A second pathway of activation of the Torpedo acetylcholine receptor channel

We have studied the interaction of the reversible acetylcholine esterase inhibitor (-)physostigmine (D-eserine) with the nicotinic acetylcholine receptor (nAChR) from Torpedo marmorata electric tissue by means of ligandinduced ion flux into nAChR-rich membrane vesicles and of equilibrium binding. We find that (—)physostigmine induces cation flux (and also binds to the receptor) even in the presence of saturating concentrations of antagonists of acetylcholine, such as D-tubocurarine, a-bungarotoxin or antibody WF6, The direct action on the acetylcholine receptor is not affected by removal of the methylcarbamate function from the drug and thus is not due to carbamylation of the receptor. Antibodies FKl and benzoquinonium antagonize channel activation (and binding) of eserine, suggesting that the eserine binding site(s) is separate from, but adjacent to, the acetylcholine binding site at the receptor. In addition to the channel activating site(s) with an affinity of binding in the 50 nM range, there exists a further class of low-affinity (K^ ~ mM) sites from which eserine acts as a direct blocker of the acetylcholine-activatcd channel. Our results suggest the existence of a second pathway of activation of the nAChR channel

Desensitization is a property of the cholinergic binding region of the nicotinic acetylcholine receptor, not of the receptor-integral ion channel

The reversible acctylchollne esternse inhibitor (-}.physostiilmine (¢serine) is th© prolotypc of a new class of nie~tinlc ucetylcholinc receptor (nAChR) activating liga,ds: it induces cation fluxes into nAChR.rich membrane vesicl~s from 7~r#eda marmoeata cle~:tric tissue even under condl. lions of antalionist blocked :tcctylcholin~ binding sil~s (Okonjo, Kuhlm~mn. Maelicke. Neuron, in press). This su~tlest's that escrine exerts it~ than. nel.activating proi'~rty via binding sites at the nAChR separate from those of tile natural transmitter. We now report thllt eserine e'-m activate the channel wen when the receptor has t~en preincub~ttcd (des©nsitiz©d) with elevated concentrations of acetylcholi~e, Titus the confornudional state Of the receptor corresponding to de~nsitixation is confined to the transmitter bindinB rclli0n, leaving the ch=tr'4nel fully activatable ,- albeit only from other than the tr~msmitter bindin~ site(s)

Analysis of contemporary HIV/AIDS health care costs in Germany: Driving factors and distribution across antiretroviral therapy lines

To analyze contemporary costs of HIV health care and the cost distribution across lines of combination antiretroviral therapy (cART). To identify variations in expenditures with patient characteristics and to identify main cost determinants. To compute cost ratios between patients with varying characteristics.Empirical data on costs are collected in Germany within a 2-year prospective observational noninterventional multicenter study. The database contains information for 1154 HIV-infected patients from 8 medical centers.Means and standard deviations of the total costs are estimated for each cost fraction and across cART lines and regimens. The costs are regressed against various patient characteristics using a generalized linear model. Relative costs are calculated using the resultant coefficients.The average annual total costs (SD) per patient are &OV0556;22,231.03 (8786.13) with a maximum of &OV0556;83,970. cART medication is the major cost fraction (83.8%) with a mean of &OV0556;18,688.62 (5289.48). The major cost-driving factors are cART regimen, CD4-T cell count, cART drug resistance, and concomitant diseases. Viral load, pathology tests, and demographics have no significant impact. Standard non-nucleoside reverse transcriptase inhibitor-based regimens induce 28% lower total costs compared with standard PI/r regimens. Resistance to 3 or more antiretroviral classes induces a significant increase in costs.HIV treatment in Germany continues to be expensive. Majority of costs are attributable to cART. Main cost determinants are CD4-T cells count, comorbidity, genotypic antiviral resistance, and therapy regimen. Combinations of characteristics associated with higher expenditures enhance the increasing effect on the costs and induce high cost cases.Janssen-Cilag Foundatio