Co-crystal of Tramadol-Celecoxib Versus Tramadol or Placebo for Acute Moderate-to-Severe Pain After Oral Surgery: Randomized, Double-Blind, Phase 3 Trial (STARDOM1).

INTRODUCTION: Co-crystal of tramadol-celecoxib (CTC) is the first analgesic co-crystal for acute pain. This completed phase 3 multicenter, double-blind trial assessed the efficacy and safety/tolerability of CTC in comparison with that of tramadol in the setting of moderate-to-severe pain up to 72 h after elective third molar extraction requiring bone removal. METHODS: Adults (n = 726) were assigned randomly to five groups (2:2:2:2:1): orally administered twice-daily CTC 100 mg (44 mg rac-tramadol hydrochloride/56 mg celecoxib; n = 164), 150 mg (66/84 mg; n = 160) or 200 mg (88/112 mg; n = 160); tramadol 100 mg four times daily (n = 159); or placebo four times daily (n = 83). Participants in CTC groups also received twice-daily placebo. The full analysis set included all participants who underwent randomization. The primary endpoint was the sum of pain intensity differences over 0 to 4 h (SPID0-4; visual analog scale). Key secondary endpoints included 4-h 50% responder and rescue medication use rates. Safety endpoints included adverse events (AEs), laboratory measures, and Opioid-Related Symptom Distress Scale (OR-SDS) score. RESULTS: All CTC doses were superior to placebo (P < 0.001) for primary and key secondary endpoints. All were superior to tramadol for SPID0-4 (analysis of covariance least squares mean differences [95% confidence interval]: - 37.1 [- 56.5, - 17.6], - 40.2 [- 59.7, - 20.6], and - 41.7 [- 61.2, - 22.2] for 100, 150, and 200 mg CTC, respectively; P < 0.001) and 4-h 50% responder rate. Four-hour 50% responder rates were 32.9% (CTC 100 mg), 33.8% (CTC 150 mg), 40.6% (CTC 200 mg), 20.1% (tramadol), and 7.2% (placebo). Rescue medication use was lower in the 100-mg (P = 0.013) and 200-mg (P = 0.003) CTC groups versus tramadol group. AE incidence and OR-SDS scores were highest for tramadol alone. CONCLUSIONS: CTC demonstrated superior pain relief compared with tramadol or placebo, as well as an improved benefit/risk profile versus tramadol. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02982161; EudraCT number, 2016-000592-24.

Co-crystal of tramadol-celecoxib (CTC) for acute moderate-to-severe pain.

OBJECTIVE: This narrative review aims to provide a clinical perspective on the potential role of co-crystal of tramadol-celecoxib (CTC) in the management of acute moderate-to-severe pain by synthesizing the available preclinical and clinical data, with emphasis on phase 3 trials. METHODS: A non-systematic literature review was performed using a targeted PubMed search for articles published between January 1, 2000, and May 2, 2023; all publication types were permitted, and selected articles were limited to those published in English. Search results were manually reviewed to identify references based on their preclinical and clinical relevance to CTC and management of acute moderate-to-severe pain. RESULTS: The crystalline structure of CTC alters the physicochemical properties of tramadol and celecoxib, modifying their pharmacokinetics. If taken in a free combination, tramadol reduces absorption of celecoxib. Conversely, administration of CTC slows tramadol absorption and lowers its maximum plasma concentration, while increasing celecoxib plasma concentration through its enhanced release. In clinical studies across models of acute moderate-to-severe pain, CTC demonstrated an early onset of analgesia, with improved efficacy and lower rescue medication use, compared with either agent alone. CTC's safety profile was in line with that expected for the individual components; no additive effects were observed. CTC exhibited tramadol-sparing effects, with efficacy seen at lower daily/cumulative opioid doses vs. tramadol alone. CONCLUSIONS: Results from phase 3 trials suggest that the modified physicochemical properties of tramadol and celecoxib in CTC translate into an improved clinical benefit-risk profile, including fewer opioid-related adverse effects due to lower overall opioid dosing.

Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: A phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial.

BACKGROUND: Celecoxib-tramadol co-crystal (CTC) is a first-in-class analgesic co-crystal of celecoxib and racemic tramadol with an improved pharmacologic profile, conferred by the co-crystal structure, compared with its active constituents administered alone/concomitantly. AIM: We evaluated CTC in moderate-to-severe acute postoperative pain. MATERIALS AND METHODS: This randomized, double-blind, factorial, active- and placebo-controlled phase 3 trial (NCT03108482) was conducted at 6 US clinical research centers. Adults with moderate-to-severe acute pain following bunionectomy with osteotomy were randomized to oral CTC (200 mg [112 mg celecoxib/88 mg rac-tramadol hydrochloride] every 12 h), tramadol (50 mg every 6 h), celecoxib (100 mg every 12 h), or placebo for 48 h. Patients, investigators, and personnel were blinded to assignment. The primary endpoint was the 0-48 h sum of pain intensity differences (SPID0-48) in all randomized patients. Pain intensity was assessed on a 0-10 numerical rating scale (NRS). Safety was analyzed in patients who received study medication. Funded by ESTEVE Pharmaceuticals. RESULTS: In 2017 (March to November), 1323 patients were screened and 637 randomized to CTC (n = 184), tramadol (n = 183), celecoxib (n = 181), or placebo (n = 89). Mean baseline NRS was 6.7 in all active groups. CTC had a significantly greater effect on SPID0-48 (least-squares mean: -139.1 [95% confidence interval: -151.8, -126.5]) than tramadol (-109.1 [-121.7, -96.4]; p < 0.001), celecoxib (-103.7 [-116.4, -91.0]; p < 0.001), or placebo (-74.6 [-92.5, -56.6]; p < 0.001). Total treatment-emergent adverse events (TEAEs) were 358 for CTC and 394 for tramadol. Drug-related TEAEs occurred in 37.7% patients in the CTC group, compared with 48.6% in the tramadol group. There were no serious TEAEs/deaths. CONCLUSION: CTC provided greater analgesia than comparable daily doses of tramadol and celecoxib, with similar tolerability to tramadol. CTC is approved in the United States.

Efficacy and safety of co-crystal of tramadol-celecoxib (CTC) in acute moderate-to-severe pain after abdominal hysterectomy: A randomized, double-blind, phase 3 trial (STARDOM2).

BACKGROUND: STARDOM2 is a randomized, double-blind, phase 3 trial evaluating the efficacy and safety of co-crystal of tramadol-celecoxib (CTC)-a first-in-class analgesic co-crystal comprising racemic tramadol hydrochloride and celecoxib in a supramolecular network that modifies their pharmacokinetic properties-for the management of acute postoperative pain (NCT03062644; EudraCT:2016-000593-38). METHODS: Patients with moderate-to-severe pain following abdominal hysterectomy were randomized 2:2:2:2:2:1 to oral CTC 100 mg (rac-tramadol hydrochloride 44 mg/celecoxib 56 mg) twice daily (BID); CTC 150 mg (66/84 mg) BID; CTC 200 mg (88/112 mg) BID; immediate-release tramadol 100 mg four times daily (QID); celecoxib 100 mg BID; or placebo, for 5 days. The primary endpoint was the sum of pain intensity differences over 0-4 h (SPID0-4 ). Key secondary endpoints were rescue medication use within 4 h, 50% response rate at 4 h, and safety/tolerability. RESULTS: Of 1355 patients enrolled, 1138 were randomized (full analysis set) and 1136 treated (safety analysis set). In the prespecified gatekeeping analysis of SPID0-4 , CTC 200 mg was not superior to tramadol but showed non-inferior efficacy (p < 0.001) that was sustained throughout the 120-h period, despite a 5-day cumulative tramadol administration of 880 mg with CTC 200 mg BID versus 2000 mg with tramadol 100 mg QID. Treatment-emergent adverse events (TEAEs) and severe TEAEs were less common with CTC 200 mg versus tramadol. Treatment-related TEAEs were 14.4% with CTC 200 mg and 23.6% with tramadol. CONCLUSIONS: Although the study did not meet its primary endpoint, CTC 200 mg showed a clinically relevant improvement in overall benefit/risk profile versus tramadol alone, with considerably lower cumulative opioid exposure. SIGNIFICANCE: In the randomized, double-blind, phase 3 STARDOM2 trial-in acute moderate-to-severe pain after abdominal hysterectomy-the novel co-crystal of tramadol-celecoxib (CTC) 200 mg BID was superior to placebo and non-inferior to tramadol 100 mg QID. Although superiority to tramadol was not reached, CTC 200 mg BID exposed patients to lower cumulative opioid (tramadol) doses than tramadol (100 mg QID) alone, with fewer treatment-emergent adverse events. CTC 200 mg thus has a clinically relevant improved benefit/risk profile compared with tramadol alone.

Comparative Bioavailability Study of a Novel Multi-Day Patch Formulation of Rivastigmine (Twice Weekly) with Exelon® Transdermal Patch (Daily)- A Randomized Clinical Trial.

BACKGROUND: Rivastigmine, a reversible AChEI for symptomatic treatment of mild to moderately severe Alzheimer's dementia, is administered once daily transdermal patches, enabling an easier and continuous drug delivery. A novel multi-day (twice week) patch formulation was developed with greater convenience for patients' therapeutic management. OBJECTIVE: To assess the bioequivalence under SS conditions of the multiple-day rivastigmine transdermal patch (Test Product, RID-TDS) in comparison to the once-daily Exelon® transdermal patch (Reference Product), both at a release rate of 9.5 mg/24 h. DESIGN: Single-center, open-label, randomized, multiple-dose study in healthy male adults in a 2- period, 2-sequence-crossover design with multiple applications. METHODS: Patches were applied on 11 consecutive days for Exelon® and a 4-3-4-day regimen for the multiday test patch (RID-TDS), separated by a 14-day wash-out period. The safety, local tolerability and inhibitory effect of rivastigmine on plasma BuChE activity were also evaluated. RESULTS: 57 subjects completed the study according to the protocol. Calculated point estimates and 90% CI for all primary parameters (AUC96-264, Cmax96-264 and Cmin96-264) were within the predefined acceptance interval of 80.00-125.00%. They were 113.64% (107.33-120.33), 105.14% (98.38- 112.38) and 107.82% (97.78-118.89) respectively. Satisfactory adhesion (CI of mean adhesion above 90%) was demonstrated for RID-TDS but not for Exelon®. CONCLUSION: Bioequivalence was demonstrated between RID-TDS mg twice a week and Exelon® once daily in SS. Patch adhesion favored RID-TDS despite the longer dosing interval. Both products were well tolerated.

Bioavailability Study of a Transdermal Patch Formulation of Rivastigmine Compared with Exelon in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Rivastigmine is a reversible cholinesterase inhibitor indicated for the treatment of all stages of Alzheimer's disease (AD). Transdermal patch formulation allows smooth and continuous drug delivery. Its tolerability, efficacy and convenience of use increase treatment compliance. This study was designed to evaluate the bioavailability and to assess the bioequivalence of two rivastigmine transdermal patches at steady state (RIV-TDS Test Product versus Exelon Marketed Reference Product), with a release rate of 13.3 mg/24 h, after multiple patch applications. As secondary objectives, safety, patch adhesion and skin irritation were evaluated. METHODS: This was an open-label, randomized, balanced, two-period, two-sequence, cross-over study of healthy adults (n = 31). The treatment period consisted of two 5-day study periods during which consecutive daily application of the investigational patches with a release rate of 13.3 mg/24 h rivastigmine took place. Serial blood samples were collected to measure plasma concentrations. Adhesion and skin irritation assessments were performed after application of patches. RESULTS: Point estimates and 90% confidence intervals of pharmacokinetic parameters at steady state, viz. area under the plasma concentration versus time curve from dosing time to the end of the dosing interval τ (profile day) at steady state [AUC0-τ,ss] (97.4; 88.8-106.9), maximum plasma concentration within the dosing interval τ (profile day) at steady state [Cmax,ss] (99.6; 90.4-109.7) and trough plasma concentration at the end of the dosing interval τ (profile day) at steady state [Cτ,ss] (96.8; 86.2-108.9), demonstrated that both patches were bioequivalent. Evaluation of patch adhesion showed better skin adherence for RIV-TDS as well as dermal response scores (skin tolerability after removal). CONCLUSIONS: For both products, bioequivalence was shown and systemic tolerability was in accordance with the safety profile of the drug substance. The trial is registered in ClinicalTrials.gov: NCT03573050 and EudraCT: 2018-000968-28.

Celecoxib-tramadol co-crystal: A Randomized 4-Way Crossover Comparative Bioavailability Study.

PURPOSE: Celecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose pharmacokinetic (PK) parameters of CTC with those of the individual reference products from the United States, immediate-release celecoxib and tramadol, taken alone and simultaneously to determine their systemic exposure. METHODS: This was a single-center, randomized, single-dose, open-label, 4-period, 4-sequence, crossover study conducted in healthy subjects between October and December 2016. Study treatments included 200-mg CTC (equivalent to 112-mg celecoxib and 88-mg tramadol; Treatment-1); 100-mg tramadol (Treatment-2); 100-mg celecoxib (Treatment-3); and 100-mg celecoxib plus 100-mg tramadol (Treatment-4). The PK parameters of interest were Cmax, AUC0-T, and AUC0-∞, which were also calculated normalized to the dose. Tmax was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the two-sided 90% CI of the ratio of geometric mean values for the Cmax, AUC0-T, and AUC0-∞ was based on ln-transformed data, and Tmax was rank-transformed. FINDINGS: Thirty-six subjects aged 18 to 55 years (21 male subjects, 15 female subjects; mean age, 35 years) participated in the study. Celecoxib from CTC presented a lower Cmax, reduced AUCs, and a faster Tmax. The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC. For Treatment-1, -3, and -4, celecoxib PK parameters were 259, 318, and 165 ng/mL (Cmax), respectively; 1930, 2348, and 1929 ng • h/mL (AUC0-T); and 1.5, 3.0, and 2.5 hours (Tmax). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower Cmax and AUCs as well as a longer Tmax. Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for Cmax; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC0-T; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for Tmax. Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4. IMPLICATIONS: The aim of this study was to compare the PK profile of the US-marketed tramadol and celecoxib products with CTC to determine their systemic exposure and to validate the dosing regimen for a subsequent pivotal factorial Phase 3study. PK parameters of each active component in CTC were favorably modified by co-crystallization and did not result in higher systemic exposure compared with US-marketed celecoxib, tramadol, and their concomitant administration. © 2021 Elsevier HS Journals, Inc.

Co-crystal of tramadol-celecoxib: preclinical and clinical evaluation of a novel analgesic.

INTRODUCTION: Pain management is a major unmet need due to the suboptimal efficacy and undesirable side effects of current analgesics. Multimodal therapies recruiting complementary mechanisms of action may help address this. Co-crystals incorporating two active pharmaceutical ingredients (APIs) constitute an innovative approach to multimodal therapy, particularly if modification of the physicochemical properties of constituent APIs can be translated into clinical benefits. AREAS COVERED: The preclinical and clinical profiles of Co-Crystal of Tramadol-Celecoxib (CTC), a novel API-API co-crystal (1:1 molecular ratio of rac-tramadol.hydrochloride and celecoxib) are described. EXPERT OPINION: CTC may provide a relevant addition to pain therapy due to its: i) unique co-crystal structure conferring differentiated intrinsic dissolution profiles on constituent APIs, ii) modified clinical pharmacokinetics (slower absorption of tramadol and faster absorption of celecoxib) compared with commercially available single-entity reference products (in agreement with modified dissolution rates), iii) superior benefit-risk ratio compared with reference products (suggested by preclinical synergistic antinociceptive effects, without potentiation of adverse effects), and iv) efficacy in a phase 2 trial of moderate to severe pain following extraction of ≥2 impacted third molars requiring bone removal, where CTC doses containing low doses of APIs exerted a significant effect. Phase 3 studies are currently ongoing.

Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III.

BACKGROUND: Mucopolysaccharidosis type III is a progressive, neurodegenerative lysosomal storage disorder for which there is currently no effective therapy. Though numerous potential therapies are in development, there are several challenges to conducting clinical research in this area. We seek to make recommendations on the approach to clinical research in MPS III, including the selection of outcome measures and trial endpoints, in order to improve the quality and impact of research in this area. RESULTS: An international workshop involving academic researchers, clinical experts and industry groups was held in June 2015, with presentations and discussions on disease pathophysiology, biomarkers, potential therapies and clinical outcome measures. A set of recommendations was subsequently prepared by a working group and reviewed by all delegates. We present a series of 11 recommendations regarding the conduct of clinical research, outcome measures and management of natural history data in Mucopolysaccharidosis type III. CONCLUSIONS: Improving the quality of clinical research in Mucopolysaccharidosis type III will require an open, collaborative and systematic approach between academic researchers, clinicians and industry. Natural history data should be published as soon as possible and ideally collated in a central repository. There should be agreement on outcome measures and instruments for evaluation of clinical outcomes to maximise the effectiveness of current and future clinical research.

Effects of olanzapine, risperidone and haloperidol on sleep after a single oral morning dose in healthy volunteers.

OBJECTIVES: To compare the effects of typical and atypical antipsychotic drugs on sleep activity and subjective sleep quality. DESIGN: Randomised, double-blind, placebo-controlled, four-period cross-over, clinical trial was used to evaluate the effects of active treatments on objective and subjective sleep variables. SETTING: Sleep laboratory evaluation. PARTICIPANTS: Twenty healthy young volunteers, both sexes. INTERVENTIONS: Single oral morning administrations of olanzapine 5 mg, risperidone 1 mg, haloperidol 3 mg and placebo. MEASUREMENTS AND RESULTS: Five polysomnographic nights were evaluated: one control night and one after each intervention. Significant increase in total sleep time, sleep efficiency, slow wave sleep (SWS) and rapid eye movement (REM) sleep with decreases in wake time were observed after olanzapine. Decreases in wake time, REM sleep and stage shifts together with increases in stage 2 were obtained after risperidone. Haloperidol showed only a tendency to increase sleep efficiency and stage 2 and to decrease wake time. Olanzapine showed decreases in power density in frequencies higher than 10 Hz during all sleep stages and in frequencies lower than 5 Hz range in SWS; decreases in the dynamics of spindle frequency activity (SFA) in the second and fourth non-rapid eye movement (NREM) episodes were also obtained. Risperidone presented increases in the 3.6-10.8 Hz frequency range in NREM sleep stages and in stage 2. Haloperidol also showed increases in NREM sleep stages and in stage 2, but these were in frequencies higher than 10 Hz, with increases in the dynamics of SFA in the first NREM episode. Only a significant improvement in subjective sleep quality was observed after olanzapine. CONCLUSIONS: Antipsychotics showed different sleep changes as their neurochemical profiles were distinct. These changes were observed even when the drug was administered 15 h before going to bed.

Sleep laboratory study on single and repeated dose effects of paroxetine, alprazolam and their combination in healthy young volunteers.

AIMS: To evaluate the potential interaction of 20 mg paroxetine and 1 mg alprazolam (early morning once-daily administration) on polysomnographic (PSG) sleep and subjective sleep and awakening quality, both after a single intake and after reaching a steady-state concentration. METHODS: Twenty-two (11 for the PSG) healthy young volunteers of both sexes with no history of sleep disturbances (Pittsburgh Sleep Quality Index <5) participated in a double-blind, double-dummy, placebo-controlled, repeated-dose, 4-period, cross-over study. All volunteers received all 4 treatment sequences: paroxetine-alprazolam placebo (PAP); paroxetine placebo-alprazolam (PPA); paroxetine-alprazolam (PA), and paroxetine placebo-alprazolam placebo (PLA), in a randomized order. Each treatment was administered over 15 consecutive days, with a treatment-free interval of 7 days prior to the subsequent study period. In each experimental period, one PSG sleep study was performed on the 1st night (single-dose effects) and another study was performed on the 15th night (repeated-dose effects). Additionally, two other PSG studies were assessed: an adaptation recording, and a control night recording. All-night PSG recordings were obtained following standard procedures. Each 30-second period was scored according to the criteria of Rechtschaffen and Kales by means of an automatic sleep analysis system: Somnolyzer 24x7. A self-rating scale for sleep and awakening quality and early morning behavior was completed no later than 15 min after awakening over the 15 days of each experimental intervention. General lineal models (treatment/time) were applied separately to each variable. RESULTS: (1) No significant effects were observed in any sleep variables when control nights were compared with the 1st night with PLA. (2) Sleep continuity: After PAP a clear awakening effect was seen both in the first and second evaluations, mainly in wake time, movement time, number of awakenings and stage-1 duration. After PPA an evident hypnotic effect was observed on night 1. This effect was mainly observed in maintenance variables and slightly in sleep initiation variables; it had decreased by night 15. After PA an intermediate behavior in the variables related to sleep continuity was seen, highlighting the absence of the tolerance phenomenon observed when PPA was administered alone. (3) Sleep architecture: The most important effects in REM sleep were observed after PAP; an increase in REM latency and decreases in REM sleep. PAP also induced decreases in the number of non-REM and REM periods and increases in the average duration of non-REM periods and sleep cycles. PA presented a similar pattern to PAP, and PPA similar to PLA. In relation to non-REM sleep, PA showed more stage-2 and less slow-wave sleep (SWS). (4) Subjective perception: No significant differences were observed between treatments while they were being taken, but impairments in subjective sleep quality, awaking quality, latency and efficiency were seen, mainly after PA but also after PPA discontinuations. CONCLUSION: The combination of PAP and PPA presented an intermediate pattern in relation to sleep continuity, with less awaking effect than PAP alone and less hypnotic effect than PPA alone, and without developing tolerance. The PAP and PPA combination also showed a similar effect to PAP on REM sleep and was the treatment with the longest stage 2 and shortest SWS. No subjective sleep and awakening effects were seen during drug intake but subjective withdrawal reports were seen after abrupt interruption. The high agreement rate for the epoch-by-epoch comparison between automatic and human scoring confirms the validity of the Somnolyzer 24x7 and thus facilitates sleep studies in neuropsychopharmacological research.

Noradrenergic stimulation enhances human action monitoring.

Noradrenergic neurotransmission has been associated with the modulation of higher cognitive functions mediated by the prefrontal cortex. In the present study, the impact of noradrenergic stimulation on the human action-monitoring system, as indexed by event-related brain potentials, was examined. After the administration of a placebo or the selective alpha2-adrenoceptor antagonist yohimbine, which stimulates firing in the locus ceruleus and noradrenaline release, electroencephalograpic recordings were obtained from healthy volunteers performing a letter flanker task. Yohimbine led to an increase in the amplitude of the error-related negativity in conjunction with a significant reduction of action errors. Reaction times were unchanged, and the drug did not modify the N2 in congruent versus incongruent trials, a measure of preresponse conflict, or posterror adjustments as measured by posterror slowing of reaction time. The present findings suggest that the locus ceruleus-noradrenaline system exerts a rather specific effect on human action monitoring.

Central and peripheral evaluation of rupatadine, a new antihistamine/platelet-activating factor antagonist, at different doses in healthy volunteers.

AIMS: To assess peripheral anti-H1 and central nervous system (CNS) activity of single increasing doses of rupatidine fumarate (RU), a new antihistamine/platelet-activating factor antagonist compound, in comparison with hydroxyzine and placebo. METHODS: Eighteen healthy young subjects of both sexes took part in a crossover, randomised, double-blind, placebo-controlled study. Treatments tested were: RU 10, 20, 40 and 80 mg and hydroxyzine 25 mg, as a positive standard. Before and several times after drug intake, peripheral anti-H1 activity was appraised by the skin reactivity to intradermal injection of histamine. CNS effects were also obtained by objective tests of psychomotor performance and subjective mood scales. RESULTS: All active treatments showed a significant reduction of the wheal and flare reaction in relation to placebo, RU displaying a potent dose-dependent inhibition pattern. The global nonparametric Friedman test to changes from placebo in 15 objective variables from psychomotor performance showed a significant impairment of similar magnitude after hydroxyzine 25 mg (p = 0.01) and RU 80 mg (p = 0.02), but this was slower in development and recovery after the latter. After RU 40 mg, a smaller impairment was also obtained (p = 0.04). Activity (p = 0.01) and drowsiness (p = 0.02) scales showed significant changes, the subjects feeling less active and more drowsy after all active treatments. CONCLUSION: RU presents a potent dose-dependent peripheral anti-H1 activity, displaying psychomotor impairment activity only at the highest dose (80 mg), while therapeutically relevant lower doses (10 and 20 mg) were similar to placebo.

Lack of pharmacologic interaction between paroxetine and alprazolam at steady state in healthy volunteers.

This investigation aimed to provide evidence on the lack of pharmacokinetic interaction of paroxetine (20 mg/d) and alprazolam (1 mg/d) in combined therapy. In addition, the central effects of both drugs when administered alone and in combination were assessed to rule out any relevant synergistic depressant central effect. Twenty-five healthy young adult volunteers participated in a double-blind, double-dummy, placebo-controlled, repeated dose (15 days), 4-period crossover study. Each subject received each of 4 treatment sequences (ie, paroxetine-alprazolam placebo, alprazolam-paroxetine placebo, paroxetine-alprazolam, and paroxetine placebo-alprazolam placebo) in randomized order. The ratios for area under the curve within a dosing interval and maximum plasma concentration of the paroxetine plus alprazolam sequence to single agent paroxetine were 1.07 (90% confidence interval = 0.99 to 1.16) and 1.05 (90% confidence interval = 0.97 to 1.13), respectively, with no statistically significant differences between the 2 treatments. Similarly, for alprazolam, ratios for the combined to the single treatment sequence were 0.99 (90% confidence interval = 0.93 to 1.05) and 1.00 (90% confidence interval = 0.94 to 1.07) for area under the curve within a dosing interval and maximum plasma concentration, respectively, showing no evidence for interaction. Comparative pharmacodynamics on the combination was assessed using 6 Psychomotor Performance Tests and 5 Visual Analogue Scales focused on mood variables. Alprazolam and paroxetine plus alprazolam induced similar and significant performance impairment and sedation after both single and repeated dose administration, being less evident on day 15. After dosing, paroxetine plus alprazolam showed a lower recovery pattern than alprazolam alone, especially on day 15. No treatment sequence showed cumulative effects after repeated dose administration. Psychomotor Performance Tests and Visual Analogue Scales data suggested lack of pharmacodynamic interactions. Accordingly, study results showed no evidence for pharmacologic interactions between paroxetine and alprazolam at steady state. The most commonly reported adverse event was drowsiness, with a higher incidence under both single and combined alprazolam treatments.

Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics.

The effects of the South American psychotropic beverage ayahuasca on subjective and cardiovascular variables and urine monoamine metabolite excretion were evaluated, together with the drug's pharmacokinetic profile, in a double-blind placebo-controlled clinical trial. This pharmacologically complex tea, commonly obtained from Banisteriopsis caapi and Psychotria viridis, combines N,N-dimethyltryptamine (DMT), an orally labile psychedelic agent showing 5-hydroxytryptamine2A agonist activity, with monoamine oxidase (MAO)-inhibiting beta-carboline alkaloids (harmine, harmaline, and tetrahydroharmine). Eighteen volunteers with prior experience in the use of psychedelics received single oral doses of encapsulated freeze-dried ayahuasca (0.6 and 0.85 mg of DMT/kg of body weight) and placebo. Ayahuasca produced significant subjective effects, peaking between 1.5 and 2 h, involving perceptual modifications and increases in ratings of positive mood and activation. Diastolic blood pressure showed a significant increase at the high dose (9 mm Hg at 75 min), whereas systolic blood pressure and heart rate were moderately and nonsignificantly increased. Cmax values for DMT after the low and high ayahuasca doses were 12.14 ng/ml and 17.44 ng/ml, respectively. Tmax (median) was observed at 1.5 h after both doses. The Tmax for DMT coincided with the peak of subjective effects. Drug administration increased urinary normetanephrine excretion, but, contrary to the typical MAO-inhibitor effect profile, deaminated monoamine metabolite levels were not decreased. This and the negligible harmine plasma levels found suggest a predominantly peripheral (gastrointestinal and liver) site of action for harmine. MAO inhibition at this level would suffice to prevent first-pass metabolism of DMT and allow its access to systemic circulation and the central nervous system.

Topographic pharmaco-EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers.

AIMS: Ayahuasca is a traditional South American psychoactive beverage used in Amazonian shamanism, and in the religious ceremonies of Brazilian-based syncretic religious groups with followers in the US and several European countries. This tea contains measurable amounts of the psychotropic indole N,N-dimethyltryptamine (DMT), and beta-carboline alkaloids with MAO-inhibiting properties. In a previous report we described a profile of stimulant and psychedelic effects for ayahuasca as measured by subjective report self-assessment instruments. In the present study the cerebral bioavailability and time-course of effects of ayahuasca were assessed in humans by means of topographic quantitative-electroencephalography (q-EEG), a noninvasive method measuring drug-induced variations in brain electrical activity. METHODS: Two doses (one low and one high) of encapsulated freeze-dried ayahuasca, equivalent to 0.6 and 0.85 mg DMT kg(-1) body weight, were administered to 18 healthy volunteers with previous experience in psychedelic drug use in a double-blind crossover placebo-controlled clinical trial. Nineteen-lead recordings were undertaken from baseline to 8 h after administration. Subjective effects were measured by means of the Hallucinogen Rating Scale (HRS). RESULTS: Ayahuasca induced a pattern of psychoactive effects which resulted in significant dose-dependent increases in all subscales of the HRS, and in significant and dose-dependent modifications of brain electrical activity. Absolute power decreased in all frequency bands, most prominently in the theta band. Mean absolute power decreases (95% CI) at a representative lead (P3) 90 min after the high dose were -20.20+/-15.23 microV2 and -2.70+/-2.21 microV2 for total power and theta power, respectively. Relative power decreased in the delta (-1.20+/-1.31% after 120 min at P3) and theta (-3.30+/-2.59% after 120 min at P3) bands, and increased in the beta band, most prominently in the faster beta-3 (1.00+/-0.88% after 90 min at P3) and beta-4 (0.30+/-0.24% after 90 min at P3) subbands. Finally, an increase was also seen for the centroid of the total activity and its deviation. EEG modifications began as early as 15-30 min, reached a peak between 45 and 120 min and decreased thereafter to return to baseline levels at 4-6 h after administration. CONCLUSIONS: The central effects of ayahuasca could be objectively measured by means of q-EEG, showing a time pattern which closely paralleled that of previously reported subjective effects. The modifications seen for the individual q-EEG variables were in line with those previously described for other serotonergic psychedelics and share some features with the profile of effects shown by pro-serotonergic and pro-dopaminergic drugs. The q-EEG profile supports the role of 5-HT2 and dopamine D2-receptor agonism in mediating the effects of ayahuasca on the central nervous system.