Generic Substitution Issues: Brand-generic Substitution, Generic-generic Substitution, and Generic Substitution of Narrow Therapeutic Index (NTI)/Critical Dose Drugs.

Doctors accuse individual variability or lack of quality of generic drugs for adverse reactions or lack of efficacy. The variability of effect of generic substitution, although accepted by clinicians as possible, is little discussed or even understood by them. The situation is really serious in the case of generic substitution of drugs with narrow therapeutic index (NTI) or critical dose.

Analysis of the kinetics of CO binding to neuronal nitric oxide synthase by flash photolysis: dual effects of substrates, inhibitors, and tetrahydrobiopterin.

The effects of substrates, inhibitors and tetrahydrobiopterin (H4B) on CO rebinding to the isolated heme-bound oxygenase domain (nNOSox) of neuronal nitric oxide synthase were examined by laser flash photolysis. The rate constant of CO recombination with substrate and inhibitor-free nNOSox in the absence of H4B was 1.0 x 10(6) M(-1) s(-1).

CO binding to the isolated oxygenase domain of neuronal nitric oxide synthase: effects of inhibitors and mutations at the substrate-binding site.

In order to understand the heme distal structure of neuronal nitric oxide synthase (nNOS), we studied the binding affinity of CO for the ferrous wild type enzyme and the Glu592Ala and Tyr588His substrate binding-site mutants (generated in the oxygenase domain, nNOSox) in the presence of substrates and inhibitors. The CO binding affinities (K(d) = 10-21 mM) of nNOSox in the presence of the substrates, L-Arg and NHA, or inhibitors such as NAME and agmatine were more than two-fold lower than in their absence (K(d) = 5 mM). The presence of NIL strongly inhibited CO binding and gave a K(d) of more than 100 mM.