Evidence suggests that compounds that increase the synaptic availability of more than one neurotransmitter have greater efficacy in the treatment of depression than single-acting drugs. Preclinical studies indicate that duloxetine acts to inhibit serotonin (5-HT) and norepinephrine (NE) transporters. The ability of duloxetine to alter 5-HT and NE reuptake was tested in 12 healthy male subjects. Placebo, desipramine 50 mg b.i.d., and duloxetine (80 mg q.d. or 60 mg b.i.d.) were compared in a randomized, double-blind, threeperiod crossover study in 12 healthy male subjects. Whole-blood 5-HT, urinary excretion of NE and major metabolites, and TYR PD 30 (IV tyramine pressor dose needed to increase systolic blood pressure by 30 mmHg) were measured at steady state. Vital signs were measured periodically. Duloxetine affected 5-HT reuptake, with whole-blood 5-HT depletion vs placebo (80 mg q.d.: p ¼ 0.07; 60 mg b.i.d.: p ¼ 0.02; combined regimens: p ¼ 0.01). Cardiovascular changes reflecting increased sympathetic tone were observed with both duloxetine and desipramine, and both treatments significantly decreased whole body NE turnover (po0.01). Duloxetine and desipramine were associated with similar mean increases in fractional extraneuronal NE concentration, although these changes did not reach statistical significance. TYR PD 30 increased significantly with desipramine dosing (po0.01). In conclusion, whole-blood measurements confirm that duloxetine inhibits platelet 5-HT uptake in vivo. Urinary and cardiovascular measurements suggest that duloxetine has an effect on NE synthesis and turnover, indicative of NE reuptake inhibition. The lack of a detectable impact of duloxetine on TYR PD 30 suggests that this may not be the most sensitive indirect measure of NE reuptake when assessing dual reuptake inhibitors.

One of the most widely used options for minimal/moderate sedation in pediatric patients is oral midazolam, as it presents an alternative to less well‐accepted routes of administration (eg, intravenous or intranasal) of this well‐known efficacious and well‐tolerated short‐acting benzodiazepine. A systematic review of the literature was conducted in order to identify clinical studies evaluating the effectiveness of oral midazolam for sedation in pediatric patients in the context of premedication before anesthesia or during diagnostic/treatment procedures. The percentage of responders (response rate) after single administration of oral midazolam was evaluated and compared versus placebo in a subset of placebo‐controlled studies. The range of oral midazolam doses providing effective sedation in the different pediatric age subsets was analyzed in order to assess optimum dosing strategies. A total of 25 pediatric clinical studies, utilizing a variety of measures of sedation effectiveness, were selected. These studies included a total of 1472 patients (aged 4 months‐18 years) treated with midazolam (0.25‐1.5 mg/kg) and 138 patients treated with placebo. The response rates [95% confidence interval] with oral midazolam ranged from 36.7% [21.6%, 54.9%] to 97.8% [86.1%, 99.7%], while with placebo response rates ranged from 4.0% [0.6%, 23.5%] to 41.0% [29.4%, 53.6%]. When considering the 4 placebo‐controlled studies, the odds ratios [95% confidence interval] for the comparison of midazolam vs. placebo ranged from 13.4 [5.0, 36.0] to 25.9 [6.7, 100.6]. The analysis of subgroups by context of sedation showed response rates [95% confidence interval] with oral midazolam ranging from 36.7% [21.6%, 54.9%] to 97.0% [94.8%, 98.3%] for anesthetic premedication and from 56.1% [43.1%, 68.4] to 97.8% [86.1%, 99.7%] for medical procedures. The efficacy of midazolam for pediatric minimal/moderate sedation from a dose of 0.25 mg/kg and above was demonstrated. The probability of occurrence of adverse events and over‐sedation increases with increasing doses.

The two dose regimens of duloxetine (80 mg QD and 60 mg BID) produced a REM sleep pattern comparable to that of most antidepressant medications. Duloxetine 80 mg QD appeared to exhibit less impact upon sleep quality than duloxetine 60 mg BID in healthy subjects.

Pharmacokinetic parameters were close to those reported in the literature with midazolam extemporaneous oral solutions or syrups, demonstrating that cyclodextrin had no significant effect on measured parameters.

Morphine-6-glucuronide (M6G), an active metabolite of morphine, has been shown to have significantly attenuated brain penetration relative to that of morphine. Recently, we have demonstrated that conjugation of various drugs to peptide vectors significantly enhances their brain uptake. In this study, we have conjugated morphine-6-glucuronide to a peptide vector SynB3 to enhance its brain uptake and its analgesic potency after systemic administration. We show by in situ brain perfusion that vectorization of M6G (Syn1001) markedly enhances the brain uptake of M6G. This enhancement results in a significant improvement in the pharmacological activity of M6G in several models of nociception. Syn1001 was about 4 times more potent than free M6G (ED 50 of 1.87 versus 8.74 mol/kg). Syn1001 showed also a prolonged duration of action compared with free M6G (300 and 120 min, respectively). Furthermore, the conjugation of M6G results in a lowered respiratory depression, as measured in a rat model. Taken together, these data strongly support the utility of peptide-mediated strategies for improving the efficacy of drugs such as M6G for the treatment of pain.The main metabolism pathway of morphine includes liver glucuronidation to morphine-6-glucuronide (M6G) and morphine-3-glucuronide. M6G is thought to contribute to the pharmacological effects of the parent drug (Abbott and Palmour, 1988;Paul et al., 1989;Frances et al., 1992), and various clinical trials have used M6G as the therapeutic drug in preference to morphine (Hanna et al., 1990;Thompson et al., 1995;Grace and Fee, 1996;Lötsch et al., 1997;Motamed et al., 2000;Penson et al., 2000). Antinociception studies in experimental animals have demonstrated that, although M6G and morphine are almost equally potent after systemic administration, the analgesic potency of M6G is more than 100-fold higher than morphine after intracerebroventricular injection, a route of administration that bypasses the bloodbrain barrier (BBB) in vivo (Abbott and Palmour, 1988;Paul et al., 1989;Frances et al., 1992). These pharmacological data suggest that the brain penetration of M6G is significantly attenuated relative to that of morphine, probably due to the presence of the glucuronide moiety of M6G, conferring a higher hydrophilic character. Recently, a weak capacity and bidirectional transport by GLUT-1 and by a digoxin-sensitive transporter, which could be oatp2, was reported to be involved in the transport of M6G through the mouse BBB (Bourasset et al., 2003). However, several studies have shown that morphine has a better BBB permeability than M6G after i.v. injection (Bickel et al., 1996;Wu et al., 1997). Thus, enhancing the brain uptake of M6G would be expected to result in an improvement in its analgesic activity.Brain delivery is still one of the major challenges for the pharmaceutical industry since many therapeutic drugs are unable to penetrate the BBB, a complex endothelial interface in vertebrates that separates the blood compartment from the extracellular fluid compartment o...