Asunaprevir Tailoring pharmacological treatment to the gene
Tailoring pharmacological treatment to the genetic background of a person can enhance therapeutic response (), increase compliance (), and decrease drug toxicity (, , ). Because cocaine addiction has a strong genetic basis, with the vulnerability to develop an addiction estimated to be as high as 72% (), pharmacotherapy of this relapsing brain disease might be better-treated with a molecular genetics approach (, , , ). Applying a molecular genetics approach to disulfiram might involve its inhibitory action on the copper-containing glycoprotein enzyme dopamine β-hydroxylase (DβH), which transforms dopamine to norepinephrine (). Inhibiting DβH decreases peripheral and central norepinephrine levels and increases dopamine levels (, ).
On the basis of twin and family studies, plasma levels of DβH vary between unrelated individuals (, , ). Some of these differences are due to polymorphisms in close proximity to the gene. Indeed, studies link the C-1021T (-1021C>T) variant to differences in circulating DβH levels (, , , ). The variant C-1021T is positioned approximately 1000 nucleotides upstream from the initiation codon of the gene (). Several studies indicate that the C-1021T variant is a functional polymorphism, which alters transcription and decreases plasma levels of DβH (, , , ). This variant accounts for up to 52% of overall variation in the enzyme levels (, , , ). Individuals that are homozygous for the T allele have the lowest levels of plasma activity. Variable DβH enzyme levels or activity is linked with a number of psychiatric disorders ranging from psychotic () to conduct disorders (, , , , ). The cerebrospinal fluid level of the dopamine metabolite homovanillic Asunaprevir is an indirect measure of monoamine concentration in the brain and is correlated with the C-1021T genotype (). Several, complementary mechanisms probably contribute to the efficacy of disulfiram and interact with this polymorphism: increased cocaine aversion by causing dopamine receptor hypersensitivity, reversal of a dopaminergic deficiency and dysphoria by increasing dopamine production in noradrenergic neurons during withdrawal, and prevention of relapse by lowering norepinephrine levels and attenuating signaling via adrenergic receptors. All of these mechanisms might be enhanced by genetically determined baseline levels of the enzyme DβH and will be returned to in the Discussion. However, no simple genetic association can be ascertained a priori for enhancing the efficacy of disulfiram, and it requires direct testing in a clinical trial, as we have done.
Arguments can be made for the efficacy of disulfiram in cocaine dependence being enhanced in individuals who have the C-1021T allele that is associated with normal DβH or low levels. However, the potential importance of this functional variant in treatment outcome merits testing. Thus, we tested this hypothesis of its importance in a placebo controlled randomized clinical trial of disulfiram at 250 mg daily by comparing the efficacy of disulfiram at reducing cocaine abuse in methadone-maintained patients with the CC genotype and normal levels with those carrying the T allele and lower DβH levels.
Methods and Materials
Discussion We found a significant reduction in cocaine-positive urines with 250 mg of disulfiram compared with placebo, which is consistent with several other previous studies in cocaine abusers (17, 18, 19, 20, 21). This reduction in cocaine use was associated with a specific functional genetic polymorphism in the gene that codes for the enzyme dopamine β-hydroxylase (DβH) (rs1611115). We found that patients having two of the alleles associated with normal levels of DβH (CC) responded to disulfiram, whereas those with the genotypes encoding lower levels (CT and TT) showed no difference from placebo. Genotype made no difference in the reduction in opioid use. The different treatment response to disulfiram between those patients with low and high DβH activity might reflect differences in brain dopamine receptors. Minimal DβH activity reduces norepinephrine but also reduces basal extracellular dopamine in the nucleus accumbens and caudate-putamen (34, 60). This reduction upregulates high-affinity postsynaptic dopamine receptors as much as sixfold and produces behavioral hypersensitivity to psychostimulants (61). Psychostimulant-induced locomotor, reinforcing, and aversive effects are enhanced in DBH knockout mice (34, 62). These findings suggest that modest reductions of norepinephrine and dopamine transmission from disulfiram might not attenuate the behavioral responses to psychostimulants in those individuals who have upregulated dopamine receptors because of their genetically low DβH levels.