861.
Österberg, Thomas
(författare)
Modelling and prediction of drug transport processes with experimental and calculated molecular properties : A multivariate approach
2000
Doktorsavhandling (övrigt vetenskapligt) abstract
Less than 2% of the lead compounds generated by the pharmaceutical industry enter the exploratory drug-development phase, from which point they stand only a 10% chance of becoming a commercial medicine. A large proportion of the compounds fail due to poor biopharmaceutical properties, such as permeability and solubility. The main theme of this thesis is, therefore, the development of better experimental and computational methods for modelling and predicting the biopharmaceutical properties of drug candidates. Immobilised liposome chromatography (ILC) was used for studying drug-membrane interactions and for the prediction of passive drug transport. For the drugs studied in this thesis, ILC and octanol/water partitioning showed a similar performance with regard to the prediction of passive drug transport.The theoretical work was directed at the modelling and prediction of drag transport processes using calculated molecular properties and PLS analysis. In the initial studies, the molecular properties were calculated with an advanced computational tool (MolSurf) that takes the three-dimensional structural information and electronic properties of the compound into consideration. Statistical models well suited to the prediction of drug transport processes such as Caco-2 cell permeability, intestinal absorption and CNS penetration were derived.This approach was also successfully applied to the modelling of the interaction of drugs with P-glycoprotein. Subsequently, rapidly calculated descriptors based on two-dimensional structural information and PLS analysis were also found to give good predictive models of drug transport properties. The preferred use of the latter models is for screening compound collections and virtual libraries. It can be concluded that calculated molecular properties in conjunction with PLS analysis are well suited to the modelling and prediction of drug transport processes and to identifying compounds with potential biopharmaceutical problems at an early stage of the drug-development process.
862.
Östergren, A, et al.
(författare)
Long-term retention of neurotoxic ß-carbolines in brain neuromelanin
2003
Ingår i: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 111:2, s. 141-157
Tidskriftsartikel (refereegranskat) abstract
beta-Carbolines show structural resemblance to the neurotoxic N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and are metabolized to mitochondrial toxicants. Humans are continuously exposed to low levels of beta-carbolines through cooked food, coffee, alcoholic beverages and tobacco smoke. beta-Carbolines have previously been detected in higher levels in the pigmented substantia nigra than in the cortex of humans. The distribution of 3H-labelled harman and norharman in the brain of pigmented and albino mice and in frogs (a species having neuromelanin) was studied by tape-section and light-microscopic autoradiography. Furthermore, the binding of these beta-carbolines to dopamine-melanin and melanin granules from Sepia officinalis was examined. The results revealed a high affinity binding to melanin and a long-term retention (up to 30 days) in pigmented tissues, including neuromelanin-containing neurons of frogs after a single injection. The role of long-term exposure to food-related beta-carbolines and a retention of these compounds in pigment-containing neurons in the induction of idiopathic Parkinson's disease should be further considered.
863.
Östh, Karin
(författare)
The Horizontal Ussing Chamber Method in Studies of Nasal Drug Delivery : Method Development and Applications Using Different Formulations
2002
Doktorsavhandling (övrigt vetenskapligt) abstract
The results from this thesis leads to the following conclusions; HUM is a useful tool that fills a gap in the in vitro methods previously available to study nasal drug delivery. Using HUM, the pig respiratory nasal mucosa can obtain acceptable viability and retain it longer than the period of time needed for a transport experiment. HUM has proven to be an appropriate tool for the study of liquids in low volume, gels, both unmodified and with controlled release properties, and particle suspensions. The potential local toxicity of formulations such as controlled release gels and surfactants could be evaluated and graded using HUM. The estimation of the apparent permeability can be corrected on a mathematical basis, for substances that bind to the chamber material. As seen using HUM, unmodified gels from Carbopol 934 (C934) are well tolerated by the nasal mucosa and may consequently be suitable for nasal administration. The release rate of testostenone, dihydroalprenolol and hydrocortisone from C934 gels can be successfully sustained. Protein-conjugated starch microparticles, intended to function as a vaccine carrier system, were taken up by non-ciliated epithelial cells of the pig respiratory nasal mucosa after incubation using HUM. The concentration-dependent effects on permeability and transepithelial electrical resistance on Caco-2 cells, of a series of nonionic polyoxyethylene surfactants, correlated with surfactant structure. Similar effects were seen on pig nasal mucosa using HUM, but the nasal mucosa appeared to be more tolerant to the surfactants than the intestinal cell model.The nasal route has advantages for several classes of drugs e.g. involved in migrain treatment, nicotine substitution therapy and mucosal vaccination. The increased development of a variety of substances, in a variety of formulation types, has increased the demand for suitable investigational tools. It is in this context that the horizontal Ussing chamber method (HUM) was developed. Using HUM, the studied formulation can be applied on the mucosa without additional buffer, giving an in vivo-like situation and the possibility to study solid and semi-solid formulations. Furthermore, the influence of gravity will not result in uneven distribution of the formulation.
864.
Saber, Amanj, 1972-, et al.
(författare)
Middle Ear Application of Hyaluronic Acid Gel Loaded with Neomycin in a Guinea Pig Model
2008
Konferensbidrag (refereegranskat) abstract
Background: One alternative for controlled drug delivery to the inner ear is application of medication to the middle ear cavity on the promise that it will diffuse through the round window membrane (RWM) into the inner ear.Objective: to evaluate the efficacy of hyaluronic acid gel (HYA) as a vehicle for drugs that are aimed to treat inner ear disorders.Methods: in this study the cochlear hair cell loss and RWM morphology were investigated after topical application. Neomycin was chosen as tracer for drug release and the ototoxic effect was evaluated. HYA, (0.5%) loaded with 3 different concentrations of neomycin, was injected to the middle ear cavity of guinea pigs. the ototoxic effect of neomycin in HYA gel was compared to that of neomycin solution applied to the middle ear cavity. Phalloidin stained surface preparation of the organ of Corti was used to estimate hair cell loss induced by neomycin. the thickness of the midportion of the RWM was measured and compared with that of controls using light and electrom microscope.Result: Neomycin induced a considerable hair cell loss in guinea pigs receiving middle ear injection of HYA loaded with the drug. One week after topical application the thickness of the RWM was dependent upon the concentration of neomycin administered to the middle ear. At 4 weeks the thickness of the RWM had returned to normal.Conclusion: HYA is a safe vehicle for drugs aimed to pass into the inner ear through the RWM. Neomycin was released from HYA and transported into the inner ear as evidenced by hair cell loss. Key words: Round window membrane (RWM), hyaluronic acid gel, HYA, hair cell loss, thickness.
