Interaction In Healthy Subjects Research Articles

Induction of dynamic hyperinflation by expiratory resistance breathing in healthy subjects - an efficacy and safety study.

New Findings What is the central question of this study? The study aimed to establish a novel model to study the chronic obstructive pulmonary disease (COPD)‐related cardiopulmonary effects of dynamic hyperinflation in healthy subjects. What is the main finding and its importance? A model of expiratory resistance breathing (ERB) was established in which dynamic hyperinflation was induced in healthy subjects, expressed both by lung volumes and intrathoracic pressures. ERB outperformed existing methods and represents an efficacious model to study cardiopulmonary mechanics of dynamic hyperinflation without potentially confounding factors as present in COPD. Dynamic hyperinflation (DH) determines symptoms and prognosis of chronic obstructive pulmonary disease (COPD). The induction of DH is used to study cardiopulmonary mechanics in healthy subjects without COPD‐related confounders like inflammation, hypoxic vasoconstriction and rarefication of pulmonary vasculature. Metronome‐paced tachypnoea (MPT) has proven effective in inducing DH in healthy subjects, but does not account for airflow limitation. We aimed to establish a novel model incorporating airflow limitation by combining tachypnoea with an expiratory airway stenosis. We investigated this expiratory resistance breathing (ERB) model in 14 healthy subjects using different stenosis diameters to assess a dose–response relationship. Via cross‐over design, we compared ERB to MPT in a random sequence. DH was quantified by inspiratory capacity (IC, litres) and intrinsic positive end‐expiratory pressure (PEEPi, cmH2O). ERB induced a stepwise decreasing IC (means (95% CI): tidal breathing: 3.66 (3.45–3.88), ERB 3 mm: 3.33 (1.75–4.91), 2 mm: 2.05 (0.76–3.34), 1.5 mm: 0.73 (0.12–1.58) litres) and increasing PEEPi (tidal breathing: 0.70 (0.50–0.80), ERB 3 mm: 11.1 (7.0–15.2), 2 mm: 22.3 (17.1–27.6), 1.5 mm: 33.4 (3.40–63) cmH2O). All three MPT patterns increased PEEPi, but to a far lesser extent than ERB. No adverse events during ERB were noted. In conclusion, ERB was proven to be a safe and efficacious model for the induction of DH and might be used for the investigation of cardiopulmonary interaction in healthy subjects.

The Combined Effects of Cr(III) Supplementation and Iron Deficiency on the Copper and Zinc Status in Wistar Rats

The aim of the study was to assess the combined effects of chromium(III) supplementation and iron deficiency on the copper (Cu) and zinc (Zn) status in female rats. The Cr, Fe, Cu and Zn dietary and tissular levels were measured by Atomic Absorption Spectrometry (AAS) method. The data show that chromium(III) supplementation compensated for the negative effects of Fe deficiency on the Cu content but it deepened the effect on Zn levels in the female rats. Detailed data on the status of trace elements and their interactions in healthy subjects and patients with metabolic disorders (e.g. anaemia, diabetes mellitus) are strongly required for effective nutritional and therapeutic strategies.

Information-Theoretic Framework for Measuring Brain--Heart Causal Interactions in Healthy Subjects and Patients with Sleep Disorders

Information-Theoretic Framework for Measuring Brain--Heart Causal Interactions in Healthy Subjects and Patients with Sleep Disorders

Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects

Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means and 90% confidence intervals. Coadministration of delamanid with tenofovir or efavirenz did not affect the PK characteristics of delamanid. Coadministration of Kaletra (lopinavir/ritonavir) with delamanid resulted in an approximately 25% higher delamanid area under the concentration-time curve from time 0 to the end of the dosing interval (AUCτ). Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by delamanid. Coadministration of delamanid with the TB drugs (ethambutol plus Rifater [rifampin, pyrazinamide, and isoniazid]) resulted in lower delamanid exposures (47 and 42% for the AUCτ and Cmax [maximum concentration of a drug in plasma] values, respectively), as well as decreased exposure of three primary metabolites (approximately 30 to 50% lower AUCτ values). Delamanid did not affect rifampin, pyrazinamide, and isoniazid exposure; the ethambutol AUCτ and Cmax values were about 25% higher with delamanid coadministration. The lack of clinically significant drug-drug interactions between delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. Although there was a decrease in the delamanid concentrations when coadministered with ethambutol plus Rifater, this is likely related to decreased delamanid absorption and not to CYP induction.

Evaluation of a Pharmacokinetic Interaction between Telmisartan and Chlorthalidone in Healthy Male Adult Subjects.

Combination therapy is recommended for the effective management of hypertension according to most treatment guidelines, including those of the US Joint National Committee. Therefore, pharmacokinetic drug interactions are an important issue in combination therapy for hypertension. In this study, the pharmacokinetic properties of telmisartan and chlorthalidone were evaluated to investigate their pharmacokinetic interactions in healthy subjects. Two separate, randomized, multiple-dose, two-period, one-sequence studies were conducted. In study A, 43 participants received 80mg of telmisartan orally for 7days, and were then administered oral chlorthalidone 25mg for 14days (days 8-21), coadministered with 80mg of telmisartan from day 15. In study B, 14 participants received oral chlorthalidone (25mg) for 13days, followed by coadministration with 80mg of telmisartan orally for 7days. The geometric mean ratios (GMRs) (90% confidence intervals [CIs]) of the maximum plasma concentration (C max,ss) and area under the concentration-time curve for the dosing interval at steady state (AUCτ,ss) of telmisartan (with and without chlorthalidone) were 1.018 (0.861-1.203) and 1.099 (1.015-1.190), respectively. For chlorthalidone (with/without telmisartan), the GMRs (90% CIs) for C max,ss and AUCτ,ss were 0.996 (0.922-1.075) and 0.992 (0.925-1.064), respectively. The GMRs and 90% CIs for telmisartan and chlorthalidone were all within the 0.80-1.25 range. Thus, in this study, there was no significant pharmacokinetic interaction between telmisartan and chlorthalidone. CLINICALTRIAL. NCT01806363.

P0910 : No evidence of pharmacokinetic drug–drug interaction in healthy subjects between coadministered grazoprevir (MK-5172)/elbasvir (MK-8742) and sofosbuvir

P0910 : No evidence of pharmacokinetic drug–drug interaction in healthy subjects between coadministered grazoprevir (MK-5172)/elbasvir (MK-8742) and sofosbuvir

Brivaracetam and carbamazepine interaction in healthy subjects and in vitro

This phase I, open-label study investigated the effects of steady-state brivaracetam administration on steady-state pharmacokinetics of carbamazepine, and steady-state carbamazepine administration on single-dose and steady-state pharmacokinetics of brivaracetam, in 14 healthy participants who received brivaracetam 200mg single doses on days 1 and 22, and 200mg twice daily (bid) on days 24–35; and were titrated to carbamazepine 300mg bid on days 4–35. Brivaracetam did not significantly alter carbamazepine area under the plasma concentration–time curve (AUC) over a dosing interval, but resulted in a 2.6-fold increase in carbamazepine-epoxide. Carbamazepine decreased brivaracetam AUC by 29%, while hydroxy-brivaracetam metabolite was increased by 17%. Urinary 6β-hydroxycortisol/cortisol ratio was unchanged by brivaracetam, but was increased 3-fold by carbamazepine. In vitro hydrolysis of carbamazepine-epoxide in human hepatocytes was inhibited by brivaracetam, with an IC50 of 8.2μM. Brivaracetam 200mg bid was predicted to increase carbamazepine-epoxide by 2.3-fold, in close agreement with the observed value. In conclusion, brivaracetam did not modify carbamazepine exposure but increased carbamazepine-epoxide. Carbamazepine modestly decreased brivaracetam exposure and increased oxidative metabolism.

Hippocampus-autonomic interactions in healthy subjects and in depressed patients

Hippocampus-autonomic interactions in healthy subjects and in depressed patients

The study on the frontoparietal networks by continuous theta burst stimulation in healthy human subjects

Frontoparietal networks (FPNs) including the regions of the posterior parietal cortex (PPC) and dorsolateral prefrontal cortex (DLPFC) have been implicated in visuospatial attention. However, the functional interactions among different regions of dorsal FPNs remain elusive. The Attention Network Test (ANT) and continuous theta burst stimulation (cTBS) were used to investigate the functional interactions in healthy subjects. During the ANT task, subjects receiving right PPC cTBS responded significantly slower in spatial cue condition, had deficits in both alerting and orienting indices compared with those receiving either the sham cTBS or left PPC cTBS. In addition, subjects receiving left-DLPFC cTBS showed significant improvements on alerting and conflict indices whereas significant deficits on the orienting index compared with those receiving the sham cTBS. Moreover, compared with subjects exposed to the sham cTBS condition, subjects exposed to cTBS to the right-DLPFC exhibited significant decreases in the efficiency of the alerting and conflict indices whereas significant increases in the orienting index. Furthermore, there were significant differences in the alerting, orienting and conflict effect indices between subjects receiving the left-DLPFC-cTBS and those receiving the right-DLPFC-cTBS. These results suggest that the right DLPFC played a pivotal role in executive control process, whereas the right PPC was associated with orienting attentional function. The current study not only supports the model of inter-hemispheric rivalry for visuospatial attention, but also indicates inter-regional competition between the different areas of the FPNs.

Corticomotor control of deep abdominal muscles in chronic low back pain and anticipatory postural adjustments

Contralateral transversus abdominis muscle (cTrA) is known to be anticipatory to rapid focal movement. The activation of ipsilateral TrA (iTrA) follows cTrA, but their anticipatory interaction in healthy subjects seems to be delayed in low back pain (LBP) patients. TrA delay in LBP is linked with reorganization of the primary motor cortex (M1), thus supporting that cortical changes underlie the altered postural control. Our study tested whether differences in postural adjustments were present in LBP for TrA onsets and co-activation, and whether these differences were paralleled by cortical motor changes. Thirteen chronic LBP patients and 9 healthy Controls were enrolled. Surface recordings of cTrA/internal oblique (IO) and iTrA/IO were collected during a rapid shoulder flexion task while standing. Transcranial magnetic stimulation of M1 tested TrA/IO corticospinal excitability, active motor threshold and short-interval intracortical inhibition (SICI). In LBP compared to Controls, iTrA/IO activation was delayed, co-activation was absent, timing between TrA/IO onsets was impaired, and SICI was missing. Between-outcomes correlations observed in one group were not significant in the other. Delay of iTrA/IO and the lacking co-activation were not explained by between-group differences of transcranial magnetic stimulation outcomes. TrA/IO co-activation is present during rapid focal movement in healthy subjects only. LBP patients displayed an important alteration of the control of spine stability that can be explained by altered mechanisms of M1 motor programming.

Age-related changes in visual-vestibular interactions in healthy subjects (an fMRI study)

Age-related changes in visual-vestibular interactions in healthy subjects (an fMRI study)

Evaluation of Herb-drug Interaction in Healthy Subjects by Comparing the Cytochrome P450 Activities before and after Multiple Administrations of Herbal Medicines

Evaluation of Herb-drug Interaction in Healthy Subjects by Comparing the Cytochrome P450 Activities before and after Multiple Administrations of Herbal Medicines

Increased International Normalized Ratio in a Patient Taking Warfarin and Celecoxib

Objective: To report a case of increased international normalized ratio (INR) associated with the addition of celecoxib therapy. Case Summary: A 77-year-old white woman who was previously stabilized at a target INR of 2–3 on warfarin 26.25 mg/wk for recurrent atrial fibrillation presented with “leg pain.” Celecoxib 100 mg twice daily orally was added to her regimen. After approximately three weeks of celecoxib therapy, her INR was elevated at 3.5, with no signs of bleeding. Her warfarin was withheld for one day and reinitiated at 23.75 mg/wk (∼10% decrease). Follow-up INRs at one and three weeks had returned to target INR range between 2 and 3. Discussion: Drug interactions are common with warfarin due to induction or inhibitions of the cytochrome P450 system and changes in protein binding. Although the celecoxib package insert states that there is not a significant interaction in healthy subjects receiving 2–5 mg/d of warfarin, the potential exists, as both are highly protein bound and metabolized through CYP2C9. Conclusions: This case report suggests that the INR may be increased after celecoxib initiation in patients undergoing anticoagulation. This may heighten the risk for clinically significant bleeding in patients previously stabilized on a warfarin regimen. Clinicians should consider more frequent INR monitoring of patients receiving warfarin after celecoxib is initiated.

Carbamazepine-nefazodone interaction in healthy subjects.

The pharmacokinetic interaction between nefazodone and carbamazepine was investigated in 12 healthy male volunteers. Subjects received nefazodone 200 mg twice daily for 5 days, and blood sample collection was performed on day 5 for 0- to 48-hour pharmacokinetic analysis. A 4-day wash-out phase then followed from days 6 to 9. Carbamazepine 200 mg was administered once daily from days 10 to 12, and then 200 mg was given twice daily from days 13 to 44. A 0- to 48-hour pharmacokinetic analysis was performed on day 38. Nefazodone 200 mg twice daily was added to the dosing regimen from days 40 to 44, and a subsequent 0- to 48-hour pharmacokinetic analysis was performed on day 44. Coadministration of nefazodone increased steady-state plasma area under the concentration-time curve (AUC) of carbamazepine from 60.77 (+/-8.44) to 74.98 (+/-12.88) microg x hr/mL (p < 0.001) and decreased the active carbamazepine-10,11-epoxide metabolite AUC concentration from 7.10 (+/-1.16) to 5.71 (+/-0.52) microg x hr/mL (p < 0.005). During the combination, the steady-state AUC of nefazodone decreased from 7,326 (+/-3,768) to 542 (+/-191) ng x hr/mL, and the AUCs of its metabolites (hydroxynefazodone, meta-chlorophenylpiperazine, and triazoledione) decreased significantly as well (p < 0.001). Coadministration of nefazodone 200 mg twice daily and carbamazepine 200 mg twice daily was found to be safe and well tolerated; however, the increased plasma exposure to carbamazepine may warrant monitoring of plasma carbamazepine concentrations with the combination. However, higher doses (>400 mg/day) of carbamazepine could yield more extensive induction, affecting tolerability of the combination. No change in the initial nefazodone dose is necessary, and subsequent dose adjustments should be made on the basis of clinical effects; however, the repercussion of carbamazepine induction of nefazodone metabolism on the antidepressant efficacy has yet to be studied.

326. - GABA-serotonin interactions in healthy subjects: Implications for psychosis

326. - GABA-serotonin interactions in healthy subjects: Implications for psychosis

Influence of Lisinopril on Urinary Electrolytes Excretion After Furosemide in Healthy Subjects

It has been reported that the urinary excretions of chloride (Cl), potassium (K), and magnesium (Mg), but not sodium (Na), after furosemide, a loop diuretic, were decreased by pretreatment with lisinopril, an ACE inhibitor in hypertensive subjects. The electrolytes disturbance induced by furosemide might be ameliorated by lisinopril. The present study re-examines this potential drug interaction in healthy subjects. Lisinopril (20 mg) or its matching placebo was given orally using a double-blind, crossover design. Four hours after lisinopril administration, furosemide (20 mg) was injected intravenously and urine was collected during the following intervals: 0-0.5, 0.5-1, 1-1.5, 1.5-2, 2-3, 3-4, and 4-6 hours. Blood samples for plasma furosemide concentration were obtained at 0.5, 1, 1.5, 2, 3, 4, and 6 hours after the agent. There were no significant differences between the two trials in plasma concentrations of furosemide or urinary excretions of the agent. Urine volume and urinary excretions of electrolytes (Na, Cl, K, and Mg) after the furosemide with lisinopril administration were not significantly different from those of placebo at any observation period. These results suggest that the urinary excretions of electrolytes after furosemide administration are not influenced by pretreatment with lisinopril.

Propranolol + propafenone: little interaction in healthy subjects

Propranolol + propafenone: little interaction in healthy subjects