A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation.

BACKGROUND: A new benzodiazepine, remimazolam, which is rapidly metabolized by tissue esterases to an inactive metabolite, has been developed to permit a fast onset, a short, predictable duration of sedative action, and a more rapid recovery profile than currently available drugs. We report on modeling of the data and simulations of dosage regimens for future study. METHODS: A phase I, single-center, double-blind, placebo and active controlled, randomized, single-dose escalation study was conducted. Fifty-four healthy subjects in 9 groups received a single 1-minute IV infusion of remimazolam (0.01-0.3 mg/kg). There were 18 control subjects taking midazolam and 9 placebos. Population pharmacokinetic and pharmacodynamic modeling of the data was undertaken and the parameters obtained were used for Monte-Carlo simulations of alternative dosing regimens. RESULTS: A 4-compartment mammillary pharmacokinetic model of midazolam and a physiologically based recirculation model of remimazolam were fitted to the observed plasma levels. The recirculation model of remimazolam explained the observed high venous, compared with arterial, concentrations at later time points. The 2 models were used to simulate the arterial concentrations required for the pharmacodynamic models of sedation (Bispectral Index and Modified Observer's Assessment of Alertness/Sedation [MOAA/S]) and gave population mean pharmacodynamic parameters as follows: Bispectral Index-IC(50): 0.26, 0.07 µg/mL; γ: 1.6, 8.6; k(e0): 0.14, 0.053 min(-1); I(MAX): 39, 19, and MOAA/S-IC(50): 0.4, 0.08 µg/mL; γ: 1.4, 3.4; k(e0): 0.25, 0.050 min(-1) for remimazolam and midazolam, respectively. Simulations to obtain >70% of the population with MOAA/S scores of 2 to 4 were developed. This criterion was achieved (95% confidence intervals: 67%-74%) with a 6-mg initial loading dose of remimazolam followed by 3-mg maintenance doses at >2-minute intervals. Recovery to a MOAA/S score of 5 is predicted to be within 16 minutes for 89% (95% confidence intervals: 87%-91%) of the treated population after this loading/maintenance dose regimen. CONCLUSIONS: Population pharmacokinetic and pharmacodynamic models developed for remimazolam and midazolam fitted the observed data well. Simulations based on these models show that remimazolam delivers extremely rapid sedation, with maximal effect being reached within 3 minutes of the start of treatment. This property will enable maintenance doses to be given more accurately than with slower-acting drugs. No covariate effects considered to be clinically relevant were observed, suggesting that dosing by body weight may offer no advantage over fixed doses in terms of consistency of exposure to remimazolam within the weight range studied (65-90 kg).

A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics.

BACKGROUND: A new benzodiazepine, remimazolam, metabolized by tissue esterases to an inactive compound, CNS 7054, has been developed to permit a fast onset, a short and more predictable duration of sedative action, and a more rapid recovery profile than with currently available benzodiazepines. We report on the safety and efficacy of the first human study. METHODS: A phase I, single-center, double-blind, placebo- and active-controlled, randomized, single-dose escalation study was conducted. Up to 10 cohorts of healthy subjects were scheduled to receive a single 1-minute IV infusion of remimazolam, midazolam, or placebo. In the 10 possible cohorts, remimazolam doses were from 0.01 to 0.35 mg/kg. In cohorts 1 to 3, 6 subjects received remimazolam and 1 placebo. From cohort 4 onward, an additional 3 subjects in each cohort received midazolam (0.075 mg/kg). Safety, pharmacokinetics, and pharmacodynamics were measured. A stop criterion of loss of consciousness for >5 minutes in >50% of subjects was predefined. RESULTS: The stop criterion was reached in cohort 9 (0.30 mg/kg remimazolam) so that 81 subjects were enrolled. Remimazolam was well tolerated in all dose cohorts, and no serious adverse events (AEs) were reported. Three AEs of mild (Spo(2) 85%-88%) hemoglobin desaturation (2 in the remimazolam groups and 1 in the midazolam group) resolved spontaneously, and 1 AE of moderate hemoglobin desaturation (Spo(2) 75%) resolved with a chin lift in the highest remimazolam dose group. No supplemental oxygen or manual ventilation was required. Vital signs remained stable throughout, although there was an increase in heart rate 2 minutes postdose for both remimazolam and midazolam. There were no reports of hypo- or hypertension. The pharmacokinetic behavior of remimazolam was linear and its systemic clearance approximately 3 times that of midazolam. Clearance was essentially independent of body weight. A rapid onset and dose-dependent sedation was observed after administration of remimazolam at 0.05 mg/kg and higher. Remimazolam (0.075 to 0.20 mg/kg) induced peak sedation levels similar to or higher than those achieved with midazolam (0.075 mg/kg). Median recovery times after approximately equieffective doses of remimazolam (0.10 and 0.15 mg/kg) and midazolam (0.075 mg/kg) were 10 and 40 minutes, respectively. CONCLUSIONS: Remimazolam provided sedation with rapid onset and offset, and was well tolerated. There was no supplemental oxygen or ventilation required. On the basis of these data, further studies on the potential utility of remimazolam for sedation/anesthesia are warranted.

CNS 7056: a novel ultra-short-acting Benzodiazepine.

BACKGROUND: A new benzodiazepine derivative, CNS 7056, has been developed to permit a superior sedative profile to current agents, i.e., more predictable fast onset, short duration of sedative action, and rapid recovery profile. This goal has been achieved by rendering the compound susceptible to metabolism via esterases. The authors now report on the profile of CNS 7056 in vitro and in vivo. METHODS: The affinity of CNS 7056 and its carboxylic acid metabolite, CNS 7054, for benzodiazepine receptors and their selectivity profiles were evaluated using radioligand binding. The activity of CNS 7056 and midazolam at subtypes (alpha1beta2gamma2, alpha2beta2gamma2, alpha3beta2gamma2, alpha5beta2gamma2) of the gamma-aminobutyric acid type A (GABAA) receptor was evaluated using the whole cell patch clamp technique. The activity of CNS 7056 at brain benzodiazepine receptors in vivo was measured in rats using extracellular electrophysiology in the substantia nigra pars reticulata. The sedative profile was measured in rodents using the loss of righting reflex test. RESULTS: CNS 7056 bound to brain benzodiazepine sites with high affinity. The carboxylic acid metabolite, CNS 7054, showed around 300 times lower affinity. CNS 7056 and CNS 7054 (10 mum) showed no affinity for a range of other receptors. CNS 7056 enhanced GABA currents in cells stably transfected with subtypes of the GABAA receptor. CNS 7056, like midazolam and other classic benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor. CNS 7056 (intravenous) caused a dose-dependent inhibition of substantia nigra pars reticulata neuronal firing and recovery to baseline firing rates was reached rapidly. CNS 7056 (intravenous) induced loss of the righting reflex in rodents. The duration of loss of righting reflex was short (< 10 min) and was inhibited by pretreatment with flumazenil. CONCLUSIONS: CNS 7065 is a high-affinity and selective ligand for the benzodiazepine site on the GABAA receptor. CNS 7056 does not show selectivity between GABAA receptor subtypes. CNS 7056 is a potent sedative in rodents with a short duration of action. Inhibition of substantia nigra pars reticulata firing and the inhibition of the effects of CNS 7056 by flumazenil show that it acts at the brain benzodiazepine receptor.

Drug development in anaesthesia: industrial perspective.

PURPOSE OF REVIEW: In this review, we summarize the new drugs in development in the anaesthesia field. RECENT FINDINGS: There are some interesting approaches, including pro-drugs of propofol such as Aquavan (MGI Pharma, Bloomington, Minnesota, USA) and novel 'soft-drug' sedatives and hypnotics (e.g. CNS-7259X and TD-4756) as well as a novel approach to terminate the action of steroidal neuromuscular blockers (sugammadex). There is also significant activity in the field of novel analgesics. Particularly addressing the fields of sedatives, hypnotics and neuromuscular blockers, however, there is relatively little drug discovery activity currently. Part of the reason for this may be that the mechanisms of action of anaesthetics are not fully understood. This cannot be the whole story, however, since attractive new targets have recently been identified. For example, an agent with selective actions at the beta3-containing subunit of the gamma-amino butyric acid-A receptor is likely to have the hypnotic effects of propofol without the cardiac depressant side-effects. SUMMARY: We consider the main reason for low activity is the perception in industry that there is little need for new drugs in anaesthesia because the needs are well addressed by existing agents. If this is not the case then anaesthesiologists need to be more effective in communicating their requirements.

Memantine. Merz.

Memantine hydrochloride, an NMDA antagonist, was launched in Germany by Merz in 1989 for the treatment of dementia, an indication for which development was continuing in other markets. It is also under development by Merz, Lundbeck, Neurobiological Technologies Inc (NTI) Forest Laboratories and Suntory for the potential treatment of Alzheimer's disease (AD), AIDS-related dementia and pain in patients with neuropathy, and by Allergan for the potential treatment of ocular disease. By July 2001, a regulatory filing for neuropathic pain was expected in 2003. In February 2002, the CPMP recommended to the EU commission to approve memantine for the treatment of moderately severe-to-severe Alzheimer's disease. At this time, marketing authorization was expected late in the first half of 2002, and Lundbeck planned to launch memantine under the brand name Ebixa during the second half of 2002. Merz and Lundbeck, filed memantine for AD in the EU in September 2000 and an NDA was submitted in November of that year. The compound was in phase H trials in the US for the treatment of AIDS-related dementia and pain by August 1996 and phase III trials for glaucoma and neuroprotection by 1999. Analysts at Merrill Lynch predicted in October 2001 that Allergan would make regulatory filings in the US for memantine in glaucoma and ocular hypertension in 2005, and that Forest Laboratories would file for memantine in the US as a supplement to Alzheimer's disease data in early 2002, and for the treatment of neuropathic pain in 2003. Sales of $25 million in 2004, rising to $75 million in 2005, were predicted by Merrill Lynch for this product.

Synthesis and physicochemical assessment of novel 2-substituted 3-hydroxypyridin-4-ones, novel iron chelators.

Novel 3-hydroxypyridin-4-one containing tridentate ligands were synthesised and their physicochemical properties characterised, including ionisation constants and stoichiometric titration with Fe(III). There is an urgent demand for orally active iron chelators with potential for the treatment of thalassaemia. In principle, tridentate ligands are likely to be more kinetically stable than bidentate molecules, but to date no satisfactory molecules have been identified. Fe(III) stability constants were assessed by competition with the hexadentate ligand EDTA. In all cases no evidence was found for a tridentate mode of iron chelation; instead the ligands behaved as bidentate hydroxypyridinones. As a consequence they provide no advantage over the more simple alkyl hydroxypyridinones.

The effect of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and its metabolites on neurohypophysial hormone release from the isolated rat hypothalamus.

Methylenedioxymethamphetamine (MDMA, 'ecstasy'), widely used as a recreational drug, can produce hyponatraemia. The possibility that this could result from stimulation of vasopressin by MDMA or one of its metabolites has been investigated in vitro. Release of both oxytocin and vasopressin from isolated hypothalami obtained from male Wistar rats was determined under basal conditions and following potassium (40 mM) stimulation. The results were compared with those obtained for basal and stimulated release in the presence of MDMA or metabolites in the dose range 1 microM to 100 pM (n=5 - 8) using Student's t-test with Dunnett's correction for multiple comparisons. All compounds tested affected neurohypophysial hormone release, HMMA (4-hydroxy-3-methoxymethamphetamine) and DHA (3,4-dihydroxyamphetamine) being more active than MDMA, and DHMA (3,4-dihydroxymethamphetamine) being the least active. The effect on vasopressin release was greater than that on oxytocin. In the presence of HMMA the ratio test:control for basal release increased for vasopressin from 1.1+/-0.16 to 2.7+/-0.44 (s.e.m., P<0.05) at 10 nM and for oxytocin from 1.0+/-0.05 to 1.6+/-0.12 in the same hypothalami. For MDMA the ratio increased to 1.5+/-0.27 for vasopressin and to 1.28+/-0.04 for oxytocin for 10 nM. MDMA and its metabolites can stimulate both oxytocin and vasopressin release in vitro, the response being dose dependent for each drug with HMMA being the most potent.