Browsing by Subject "Healthy Volunteers"

Now showing 1 - 3 of 3
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    Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers
    (ASPET, 2016-08) Masters, Andrea R.; Gufford, Brandon T.; Lu, Jessica Bo Li; Metzger, Ingrid F.; Jones, David R.; Desta, Zeruesenay; Medicine, School of Medicine
    Bupropion, widely used as an antidepressant and smoking cessation aid, undergoes complex metabolism to yield numerous metabolites with unique disposition, effect, and drug–drug interactions (DDIs) in humans. The stereoselective plasma and urinary pharmacokinetics of bupropion and its metabolites were evaluated to understand their potential contributions to bupropion effects. Healthy human volunteers (n = 15) were administered a single oral dose of racemic bupropion (100 mg), which was followed by collection of plasma and urine samples and determination of bupropion and metabolite concentrations using novel liquid chromatography–tandem mass spectrometry assays. Time-dependent, elimination rate–limited, stereoselective pharmacokinetics were observed for all bupropion metabolites. Area under the plasma concentration-time curve from zero to infinity ratios were on average approximately 65, 6, 6, and 4 and Cmax ratios were approximately 35, 6, 3, and 0.5 for (2R,3R)-/(2S,3S)-hydroxybupropion, R-/S-bupropion, (1S,2R)-/(1R,2S)-erythrohydrobupropion, and (1R,2R)-/(1S,2S)-threohydrobupropion, respectively. The R-/S-bupropion and (1R,2R)-/(1S,2S)-threohydrobupropion ratios are likely indicative of higher presystemic metabolism of S- versus R-bupropion by carbonyl reductases. Interestingly, the apparent renal clearance of (2S,3S)-hydroxybupropion was almost 10-fold higher than that of (2R,3R)-hydroxybupropion. The prediction of steady-state pharmacokinetics demonstrated differential stereospecific accumulation [partial area under the plasma concentration-time curve after the final simulated bupropion dose (300–312 hours) from 185 to 37,447 nM⋅h] and elimination [terminal half-life of approximately 7–46 hours] of bupropion metabolites, which may explain observed stereoselective differences in bupropion effect and DDI risk with CYP2D6 at steady state. Further elucidation of bupropion and metabolite disposition suggests that bupropion is not a reliable in vivo marker of CYP2B6 activity. In summary, to our knowledge, this is the first comprehensive report to provide novel insight into mechanisms underlying bupropion disposition by detailing the stereoselective pharmacokinetics of individual bupropion metabolites, which will enhance clinical understanding of bupropion’s effects and DDIs with CYP2D6.
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    Differential processing of nociceptive input within upper limb muscles
    (Public Library of Science, 2018-04-25) Eckert, Nathanial R.; Poston, Brach; Riley, Zachary A.; Kinesiology, School of Physical Education and Tourism Management
    The cutaneous silent period is an inhibitory evoked response that demonstrates a wide variety of responses in muscles of the human upper limb. Classically, the cutaneous silent period results in a characteristic muscle pattern of extensor inhibition and flexor facilitation within the upper limb, in the presence of nociceptive input. The aims of the current study were: 1) to primarily investigate the presence and characteristics of the cutaneous silent period response across multiple extensor and flexor muscles of the upper limb, and 2) to secondarily investigate the influence of stimulation site on this nociceptive reflex response. It was hypothesized that the cutaneous silent period would be present in all muscles, regardless of role (flexion/extension) or the stimulation site. Twenty-two healthy, university-age adults (14 males; 8 females; 23 ± 5 yrs) participated in the study. Testing consisted of three different stimulation sites (Digit II, V, and II+III nociceptive stimulation) during a low intensity, sustained muscle contraction, in which, 7 upper limb muscles were monitored via surface EMG recording electrodes. Distal muscles of the upper limb presented with the earliest reflex onset times, longest reflex duration, and lowest level of EMG suppression when compared to the more proximal muscles, regardless of extensor/flexor role. Additionally, the greatest overall inhibitory influence was expressed within the distal muscles. In conclusion, the present study provides a new level of refinement within the current understanding of the spinal organization associated with nociceptive input processing and the associated motor control of the upper limb. Subsequently, these results have further implications on the impact of nociception on supraspinal processing.
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    A (p)ppGpp-Null Mutant of Haemophilus ducreyi Is Partially Attenuated in Humans Due to Multiple Conflicting Phenotypes
    (American Society for Microbiology (ASM), 2014-08) Holley, Concerta; Gangaiah, Dharanesh; Li, Wei; Fortney, Kate R.; Janowicz, Diane M.; Ellinger, Sheila; Zwickl, Beth; Katz, Barry P.; Spinola, Stanley M.; Department of Microbiology & Immunology, IU School of Medicine
    (p)ppGpp responds to nutrient limitation through a global change in gene regulation patterns to increase survival. The stringent response has been implicated in the virulence of several pathogenic bacterial species. Haemophilus ducreyi, the causative agent of chancroid, has homologs of both relA and spoT, which primarily synthesize and hydrolyze (p)ppGpp in Escherichia coli. We constructed relA and relA spoT deletion mutants to assess the contribution of (p)ppGpp to H. ducreyi pathogenesis. Both the relA single mutant and the relA spoT double mutant failed to synthesize (p)ppGpp, suggesting that relA is the primary synthetase of (p)ppGpp in H. ducreyi. Compared to the parent strain, the double mutant was partially attenuated for pustule formation in human volunteers. The double mutant had several phenotypes that favored attenuation, including increased sensitivity to oxidative stress. The increased sensitivity to oxidative stress could be complemented in trans. However, the double mutant also exhibited phenotypes that favored virulence. When grown to the mid-log phase, the double mutant was significantly more resistant than its parent to being taken up by human macrophages and exhibited increased transcription of lspB, which is involved in resistance to phagocytosis. Additionally, compared to the parent, the double mutant also exhibited prolonged survival in the stationary phase. In E. coli, overexpression of DksA compensates for the loss of (p)ppGpp; the H. ducreyi double mutant expressed higher transcript levels of dksA than the parent strain. These data suggest that the partial attenuation of the double mutant is likely the net result of multiple conflicting phenotypes.