Differential role of nitric oxide in the psychedelic symptoms induced by racemic ketamine and esketamine in human volunteers.

BACKGROUND: Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(+)- and R(-)-ketamine isomers, or esketamine, containing just the S(+)-isomer. METHODS: In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 µg kg-1 min-1 or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point. RESULTS: Sodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P=0.02], internal perception AUC [placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01] and external perception AUC [placebo 4110 (2840) vs nitroprusside 2890 (2120), P=0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion. CONCLUSIONS: These data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(-)- but not S(+)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms. CLINICAL TRIAL REGISTRATION: NTR 5359.

Esketamine counters opioid-induced respiratory depression.

BACKGROUND: Opioids can produce life-threatening respiratory depression. This study tested whether subanaesthetic doses of esketamine stimulate breathing in an established human model of opioid-induced respiratory depression. METHODS: In a study with a randomised, double blind, placebo controlled, crossover design, 12 healthy, young volunteers of either sex received a dose escalating infusion of esketamine (cumulative dose 40 mg infused in 1 h) on top of remifentanil-induced respiratory depression. A population pharmacokinetic-pharmacodynamic analysis was performed with sites of drug action at baseline ventilation, ventilatory CO2-chemosensitivity, or both. RESULTS: Remifentanil reduced isohypercapnic ventilation (end-tidal PCO2 6.5 kPa) by approximately 40% (from 20 to 12 litre min-1) in esketamine and placebo arms of the study, through an effect on baseline ventilation and ventilatory CO2 sensitivity. The reduction in ventilation was related to a remifentanil effect on ventilatory CO2 sensitivity (~39%) and on baseline ventilation (~61%). Esketamine increased breathing through an exclusive stimulatory effect on ventilatory CO2 sensitivity. The remifentanil concentration that reduced ventilatory CO2 sensitivity by 50% (C50) was doubled at an esketamine concentration of 127 (84-191) ng ml-1 [median (interquartile range)]; the esketamine effect was rapid and driven by plasma pharmacokinetics. Placebo had no systematic effect on opioid-induced respiratory depression. CONCLUSIONS: Esketamine effectively countered remifentanil-induced respiratory depression, an effect that was attributed to an increase in remifentanil-reduced ventilatory CO2 chemosensitivity.

An experimental study comparing the respiratory effects of tapentadol and oxycodone in healthy volunteers.

Background: There is a clinical need for potent opioids that produce little or no respiratory depression. In the current study we compared the respiratory effects of tapentadol, a mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and oxycodone, a selective mu-opioid receptor agonist. We hypothesize that tapentadol 100 mg has a lesser effect on the control of breathing than oxycodone 20 mg. Methods: Fifteen healthy volunteers were randomized to receive oral tapentadol (100 and 150 mg), oxycodone 20 mg or placebo immediate release tablets in a crossover double-blind randomized design. The main end-point of the study was the effect of treatment on the ventilatory response to hypercapnia and ventilation at an extrapolated end-tidal PCO2 of 7.3 kPa (55 mmHg, VE55); VE55 was assessed prior and for 6-h following drug intake. Results: All three treatments had typical opioid effects on the hypercapnic ventilatory response: a shift to the right coupled to a decrease of the response slope. Oxycodone 20 mg had a significantly larger respiratory depressant effect than tapentadol 100 mg (mean difference -5.0 L min-1, 95% confidence interval: -7.1 to -2.9 L min-1, P<0.01), but not larger than tapentadol 150 mg (oxycodone vs. tapentadol 150 mg: P>0.05). Conclusions: In this exploratory study we observed that both tapentadol and oxycodone produce respiratory depression. Tapentadol 100 mg but not 150 mg had a modest respiratory advantage over oxycodone 20 mg. Further studies are needed to explore how these results translate to the clinical setting.

Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients.

PURPOSE: The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure. METHODS: Stable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients. RESULTS: Pharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration. CONCLUSIONS: Both donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.

Effect of subanaesthetic ketamine on plasma and saliva cortisol secretion.

BACKGROUND: The commonality between chronic conditions that are treated with low-dose ketamine, such as specific chronic pain conditions, depression, and post-traumatic stress disorder, can be found in relation to the stress system, particularly the hypothalamus-pituitary-adrenal axis. In this study we assess the effect of ketamine on the stress system by measuring plasma and saliva cortisol production during and following exposure to low-dose ketamine. METHODS: In a double-blind, randomized, placebo-controlled study, the influence of subanaesthetic ketamine (0.29 mg kg(-1) h(-1) for 1 h, followed by 0.57 mg kg(-1) h(-1) for another hour) was studied with repeated plasma and saliva cortisol samples in 12 healthy male volunteers. A pharmacokinetic-pharmacodynamic model was used to describe the circadian rhythm-dependent ketamine-induced production of cortisol. RESULTS: The endogenous mean baseline cortisol production was 7.9 (SE 1.5) nM min(-1). Consistent with the circadian rhythm, cortisol production decayed by 1.25 nM min(-1) h(-1). Ketamine doubled the cortisol production at a concentration of 165 (SE 35) ng ml(-1). The salivary cortisol concentration closely mirrored the plasma concentration and was exponentially related to the plasma concentration with, at 100 ng ml(-1) ketamine, a saliva:plasma ratio of 0.036 (se 0.006). CONCLUSIONS: Ketamine has an appreciable effect on cortisol production. This may impact on critical physiological and psychological functions. CLINICAL TRIAL REGISTRATION: This study was registered in the Dutch Trial Register under number NTR2717 at www.trialregister.nl.

Validation of a novel respiratory rate monitor based on exhaled humidity.

BACKGROUND: Postoperative monitoring of ventilation is largely restricted to the measurement of haemoglobin-oxygen saturation and respiratory rate (RR) derived from the ECG. measurement is inadequate when used with supplemental oxygen and ECG-derived RR is subject to artifacts. A new monitor measures RR by quantifying the humidity of exhaled air (respiR8(®)). METHODS: The accuracy of the system was tested using a breathing simulator. In healthy volunteers, the respiR8(®) monitor was compared with two other methods of measuring RR: capnometry and counting of thoracic breathing movements. The ability of the monitor to track changes in RR resulting from the infusion of 2.5 µg kg(-1) fentanyl was assessed and compared with RR measured from a validated flow measurement system. The RR in 50 postoperative patients measured with the respiR8(®) was compared with that derived from the ECG. RR values were compared by population-based Bland-Altman analyses. RESULTS: The respiR8(®) monitor was accurate in the range required in clinical practice. There was a close agreement between RR from respiR8(®), capnometry, and manual counting of respiratory movements without bias (limits of agreement ±1 bpm). The respiR8(®) monitor was well able to accurately track RR changes from fentanyl. In postoperative patients, RR from respiR8(®) and ECG had a bias of 1.7 (5.7) bpm due to greater RR values observed from the ECG due to artifacts. CONCLUSIONS: The respiR8(®) gives an accurate measurement of RR and is useful in postoperative care.

Comparison of neuromuscular block measured by compressomyography at the upper arm and electromyography at the adductor pollicis muscle in obese and non-obese patients: An observational study.

STUDY OBJECTIVE: Quantitative neuromuscular monitoring is traditionally evaluated at the adductor pollicis muscle. By contrast, the TOF-Cuff compressomyograph evaluates neuromuscular block (NMB) at the upper arm. However, compressomyography has not been fully validated against other monitoring entities. This study evaluates the agreement between NMB measured by compressomyography at the upper arm and electromyography at the adductor pollicis muscle during various levels of neuromuscular block in patients with and without obesity. INTERVENTIONS: NMB was measured at the upper arm by compressomyography (TOF-Cuff) and by electromyography (GE-NMT) at the adductor pollicis. DESIGN: Prospective, multicenter, observational study. SETTING: Secondary and tertiary care hospitals' operating theatres. PATIENTS: 200 non-obese and 50 obese patients. MEASUREMENTS: During onset and offset of deep (post-tetanic-count 1-15 twitches), moderate (Train-of-Four-count 1-3 twitches) and shallow (Train-of-Four-ratio 0.01-1.0) depths of NMB were measured in obese and non-obese patients. The bias and limits of agreement of both devices were calculated using a Bland-Altman analysis for repeated measurements. Data obtained during spontaneous recovery (i.e. without the use of reversal agents) were used in the primary analyses. MAIN RESULTS: Data from enrolled patients yielded 942 paired post-tetanic-counts, 1175 paired train-of-four-counts and 1574 paired train-of-four ratios during spontaneous recovery. In non-obese patients, mean bias (95% CI) between the two devices was 3.405 (2.294 to 4.517) during deep NMB; -0.023 (-0.205 to 0.160) during moderate NMB and 0.312 (0.287 to 0.338) during shallow NMB. In obese patients, bias was -0.170 (-2.872 to 2.531); 0.178 (-0.202 to 0.558); 0.384 (0.299 to 0.469) for deep, moderate and shallow NMB respectively. CONCLUSIONS: There is variable disagreement between the level of NMB measured at the upper arm by compressomyography and at the adductor pollicis muscle measured by electromyography, throughout the various stages of NMB in obese and non-obese patients. Recovery of NMB on compressomyography preceded recovery on electromyography, which may have consequences for reversal and extubation decisions in clinical practice.

Permutation entropy of the electroencephalogram: a measure of anaesthetic drug effect.

BACKGROUND: It would be useful to have an open-source electroencephalographic (EEG) index of gamma-amino-butyric acid (GABA)-ergic anaesthetic drug effect that is resistant to eye-blink artifact, responds rapidly to changes in EEG pattern, and can be linked to underlying neurophysiological and neuropharmacological mechanisms that control the conscious state. METHODS: The EEG waveform can be described as a sequence of ordinal patterns. The permutation entropy (PE) describes the relative occurrence of each of these patterns. It is high ( approximately 1.0) when the signal has predominantly high frequencies and low ( approximately 0.4) when the signal consists of only low frequencies. The response of the PE to various computer-generated EEG-like waveforms was assessed. A composite PE index (CPEI) was developed, which was the sum of two simple PEs and included a small measurement-noise threshold (0.5 microV). We also applied the CPEI to two small pilot EEG data sets from patients receiving sevoflurane (n=21) or propofol (n=9) anaesthesia. RESULTS: With minimal pre-processing or artifact rejection, the CPEI reliably tracked the anaesthetic-related EEG changes, namely loss of high frequencies, spindle-like waves, and delta waves. Using NONMEM, it was possible to construct adequate pharmacokinetic-pharmacodynamic models from the data. The CPEI was comparable with models derived using the bispectral index [BIS R(2)=0.88 (0.08) vs CPEI R(2)=0.91 (0.06) for the propofol data] and M-entropy indices [M-entropy R(2)=0.91 (0.06) vs CPEI R(2)=0.87 (0.09) for the sevoflurane data]. CONCLUSIONS: PE of the EEG shows promise as a simple measure of GABAergic anaesthetic drug effect.

Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers.

The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of buprenorphine and fentanyl for the respiratory depressant effect in healthy volunteers. Data on the time course of the ventilatory response at a fixed P(ET)CO(2) of 50 mm Hg and P(ET)O(2) of 110 mm Hg following intravenous administration of buprenorphine and fentanyl were obtained from two phase I studies (50 volunteers received buprenorphine: 0.05-0.6 mg/70 kg and 24 volunteers received fentanyl: 0.075-0.5 mg/70 kg). The PK/PD correlations were analyzed using nonlinear mixed effects modeling. A two- and three-compartment pharmacokinetic model characterized the time course of fentanyl and buprenorphine concentration, respectively. Three structurally different PK/PD models were evaluated for their appropriateness to describe the time course of respiratory depression: (1) a biophase distribution model with a fractional sigmoid E(max) pharmacodynamic model, (2) a receptor association/dissociation model with a linear transduction function, and (3) a combined biophase distribution-receptor association/dissociation model with a linear transduction function. The results show that for fentanyl hysteresis is entirely determined by the biophase distribution kinetics, whereas for buprenorphine hysteresis is caused by a combination of biophase distribution kinetics and receptor association/dissociation kinetics. The half-time values of biophase equilibration (t(1/2, k(eo))) were 16.4 and 75.3 min for fentanyl and buprenorphine, respectively. In addition, for buprenorphine, the value of k(on) was 0.246 ml/ng/min and the value of k(off) was 0.0102 min(-1). The concentration-effect relationship of buprenorphine was characterized by a ceiling effect at higher concentrations (intrinsic activity alpha=0.56, 95% confidence interval (CI): 0.50-0.62), whereas fentanyl displayed full respiratory depressant effect (alpha=0.91, 95% CI: 0.19-1.62).

Doxapram-mediated Increase in Cardiac Output Reduces Opioid Plasma Concentrations: A Pharmacokinetic/Pharmacodynamic-Pharmacokinetic/Pharmacodynamic Modeling Study in Healthy Volunteers.

Doxapram is an analeptic that induces ventilatory stimulation and increases blood pressure and cardiac output (CO). Its mechanism of action is the blockade of background K+ -channels expressed on type 1 carotid body cells. In the randomized controlled trial, the authors explored the role of the increase in CO by doxapram (plasma concentration (Cp) 1,000-3,500 ng/mL) on the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the potent opioid alfentanil (Cp 100-200 ng/mL). Population PK-PD analyses were performed on the doxapram PK-CO data and the alfentanil PK-antinociception data. The analyses showed that the doxapram-induced increase in CO explained the increase in alfentanil distribution and elimination clearances causing a significant reduction in plasma alfentanil Cp and antinociception. This novel approach in which one PK-PD model effectively drives another PK-PD model highlights the importance of physiological influences on PK and PD of a potent opioid with rapid onset of effect and low clinical margin of safety.

Searching for biological rhythms: peak detection in the periodogram of unequally spaced data.

The classical power spectrum, computed in the frequency domain, outranks traditionally used periodograms derived in the time domain (such as the chi2 periodogram) regarding the search for biological rhythms. Unfortunately, classical power spectral analysis is not possible with unequally spaced data (e.g., time series with missing data). The Lomb-Scargle periodogram fixes this shortcoming. However, peak detection in the Lomb-Scargle periodogram of unequally spaced data requires some careful consideration. To guide researchers in the proper evaluation of detected peaks, therefore, a novel procedure and a computer program have recently become available. It is recommended that the Lomb-Scargle periodogram be the default method of periodogram analysis in future biomedical applications of rhythm investigation.

A randomized controlled trial and novel mathematical analysis of the analgesic effect of oxycodone versus paracetamol orodispersible tablets.

BACKGROUND: For effective treatment of acute pain, a rapid onset of action is important. Here we quantify the antinociceptive profile of an orodispersible oxycodone tablet (OOT) in a randomized, double-blind, active comparator (paracetamol orodispersible tablet, POT), crossover study design in a population of healthy volunteers. METHODS: Twelve female volunteers were randomized to receive 20 mg OOT and 500 mg POT sublingually on two occasions. The electrical pain threshold (EPTh), electrical pain tolerance (EPTol) and pressure pain threshold (PPT) were obtained at regular intervals for 5 h. Time-response data were analysed with a longitudinal pharmacodynamic model characterized by rate constants for analgesia onset (kON ), offset (kOFF ), potency parameter (EFF) and validated with a bootstrap analysis. Values are the median (95% CI) as derived from the bootstrap analysis. RESULTS: OOT produced a rapid increase in response values. For electrical pain analgesia onset, t½kON , 44 (25-67) versus analgesia offset, t½kOFF , 156 (63-552) min, p < 0.01. For pressure pain, t½kON equalled t½kOFF : 30 (16-48) min. OOT was most potent on EPTol: EFF 0.95 (0.39-1.71), p < 0.01, with similar potencies on EPTh, 0.43 (0.19-0.87) and PPT, 0.40 (0.21-0.67). Paracetamol displayed 14% of the analgesic efficacy of oxycodone. CONCLUSIONS: The analgesic effect of orodispersible oxycodone was successfully quantified using a mathematical model of analgesia evolution. This method allows quantification of a variety of responses times from sparse data sets. Response times as defined by a 30% increase in response thresholds varied significantly among end points: EPTol 15 min, PPTh 18 min and EPTh 41 min.

Reversal of opioid-induced respiratory depression by BK-channel blocker GAL021: A pharmacokinetic-pharmacodynamic modeling study in healthy volunteers.

Opioid-induced respiratory depression (OIRD) is a serious and potentially life-threatening complication of opioid overdose, abuse, and misuse. An option to avert OIRD is to treat patients on strong opioids with respiratory stimulants that do not interact with the opioid system and consequently do not compromise opioid analgesic efficacy. The BK-channel blocker GAL021 is a respiratory stimulant acting at K(+) -channels expressed on type 1 carotid body cells. The authors performed a population pharmacokinetic-pharmacodynamic (PKPD) analysis on the ability of GAL021 to reverse alfentanil-induced respiratory depression in 12 male volunteers using an isohypercapnic experimental design. The analysis showed that (1) GAL021 interacts in a multiplicative fashion with alfentanil and GAL021, which predicts that GAL021 efficacy is reduced at low ventilation levels; (2) GAL021 has a rapid onset/offset with a blood-effect site equilibration half-life not different from zero; and (3) GAL021 displays ceiling in its efficacy to reverse OIRD.

A procedure of multiple period searching in unequally spaced time-series with the Lomb-Scargle method.

Periodogram analysis of unequally spaced time-series, as part of many biological rhythm investigations, is complicated. The mathematical framework is scattered over the literature, and the interpretation of results is often debatable. In this paper, we show that the Lomb-Scargle method is the appropriate tool for periodogram analysis of unequally spaced data. A unique procedure of multiple period searching is derived, facilitating the assessment of the various rhythms that may be present in a time-series. All relevant mathematical and statistical aspects are considered in detail, and much attention is given to the correct interpretation of results. The use of the procedure is illustrated by examples, and problems that may be encountered are discussed. It is argued that, when following the procedure of multiple period searching, we can even benefit from the unequal spacing of a time-series in biological rhythm research.

A novel approach to identify responder subgroups and predictors of response to low- and high-dose capsaicin patches in postherpetic neuralgia.

BACKGROUND: Treatment of chronic pain conditions is commonly assessed at specific endpoints at preset times during or after treatment by analysis of the total study population. An alternative approach is the identification of specific patient subgroups characterized by differential response patterns in their analgesic response and to determine the presence of significant predictors of effect. METHODS: Data from four double-blind, randomized controlled trials on the efficacy of topical capsaicin 8% (Qutenza) versus an active control (capsaicin 0.04%) in patients with postherpetic neuropathic pain were combined. Longitudinal pharmacodynamic, mixture and covariate analyses were performed on the pooled dataset. RESULTS: Data from 1248 patients treated with Qutenza (n = 722) or topical low-dose capsaicin 0.04% (n = 526) were successfully analysed. Five distinct response subgroups were detected with different treatment efficacies, including a group of non-responders, a group showing partial analgesic effect and a group showing full analgesic effect. Active control and Qutenza had similar response profiles, but the proportional distribution of patients among the five response groups was in favour of Qutenza, with 40% less non-responders and 25% more patients showing a full analgesic response. For Qutenza, important predictors of efficacy were efficacy of lidocaine pretreatment and greater pretreatment pain score variability. CONCLUSIONS: The analyses indicate the existence of different response groups to treatment with Qutenza and an active control patch that may possibly be related to different pain mechanisms among these groups, despite a presumed common underlying disease process, and that require different treatment approaches among subgroups.