyceride solution (LCT-solution) and self-microemulsifying drug delivery systems (SMEDDS) based on long-chain (C18) lipids (LC-SMEDDS) and medium-chain (C8-C10) lipids (MC-SMEDDS)] were adminis- tered to fasted beagle dogs and compared with a micronized danazol formulation administered postprandially and in the fasted state. In vitro dispersion and particle size data for the two SMEDDS were compared, and the distribution/solubilization patterns of danazol across the various phases produced during in vitro digestion quantified.
Results. The LCT-solution and LC-SMEDDS formulations significantly enhanced the oral bioavailability of danazol when compared to fasted administration of the powder formulation. In contrast, and despite displaying excellent dispersion properties, the MC-SMEDDS resulted in little enhancement in danazol bioavailability. In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations.
Conclusions. Digestion of microemulsion preconcentrate formulations based on medium-chain lipids may limit in vivo utility when compared with similar formulations based on long chain lipids.
229 citations
TL;DR: The potential utility of in vitro digestion models to assess and rank order the in vivo performance of lipid solution and suspension formulations of poorly water-soluble drugs such as Hf is demonstrated.
212 citations
TL;DR: The solubilization behavior of lipophilic drugs on digestion of simple TG lipid formulations is a function of the lipophilicity of the drug, the nature of the colloidal phases produced on digestionof the different formulation lipids, and the kinetics of drug transfer between the digesting formulation and the colloid phases produced.
Abstract: Purpose. The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during digestion of either long-chain or medium-chain triglyceride (TG) lipid formulations.
201 citations
TL;DR: In this article, phase diagrams were produced to determine the phase behavior of the digestion products of common formulation lipids (C8:0, C12:0 and C18:1) under model physiological conditions.
130 citations
TL;DR: Suspensions of drugs, which are poorly soluble in water and TG lipid, may prove beneficial as the relatively high solubilizing capacity of the colloidal phases produced on TG digestion will likely exceed the mass of drug that could have been administered as a simple lipid solution, however, for more lipid-soluble drugs, suspension formulations may offer little benefit.
Abstract: Purpose. The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during the in vitro digestion of long-chain or medium-chain triglyceride (TG) lipid suspension formulations.
123 citations
TL;DR: Oral and intravenous pharmacokinetic studies of manzamine A in rats indicated the compound to have low metabolic clearance, a reasonably long pharmacokinetics half-life, and good absolute oral bioavailability of 20.6%, which supports the value of these compounds as potential leads for further preclinical assessment and possible development.
Abstract: 12,28-Oxamanzamine A (1), 12,28-oxa-8-hydroxymanzamine A (2), and 31-keto-12,34-oxa-32,33-dihydroircinal A (3) were isolated from two collections of an Indo-Pacific sponge, and their structures were assigned on the basis of 1D and 2D NMR spectroscopic data. These compounds possess a novel manzamine-type ring system generated through a new ether bridge formed between carbons 12 and 28 or between carbons 12 and 34 of the typical manzamine structure and add to our growing understanding of manzamine SAR and metabolism. Based on molecular modeling studies, the formation of these oxidation products is highly sterically favored. The potent antiinflammatory, antifungal, and anti-HIV-1 activity for a number of previously reported manzamines is also presented in addition to the pharmacokinetic studies of manzamine A (5). Oral and intravenous pharmacokinetic studies of manzamine A in rats indicated the compound to have low metabolic clearance, a reasonably long pharmacokinetic half-life, and good absolute oral bioavailability of 20.6%, which supports the value of these compounds as potential leads for further preclinical assessment and possible development.
100 citations
TL;DR: The results of this study suggest that this cubic phase may potentially be of benefit in the delivery of poorly water-soluble compounds due to its high loading capacity and potential for sustained release.
68 citations
TL;DR: New fluoroart Artemisinin derivatives containing polar or water-soluble functionalities at C-16 (11a-j, 12a-g) were synthesized using the key intermediate 16-bromo-10-trifluoromethyl anhydrodihydroartemisinin 10, and among them, amines 11a-c appeared to be highly in vivo efficient antimalarials on mice infected with Plasmodium berghei.
Abstract: New fluoroartemisinin derivatives containing polar or water-soluble functionalities at C-16 (11a-j, 12a-g) were synthesized using the key intermediate 16-bromo-10-trifluoromethyl anhydrodihydroartemisinin 10 The substitution reaction from 10 was more selective than that from the nonfluorinated parent bromide; the allylic bromide 10 underwent no allylic rearrangement and provided only nucleophilic substitution products in high yields with N-, O-, and C-nucleophiles Among them, amines 11a-c appeared to be highly in vivo efficient antimalarials on mice infected with Plasmodium berghei, more than the reference sodium artesunate 1d In particular, the most effective piperazinoethanol derivative 11b cured all mice after oral treatment at a dose lower than 10 mg/kg Further pharmacokinetic studies showed that the bioavailability in rats following oral administration was 25 times greater for 11b than for artemether 1b
46 citations
TL;DR: Density gradient ultracentrifugation techniques were employed to determine drug association in triglyceride rich (TRL), low-density (LDL) and high-density lipoproteins (HDL), under both fasted and post-prandial conditions.
7 citations
Patent•
30 Jul 2004
TL;DR: An oral drug delivery system which comprises a biliquid foam comprising of a continuous hydrophilic phase, from 70 to 98% by weight of a pharmaceutically acceptable oil which forms a discontinuous phase, is described in this article.
Abstract: An oral drug delivery system which comprises a biliquid foam comprising: from 1 to 20% by weight of a continuous hydrophilic phase, from 70 to 98% by weight of a pharmaceutically acceptable oil which forms a discontinuous phase, the said pharmaceutically acceptable oil having dissolved or dispersed therein a poorly water-soluble drug in an amount of from 0.1 to 20% by weight and the biliquid foam including therein from 0.5 to 10% by weight of a surfactant to enable the formation of a stable biliquid foam, all percentages being based upon the total weight of the formulation.
TL;DR: Oral and intravenous pharmacokinetic studies of manzamine A in rats indicated the compound to have low metabolic clearance, a reasonably long pharmacokinetics half-life, and good absolute oral bioavailability of 20.6%, which supports the value of these compounds as potential leads for further preclinical assessment and possible development.
Abstract: 12,28-Oxamanzamine A (1), 12,28-oxa-8-hydroxymanzamine A (2), and 31-keto-12,34-oxa-32,33-dihydroircinal A (3) were isolated from two collections of an Indo-Pacific sponge, and their structures were assigned on the basis of 1D and 2D NMR spectroscopic data. These compounds possess a novel manzamine-type ring system generated through a new ether bridge formed between carbons 12 and 28 or between carbons 12 and 34 of the typical manzamine structure and add to our growing understanding of manzamine SAR and metabolism. Based on molecular modeling studies, the formation of these oxidation products is highly sterically favored. The potent antiinflammatory, antifungal, and anti-HIV-1 activity for a number of previously reported manzamines is also presented in addition to the pharmacokinetic studies of manzamine A (5). Oral and intravenous pharmacokinetic studies of manzamine A in rats indicated the compound to have low metabolic clearance, a reasonably long pharmacokinetic half-life, and good absolute oral bioavailability of 20.6%, which supports the value of these compounds as potential leads for further preclinical assessment and possible development.
Patent•
30 Jul 2004
TL;DR: An oral drug delivery system which comprises a biliquid foam comprising of a continuous hydrophilic phase, from 70 to 98% by weight of a pharmaceutically acceptable oil which forms a discontinuous phase, is described in this article.
Abstract: An oral drug delivery system which comprises a biliquid foam comprising: from 1 to 20% by weight of a continuous hydrophilic phase, from 70 to 98% by weight of a pharmaceutically acceptable oil which forms a discontinuous phase, the said pharmaceutically acceptable oil having dissolved or dispersed therein a poorly water-soluble drug in an amount of from 0.1 to 20% by weight and the biliquid foam including therein from 0.5 to 10% by weight of a surfactant to enable the formation of a stable biliquid foam, all percentages being based upon the total weight of the formulation.