Human studies transporters

The increased dopamine hypothesis is supported by findings of gene induction in the target areas and the indications that individual differences in dopamine receptors and transporters may underlie impulsive and addictive behaviour in humans. Studies in knock-out mice have, however, provided evidence for complex roles of 5-HT in these processes. 

Yan, Q. and W. Sadee. Human membrane transporter database a Web-accessible relational database for drug transport studies and pharma-cogenomics. AAPS PharmSci. 2000, 2, E20. 

Melikian, H. E., McDonald, J. K., Gu, H., Rudnick, G., Moore, K. R., and Blakely, R. D. (1994) Human norepinephrine transporter. Biosynthetic studies using a site-directed polyclonal antibody. J. Biol. Chem. 269,12290-12297. 

B.V. Sastry. Techniques to study human placental transport. Adv Drug Deliv Rev. 38 17-39 (1999). 

The intention to study transport processes at pulmonary epithelia, however, raised two particular problems (i) the apical side of these epithelia is typically in contact with air rather than with a liquid and (ii) in order to maximize the surface area, the lungs have a complex treelike structure, ending in millions of tiny alveolar bubbles. The total surface area of the human alveolar epithelium is almost half of that of the intestines (100-120 m2), with its macroscopic appearance resembling a sponge, and it is virtually impossible to use such a tissue for transport experiments in a diffusion-chamber setup. 

These drugs increase synaptic serotonin by selectively blocking the serotonin reuptake transporter. In preclinical and human studies acute doses tend to be anxiogenic (Bell and Nutt 1998) but chronic administration has anxiolytic effects, possibly due to downregulation of presynaptic autoreceptors (Blier et al. 1990). There are five SSRIs widely available citalopram, fluoxetine, fluvoxam-ine, paroxetine and sertraline. Escitalopram, the S-enantiomer of citalopram. 

Gelernter J, Cubells JF, Kidd JR, Pakstis AJ, Kidd KK (1999) Population studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet 88 61-66 Hahn MK, Blakely RD (2002) Monoamine transporter gene structure and polymorphisms in relation to psychiatric and other complex disorders. Pharmacogenomics J 2 217-235 HeUs A, Teufel A, Petri S, et al (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66 2621-2624... 

CRITICAL ASSESSMENT OF THE METHOD VolSurf descriptors are able to predict absorption for a diverse set of drugs. The presented model is derived using a consistent frame of relevant chemically interpretable descriptors, which find applications in different local and general models. However, absorption is not only controlled by passive membrane permeability. There are other factors influencing in vivo human absorption namely the in vivo dissolution rate in small intestinal fluid and the dose used for the human study. Furthermore, active transport or efflux mechanisms are difficult to rule out but can only be partially monitored by in vitro experiments. These important pieces of information should be known before any QSAR analysis is attempted on human absorption. This lack of consistent information throughout the literature is difficult to overcome, in particular for human studies. Hence, this study for the dataset from Zhao et al. (2001) provides a reasonable attempt to address these problems to carefully selecting members of the final dataset. 

Sawada, Y., Hiraga, S., Francis, B. (1990). Kinetic analysis of 3-quinuclidinyl 4-[125I]iodobenzilate transport and specific binding to muscarinic acetylcholine receptor in rat brain in vivo implications for human studies. J. Cereb. Blood Flow Metab. 10 781-807. 

Ciliary action removes deposited particles from both the bronchi and bronchioles. Though it is generally thought that mucocilliary action rapidly transports most particles deposited here toward the pharynx, a fraction of these particles are cleared more slowly. Evidence for this is found in human studies. For humans, retention of particles deposited in the lungs (BB and bb) is apparently biphasic. The slow action of the cilia may remove as many as half of the bronchi- and bronchiole-deposited particles. In human bronchi and bronchiole regions, mucus moves more slowly the closer to the alveoli it is. For the faster compartment it has been estimated that it takes about 2 days for particles to travel from the bronchioles to the bronchi and 10 days from the bronchi to the pharynx. The second (slower) compartment is assumed to have approximately equal fractions deposited between BB2 and bb2 and both with clearance... 

Safe and effective delivery of peptides has also been successfully demonstrated in human studies using iontophoresis, a technique that uses mild electric current to facilitate transport of molecules across the skin. ° Iontophoresis works primarily by a combination of two forces, electro-repulsion of charged drug molecule away from the electrode and into the skin, and electroosmosis, a convective solvent flow in the direction of the counter-ion transport. In general, cationic proteins and peptides are delivered more efficiently than anionic molecules because electro-osmosis works in the same direction as electro-migration for cationic species. 

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