First Human Study of the Investigational Sedative and Anesthetic Drug AZD3043: A Dose-Escalation Trial to Assess the Safety, Pharmacokinetics, and Efficacy of a 30-Minute Infusion in Healthy Male Volunteers.

BACKGROUND: AZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor that is rapidly metabolized to an inactive metabolite by esterases present in blood and liver. Preclinical results suggest that AZD3043 has the potential as a short-acting IV sedative/anesthetic drug with rapid and predictable recovery characteristics and a favorable safety and tolerability profile. METHODS: Our primary objective in this phase 1, single-center, open-label study was to evaluate the safety and tolerability of AZD3043 after IV infusion and to estimate the maximal tolerated dose. Secondary objectives included the evaluation of AZD3043 pharmacokinetics, pharmacodynamics, and efficacy. Sequential ascending-dose cohorts of 5 or 6 healthy male volunteers aged 18 to 45 years received a single 30-minute IV infusion of AZD3043. Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index. RESULTS: Fifty-three subjects received AZD3043 in infusion rate cohorts of 1, 3, 6, 12, 18, 27, 36, 54, and 81 mg/kg/h. There were no discontinuations, and dose escalation was stopped on reaching the predefined exposure limit. Adverse events occurring in >1 subject were headache (n = 4), erythema (n = 3), chest discomfort (n = 2), nausea (n = 2), and dyspnea (n = 2). The frequency and character of adverse events appeared unrelated to dose. There were no spontaneous reports of pain on injection and no clinically relevant changes in respiratory rate or arterial blood pressure. However, heart rate increased dose-dependently at infusion rates >18 mg/kg/h. Occurrence of sedation/anesthesia corresponded with dose; the lowest applied infusion rate to induce anesthesia according to clinical signs of sedation/anesthesia at predefined time points was 12 mg/kg/h (1 of 6 subjects anesthetized), and all subjects in the 3 highest dose groups were anesthetized. The onset of anesthesia ranged from 4 minutes in the highest infusion rate group to 29 minutes in the 12-mg/kg/h infusion rate group. Return of response to oral command occurred at 3 minutes after the end of infusion in the single subject who was anesthetized in the 12-mg/kg/h group and median 25 minutes in the 81-mg/kg/h group. Involuntary movements ranging from minor twitches to extensive movements were accompanied by increased muscle tone. CONCLUSIONS: AZD3043 was well tolerated in this first human study and seems to exhibit rapid onset and recovery, indicating potential use as a short-acting drug for anesthesia and sedation.

A Bolus and Bolus Followed by Infusion Study of AZD3043, an Investigational Intravenous Drug for Sedation and Anesthesia: Safety and Pharmacodynamics in Healthy Male and Female Volunteers.

BACKGROUND: AZD3043 (THRX-918661) is an investigational phenylpropanoid sedative/anesthetic that is rapidly metabolized by esterases in blood and liver. In the first-in-man study, a 30-minute constant IV infusion of AZD3043 induced anesthesia without major safety or tolerability concerns and with rapid recovery characteristics. METHODS: The primary objective of this phase 1, single-center, open-label study (clinicaltrials.gov NCT00984880) was to evaluate the safety and tolerability of AZD3043 administered as a single IV bolus and as a bolus followed by infusion. Secondary objectives included evaluation of AZD3043 pharmacodynamics and efficacy. Sequential ascending dose cohorts of 8 healthy volunteers aged 18 to 65 years received either a single 1-minute bolus IV infusion (part A) or a 1-minute bolus followed by a 30-minute infusion (part B). Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index score. RESULTS: Seventy-two subjects (8 females, 64 males) received AZD3043 doses of 1, 1.5, 2, 4, and 6 mg/kg bolus over 1 minute (part A) or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 mg/kg bolus + mg/kg/h infusion for 30 minutes (part B). There were no discontinuations. Adverse events occurring in >1 subject were headache (n = 15; 21%), nausea (n = 7; 10%), vomiting (n = 3; 4%), and fatigue (n = 2; 3%). Twenty-one subjects experienced at least 1 adverse event. There seemed to be no dose relationship associated with any adverse event. Ventilation was maintained, but there was a dose-dependent increase in heart rate. There were no spontaneous reports of pain on injection. Thirty-two subjects were anesthetized, including all subjects in the highest dose group in part A and all subjects in the 2 highest dose groups in part B. Recovery from anesthesia was rapid, with swift return of orientation and proprioception. All subjects were able to walk 10 m without support at their first assessment, 30 minutes after end of dosing, except for 1 subject in each of the 2 mg/kg bolus (part A) and 4 mg/kg bolus + 40 mg/kg/h 30-minute infusion (part B) dose groups, who passed this test at the subsequent assessment, 45 minutes after the end of dosing. Involuntary movements were observed at higher doses, accompanied by increased muscle tone. CONCLUSIONS: AZD3043 provided rapid recovery from anesthesia with maintained ventilation. Further studies are warranted in a clinical setting.

Clinical pharmacokinetics of the nicotinic channel modulator dexmecamylamine (TC-5214) in subjects with various degrees of renal impairment.

BACKGROUND AND OBJECTIVE: Dexmecamylamine (TC-5214) is a nicotinic channel modulator that was evaluated as a potential adjunct treatment to an antidepressant for patients with major depressive disorder. Dexmecamylamine is almost completely eliminated via the kidneys, with more than 90 % of a given dose excreted unchanged in urine. The aim of this study was to assess the single-dose pharmacokinetics of dexmecamylamine in subjects with various degrees of renal impairment and subjects undergoing hemodialysis. METHODS: A single-dose, open-label, parallel-group study was conducted at two study centers in the USA. There were four treatment groups with eight subjects in each, receiving a single dose of dexmecamylamine 8 mg (subjects with normal renal function and mild renal impairment) or TC-5412 2 mg [subjects with moderate renal impairment and end-stage renal disease (ESRD)]. The pharmacokinetics of dexmecamylamine in plasma, urine, and dialysate were evaluated using non-compartmental analysis. RESULTS: The plasma pharmacokinetics of dexmecamylamine were influenced by renal function. The increase in dose-normalized area under the plasma concentration-time curve (AUC) was statistically significant with an approximately doubled exposure in subjects with moderate renal impairment compared with subjects with normal renal function. The maximum plasma concentration was not impacted by renal function. Plasma clearance of dexmecamylamine in ESRD subjects appeared negligible, with flat plasma concentration-time profiles. Hemodialysis had a relatively modest effect on reduction of dexmecamylamine plasma concentrations. There was no discernable relationship between renal clearance and urinary pH. CONCLUSION: Renal impairment increased the AUC, prolonged the elimination half-life, and decreased the clearance of dexmecamylamine following administration as a single oral dose. It is likely that renal function would need to be taken into account when setting the dose. Dexmecamylamine administration should be avoided or the dose significantly reduced in patients with severe renal impairment and ESRD.

Circadian tryptophan hydroxylase levels and serotonin release in the suprachiasmatic nucleus of the rat.

Serotonin (5-HT) plays an important role in the regulation of the time-keeping system in rodents. In the present study, we have investigated the interplay between the rhythms of 5-HT synthesis and release in the suprachiasmatic nuclei (SCN) of the rat. The quantitative distribution of tryptophan hydroxylase (TpH) protein was used as an index of 5-HT synthesis, in perikarya and terminals areas. In the raphe medianus, the maximal levels of TpH was reached in the early daytime period, followed by a decrease before the onset of darkness. Conversely, in the axon terminals of the SCN the highest levels of TpH were found before the onset of the dark-period. Furthermore, TpH amount in SCN displays variations depending on the anatomical area of the SCN. Extracellular 5-HT peaked at the beginning of the night, as evidenced by in vivo microdialysis in the SCN. The 5-HT metabolite, 5-HIAA, presented a similar pattern, but the acrophase occurred in the middle of the dark period. These results suggest that TpH is transported from the soma to the nerve terminals in which 5-HT is synthesized during daytime. This would fill the intracellular stores of 5-HT to provide for its nocturnal release.

In the rat, exogenous melatonin increases the amplitude of pineal melatonin secretion by a direct action on the circadian clock.

The effect of exogenous melatonin on pineal melatonin synthesis was studied in the rat in vivo. Daily melatonin profiles were measured by transpineal microdialysis over 4 consecutive days in rats maintained on a 12-h light : 12-h dark schedule (LD 12 : 12). Curve-fitting was used to determine the amplitude of the peak of melatonin production, and the times of its onset (IT50) and offset (DT50). A subcutaneous injection of melatonin (1 mg/kg) at the onset of darkness (ZT12) induced an advance of IT50 on the second day after the treatment, in 50% of the animals kept in LD. When the animals were switched to constant darkness, the treatment caused no detectable advance of IT50, while 70% of individuals showed a significant delay in DT50 2 days after the injection. Locally infusing the drug by reverse microdialysis into the suprachiasmatic nuclei (SCN) failed to enhance the shift in melatonin onset. Following subcutaneous melatonin injection, a significant increase ( approximately 100%) in melatonin peak amplitude was observed. This increase persisted over 2 days and occurred only when the melatonin was applied at ZT12, but not at ZT6, 17 or 22. The effect was also observed when the drug was infused directly into the SCN, but not into the pineal. Thus, the SCN are the target site for the effect of exogenous melatonin on the amplitude of the endogenous melatonin rhythm, with a similar window of sensitivity as its phase-shifting effect on the pacemaker.