Efficacy of oral midazolam for minimal and moderate sedation in pediatric patients: A systematic review.

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.

Population pharmacokinetic evaluation of ADV6209, an innovative oral solution of midazolam containing cyclodextrin.

INTRODUCTION: In the absence of a licensed formulation in many countries worldwide, ADV6209, an innovative 2mg/ml oral solution of midazolam containing cyclodextrin, has been developed for moderate sedation in paediatric patients. Population pharmacokinetics for ADV6209 is reported. METHODS: Plasma concentration data were collected from 37 paediatric patients and 12 healthy adults recruited in a single dose, open-label phase II pharmacokinetic study and in a single dose, randomised, open-label two-period crossover bioavailability study, respectively. Data were analysed using non-linear mixed effect modelling. Plasma concentrations of midazolam were described by a two-compartment model. An additional one-compartment model was added for α- hydroxymidazolam. RESULTS: The body weight covariate was found to have a significant impact on midazolam and α-hydroxymidazolam clearance, and on midazolam volume of distribution. The population pharmacokinetic model indicated that 77% of the midazolam dose was absorbed within 30min after oral administration. Parameter estimations for a subject of 34kg indicated values of midazolam clearance of 34.7l·h-1, a central volume of distribution of 27.9l and a peripheral volume of distribution of 413l. A higher metabolic ratio and a higher midazolam clearance per body weight were observed in the youngest group of subjects, in accordance with literature data. The clearance per body weight of α-hydroxymidazolam remained constant over the different age groups. CONCLUSION: 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.

Transepithelial transport across Caco-2 cell monolayers of antihypertensive egg-derived peptides. PepT1-mediated flux of Tyr-Pro-Ile.

This paper examines the in vitro transepithelial transport of antihypertensive peptides derived from egg proteins using Caco-2 cell monolayers. Ovokinin (FRADHPFL) was absorbed intact through the Caco-2 cell epithelium, although it was also susceptible to the action of brush-border aminopeptidases that yielded shorter fragments prior to their transport. The tripeptide YPI was resistant to cellular peptidases and transported through the monolayer, what suggests that the reduction in systemic blood pressure caused by this peptide may be mediated by effects at tissue level. Its pathway for transepithelial absorption was examined using inhibitors of the different mechanisms for oligopeptide transport in the intestinal tract. The main route involved in the transepithelial flux of YPI is probably the peptide H(+)-coupled transporter PepT1. These results highlight the potential of antihypertensive peptides to be used in the formulation of functional foods.

Effect of the long-term intake of an egg white hydrolysate on the oxidative status and blood lipid profile of spontaneously hypertensive rats.

This paper examines the effects of the long-term consumption of egg white hydrolysed with pepsin (hEW) on the antioxidant status and lipid profile of spontaneously hypertensive rats (SHR). The antioxidant capacity was measured by the oxygen radical absorbance capacity (ORAC) and the oxidative status by the malon-dialdehyde (MDA) assay. The lipid profile was analysed spectrophotometrically. The radical-scavenging capacity of the plasma was increased and the MDA concentration in the aorta was decreased in the SHR treated with 0.5g/kg/day of hEW. Our findings indicate that hEW played an important role in antioxidative defence of SHR and exerted a beneficial effect on the lipid profile, lowering triglycerides and total cholesterol without changing HDL levels. Therefore, hEW may be useful to prevent or reverse abnormalities associated with the metabolic syndrome and its complications, such as hypertension, oxidative stress and hyperlipidemia.

Angiotensin-converting enzyme activity in plasma and tissues of spontaneously hypertensive rats after the short- and long-term intake of hydrolysed egg white.

This paper evaluates the effects of the short- (1 g/kg) and long-term (0.5 and 1 g/kg/day) oral intake of egg white hydrolysed with pepsin (hEW) and the long-term oral intake (1 g/kg/day) of egg white (EW) on local angiotensin-converting enzyme (ACE) activities in plasma and other tissues of spontaneously hypertensive rats (SHR), as compared to the effect of the ACE inhibitor prototype captopril. The rats treated with hEW were classed in a different group than the control rats and the rats treated with EW by cluster analysis, taking into account their tissue ACE activities and their systolic blood pressure (SBP). Principal component analysis (PCA) showed that SBP in SHR was negatively related with ACE activity in plasma and positively related with ACE activity in aorta and kidney. ACE activity in plasma significantly increased after the long-term treatment with hEW (0.5 g/kg/day). ACE activity in aorta and kidney was significantly inhibited 4 h after the short-term administration of hEW. The long-term treatment with hEW caused local effects on ACE activity in aorta, kidney and lungs that followed a pattern similar, but less pronounced, than that caused by captopril.

Determination of vegetal proteins in milk powder by sodium dodecyl sulfate-capillary gel electrophoresis: interlaboratory study.

An interlaboratory study, with the participation of 8 laboratories, was conducted to evaluate a sodium dodecyl sulfate-capillary gel electrophoresis method for determination of adulteration of milk powder with soy and pea proteins. Calibration standards (0-8%, w/w, soy and pea protein in total protein) and adulterated skim milk powders (0-5%, w/w, soy and pea proteins in total protein) were produced. Vegetal proteins were determined after removal of milk proteins by pretreatment of the samples with tetraborate-EDTA buffer, pH 8.3. Repeatability standard deviations ranged from 9 to 15% and reproducibility standard deviations ranged from 25 to 30% in the samples containing 5% vegetal protein in total protein.