Drugs with poor oral bioavailability usually are administered by hypodermic injection, which causes pain, poor patient compliance, the need for trained personnel, and risk of infectious disease transmission. Transdermal (TD) delivery provides an excellent alternative, but the barrier of skin's outer stratum corneum (SC) prevents delivery of most drugs. Micrometer-scale microneedles (MNs) have been used to pierce animal and human cadaver skin and thereby enable TD delivery of small molecules, proteins, DNA, and vaccines for systemic action. Here, we present a clinical study of MN-enhanced delivery of a medication to humans. Naltrexone (NTX) is a potent mu-opioid receptor antagonist used to treat opiate and alcohol dependence. This hydrophilic and skin-impermeant molecule was delivered from a TD patch to healthy human subjects with and without pretreatment of the skin with MNs. Whereas delivery from a standard NTX TD patch over a 72-h period yielded undetectable drug plasma levels, pretreatment of skin with MNs achieved steady-state plasma concentrations within 2 h of patch application and were maintained for at least 48 h. The MNs and NTX patch were well tolerated with mild systemic and application site side effects. The MN arrays were painless upon administration and not damaged during skin insertion, and no MNs were broken off into the skin. This human proof-of-concept study demonstrates systemic administration of a hydrophilic medication by MN-enhanced TD delivery. These findings set the stage for future human studies of skin-impermeant medications and biopharmaceuticals for clinical applications.naltrexone ͉ stratum corneum ͉ drug delivery ͉ microfabrication
The results of recent research indicate that agonist replacement may be a viable option in the treatment of cocaine dependence. For example, d-amphetamine and modafinil have shown promise in managing cocaine dependence in preliminary clinical trials. The aim of this study was to determine the physiological and subject-rated effects of acute intranasal cocaine doses during chronic atomoxetine treatment. Atomoxetine was chosen because it produces pharmacological and subjectrated effects similar to those of prototypical stimulants and thus may also be a viable agonist replacement therapy. To this end, seven cocaine dependent subjects were maintained on doses of atomoxetine (0 [lead in], 5, 10, 20 and 0 [washout] mg, four times daily) for 3-5 days prior to completing experimental sessions in which ascending doses of intranasal cocaine (4, 20, 40 and 60 mg) were administered. Cocaine produced prototypical cardiovascular and subject-rated effects. Atomoxetine attenuated the systolic pressure increasing effects and enhanced the heart rate increasing effects of cocaine, but was otherwise devoid of effects. These results indicate that cocaine is well tolerated during atomoxetine maintenance. Further research is needed to better determine the effects of atomoxetine and cocaine combinations.
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