Single Dose Of Midazolam Research Articles

Pharmacodynamics, pharmacokinetics and CYP3A4 interaction potential of the selective P2X3 receptor antagonist filapixant: A randomized multiple ascending-dose study in healthy young men.

We report on investigations exploring the P2X3-receptor antagonist filapixant's effect on taste perception and cough-reflex sensitivity and describe its pharmacokinetics, including its CYP3A4-interaction potential. In a randomized, placebo-controlled, double-blind study, 3 × 12 healthy men (18-45 years) were assigned (3:1) to filapixant (20, 80 or 250 mg by mouth) or placebo twice daily over 2weeks. A single dose of midazolam (1mg), a CYP3A4 substrate, was administered with and without filapixant. Assessments included a taste-strips test, a taste questionnaire, cough challenge with adenosine triphosphate, adverse event reports and standard safety assessments. Taste disturbances were observed mainly in the 250-mg group: six of nine participants (67%) in this group reported hypo- or dysgeusia in the questionnaire; eight participants (89%) reported taste-related adverse events. Five participants (56%) had a decrease in overall taste-strips-test scores ≥2 points (point estimate -1.1 points, 90% confidence interval [-3.3; 1.1]). Cough counts increased with adenosine triphosphate concentration but without major differences between treatments. Filapixant exposure increased proportionally to dose. Co-administration of filapixant had no clinically relevant effect on midazolam pharmacokinetics. Area under the concentration-time curve ratios and 90% confidence intervals were within 80-125%. No serious or severe adverse events were reported. Overall, filapixant was safe and well tolerated, apart from mild, transient taste disturbances. Such disturbances occurred more frequently than expected based on (in vitro) receptor-selectivity data, suggesting that other factors than P2X3:P2X2/3 selectivity might also play an important role in this context. The cough-challenge test showed no clear treatment effect. Filapixant has no clinically relevant CYP3A4 interaction potential.

Efficacy and safety of the ghrelin-O-acyltransferase inhibitor BI 1356225 in overweight/obesity: Data from two Phase I, randomised, placebo-controlled studies

BackgroundObesity is a complex disease associated with multiple concurrent complications, and the coordinated targeting of multiple pathways in pharmacological treatment may improve weight loss outcomes. During synthesis, ghrelin is converted from the ‘inactive’ unacylated ghrelin (UAG) to the active acylated ghrelin (AG) by the enzyme ghrelin-O-acyltransferase (GOAT), stimulating appetite and food intake. AimsTo report the results of two Phase I studies investigating single rising doses (SRDs) or multiple rising doses (MRDs) of the novel oral GOAT inhibitor BI 1356225 versus placebo in male and postmenopausal/sterilised female subjects with overweight or obesity. MethodsThe SRD study investigated single doses of BI 1356225 (0.1–20.0 mg) in healthy male subjects with a BMI of 18.5–29.9 kg/m2 (SRD cohort) and assessed doses of 2.5 mg BI 1356225 under fed and fasted conditions (bioavailability [BA] cohort). The MRD study investigated multiple doses of BI 1356225 (0.2, 1.0, 2.5 or 10.0 mg) or 5.0 mg BI 1356225 with a single dose of midazolam and celecoxib (drug–drug interaction part) over 28 days in adults with a BMI of 27.0–39.9 kg/m2. ResultsSixty-five subjects were treated in the SRD study. Drug-related adverse events (AEs) were reported for five subjects (9.1 %) in the SRD cohort and two subjects (20.0 %) in the BA cohort, with the most frequent being headache (SRD: n = 4, 9.8 %; BA: n = 1, 10.0 %). In the MRD study, two (2.3 %) of the 87 subjects treated discontinued treatment because of AEs. Drug-related AEs were reported for 18 subjects (20.7 %), did not increase with dose and were most frequently reported as headache (n = 5, 5.7 %) and gastrointestinal disorders (n = 5, 5.7 %). In both studies, exposure parameters (area under the concentration–time curve [AUC] and maximum plasma concentration [Cmax]) of BI 1356225 increased across dose groups, although this was less than dose-proportional across the entire dose range. In the BA cohort of the SRD study, AUC0–∞ was slightly increased and Cmax slightly decreased in fed versus fasted conditions, with fed/fasted ratios (90 % CI) of 101.10 % (92.42, 110.60) and 91.67 % (78.50, 107.05), respectively. In both studies, AG concentrations and the AG/UAG ratio were dose-dependently decreased after BI 1356225 treatment from baseline versus placebo. In the MRD study, UAG concentrations were increased from baseline, but not dose-dependently. No differences were observed in bodyweight, appetite, food cravings, ad libitum food uptake or obesity-related biomarkers after 28 days of treatment with BI 1356225. ConclusionsTreatment with SRDs and MRDs of BI 1356225 was well tolerated by healthy males and subjects with overweight/obesity. BI 1356225 treatment over 28 days reduced AG concentrations and the AG/UAG ratio by >80 %, but no effect was seen on bodyweight, hunger/satiety, control of eating or energy intake. Although, at 4 weeks, the MRD study was fairly short, a reduction in bodyweight would be expected to be evident by this time, suggesting that a reduction of AG via a GOAT inhibitor is not sufficient to induce clinically relevant bodyweight loss.

Safety of Dexmedetomidine as an Alternative Pediatric Magnetic Resonance Imaging (MRI) Sedative: A Retrospective Single-Center Study.

BackgroundDexmedetomidine provides anxiolysis, sedation, dose-dependent hypnosis, and mild analgesia with minimal respiratory function effects. The aim of this study was to assess the efficacy and safety of dexmedetomidine for pediatric patients during MRI.Material/MethodsWe retrospectively analyzed 87 cases of pediatric sedations for MRI. Dexmedetomidine and a single dose of midazolam were used in all the cases, according to the in-house pediatric sedation protocol for MRI. The patients were divided in to 2 groups: group 1, who reached adequate sedation up to 10 min of induction and group 2, who achieved proper sedation after 10 min.ResultsThe median age was 3 years (0–17). The median duration of procedure was 75 min (40–150). The induction of standardized sedation was performed without additional sedatives and proper depth of sedation was reached in the majority of cases (94.3%). Five patients (5.7%) received additional sedative after 10 min of induction. The median time of adequate sedation was 8 min (3–13) after induction, and 51% of patients achieved RASS-4 in 8 min. There was no significant difference between groups 1 and 2. Ten patients (11.5%) experienced bradycardia, regardless of the usage of additional drugs, dexmedetomidine boluses, duration of the procedure, or induction time.ConclusionsHigh-dose dexmedetomidine with a single dose of midazolam might be an effective combination at the induction stage for pediatric sedation for MRI, with very few adverse events. Over 50% of enrolled patients achieved an adequate level of sedation before 10 min. We conclude that induction of dexmedetomidine infusion can be shortened up to 8 min.

Pharmacokinetic study of midazolam and α-hydroxymidazolam in guinea pig blood and hair roots after a single dose of midazolam

The appearance of midazolam (M) and its metabolites into the hair root following a single administration was examined by following the time course of M and α-hydroxymidazolam (αHM) in hair roots and blood from guinea pigs. The back hair of guinea pigs was shaved before drug administration and before each sampling, and hair roots (3–5 mm) were plucked at 5, 15, and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120, 144 h, and 7, 14, 21, and 28 days. The kinetic parameters of M and αHM in guinea pig blood and hair roots were determined for three doses (5, 10, and 25 mg/kg). Comparisons of drug time course between hair roots and blood indicated an association between drug concentrations in the hair root and the blood. M and αHM entered the hair root within 5 min after a single exposure. The detection windows were also longer for the hair root than for the blood. Consequently, the hair root can be a valuable specimen in acute poisonings or drug-facilitated crime (DFC) cases, if other matrices are unavailable, or if blood and urine results are negative. Hair shafts (with hair roots) were plucked at 28 days and segmented. The concentrations of M and αHM were lower in the hair shafts than in the hair roots. The concentrations of the metabolite αHM in hair shafts were barely detectable. The concentrations of M and αHM in the hair root showed a moderate correlation with dose. Comparison of drug levels in hair roots between the washed group and the unwashed group indicated a generally stable percentage between the washed and unwashed groups of 40–60 % during the entire time course. This indicates that drugs are likely to be immobilized in the hair root at the beginning of the incorporation process.

Psychomotor Recovery Following Remimazolam-induced Sedation and the Effectiveness of Flumazenil as an Antidote

PurposeRemimazolam tosylate (HR-7056) is a novel ester-type benzodiazepine with ultrafast onset of effect. The compound is being developed for sedation induction and maintenance during anesthesia. It was approved for procedural anesthesia in December 2019 by the National Medical Products Administration of China. Previous studies have reported on remimazolam's effects on consciousness and cognition. Although the time to full psychomotor recovery after remimazolam-mediated sedation is critical for decisions regarding hospital discharge, relevant clinical evidence is still lacking. This study investigated the residual psychomotor effects of remimazolam and their recovery from sedating treatment in 2 simulated clinical settings: (1) single-dose administration for sedation initiation; and (2) constant rate infusion for sedation maintenance. MethodsA single-ascending-dose, parallel-group, midazolam-controlled study and a 2-way crossover study evaluating the reversal effect of flumazenil versus placebo after a 2-h constant rate infusion were conducted with HR-7056 in 87 Chinese healthy volunteers; the studies used a double-blind, randomized trial design. A battery of psychomotor tests was administered before dosing and several times postdose over 4–6 h. Pharmacokinetic, sedation, and safety assessments were performed throughout the studies. FindingsAfter bolus infusion, the Bispectral Index score decreased in a concentration-dependent manner with HR-7056, accompanied by a sharp drop of Modified Observer's Assessment of Alertness/Sedation score. The recovery of consciousness was much faster with HR-7056 than with midazolam. During the constant rate infusion, the Bispectral Index score was maintained between 40 and 60 with an average plasma remimazolam concentration of ~1000 ng/mL. Subjects' performance in saccadic and smooth pursuit eye movement, body sway, test of choice reaction time, and word recall was significantly impaired after single-dose midazolam and after constant rate infusion of remimazolam. The end-of-infusion injection of flumazenil shortened the median time to full alertness to 3.5 min and effectively reversed psychomotor and cardiovascular dysfunction. ImplicationsThe study results showed quicker psychomotor recovery from sedation in the remimazolam-treated group. The moderate and short-lasting residual effect of remimazolam after 2-h conscious sedation proposes a need for psychomotor assessment(s) before hospital discharge. ClinicalTrials.gov identifiers: NCT01970072 and NCT03444480.

Development of Ketamine Administration as a Treatment for Chronic PTSD

Posttraumatic stress disorder (PTSD) is a highly prevalent, chronic, and disabling condition for which currently available pharmacotherapies are insufficiently effective. Ketamine, which is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a promising and rapid-acting novel treatment intervention for this disorder. Findings from a proof-of-concept, randomized, controlled crossover study of single-dose intravenous ketamine administration (compared to single-dose midazolam) in patients with chronic PTSD suggest that ketamine is associated with rapid improvement in core PTSD symptoms and comorbid depressive symptoms, and is generally well tolerated. Additional research is needed to confirm its efficacy and safety for patients with PTSD. Results from ongoing trials of repeated intravenous administration for PTSD are expected to yield more definitive evidence. Potential mechanisms of action as well as future research directions are discussed. [ Psychiatr Ann . 2020;50(2):68–76.]

Prolonged Anesthetic Recovery after Continuous Infusion of Midazolam in 2 Domestic Cats (Felis catus).

Two healthy research cats involved in a randomized, blinded prospective pharmacodynamics study evaluating midazolam continuous-rate infusion as a means to decrease sevoflurane concentrations experienced unexpectedly prolonged recoveries. Midazolam loading doses, infusion rates, and the targeted plasma midazolam concentrations at steady-state were determined by pharmacokinetic modeling based on the results of a preliminary pharmacokinetic study using a single dose of midazolam. In the pharmacodynamics study, cats remained oversedated after recovery from anesthesia, and plasma concentrations of midazolam and its primary metabolite (1-hydroxymidazolam) remained elevated. The use of flumazenil was unsuccessful in timely treatment of oversedation. Administration of intravenous lipid emulsion was used in one of the cats to facilitate recovery and appeared to be effective in both reducing the depth of midazolam-induced oversedation and significantly reducing the plasma concentration of 1-hydroxymidazolam. The effects after the administration of both treatment modalities on clinical signs and plasma drug concentrations in cats are discussed. The observations suggest that cats may eliminate 1-hydroxymidazolam more slowly than expected; consequently dose adjustments may be required when continuous infusion of midazolam is intended. In addition, intravenous lipid emulsion may facilitate recovery from midazolam oversedation, particularly in cases unresponsive to traditional treatment modalities. However, further investigations are warranted to delineate the efficacy of this modality in the treatment of midazolam oversedation.

Effects of midazolam on cardiovascular responses and isoflurane requirement during elective ovariohysterectomy in dogs

BackgroundA prospective, randomized, placebo-controlled, blinded clinical study was conducted to determine whether a single dose of midazolam affects the cardiovascular response to surgical manipulation of the ovaries during elective ovariohysterectomy. Thirty-nine client-owned dogs undergoing elective ovariohysterectomy were recruited. After scoring cage demeanour, dogs were premedicated with acepromazine (0.03 mg kg-1) and pethidine (3 mg kg-1) intramuscularly into the quadriceps muscle and 20 min later sedation was scored. Anaesthesia was induced with propofol intravenously (IV) to effect. The study treatment (group M: midazolam (0.25 mg kg-1); or group P: placebo (Hartmann’s solution) (0.125 ml kg-1)) was administered IV before the intra-operative manipulation of the first ovary. Anaesthesia was maintained with isoflurane in oxygen. Morphine (0.3 mg kg-1 IV) was administered prior to the start of surgery. The vaporizer setting was adjusted according to the depth of anaesthesia. If an end-tidal isoflurane concentration (FE’Iso) above 1.6% was required additional analgesia was provided with fentanyl (2 μg kg-1). Dogs received meloxicam (0.2 mg kg-1 IV) at the end of procedure. Heart rate, mean arterial blood pressure, respiratory rate and end-tidal partial pressure of carbon dioxide as well as FE’Iso were recorded and analysed.ResultsA statistical significant difference between groups was detected in FE’Iso, with group M requiring a significantly lower FE’Iso than group P (14.3%) after administration of midazolam. No differences between groups was shown for percentage change in heart rate and mean arterial blood pressure, or end-tidal carbon dioxide and requirement for mechanical ventilation, or rescue analgesia. There was no statistically significant difference in the incidence of complications in group M and P. Group M received significantly more succinylated gelatin solution pre-administration of midazolam than group P, but no differences in fluid administration post-administration of the study treatment (midazolam/placebo) were detected. No statistical significant difference was demonstrated for the use of anticholinergic agents, dobutamine or noradrenaline.ConclusionNo significant effect on cardiovascular parameters could be observed with administration of midazolam, but a modest (14.3%) isoflurane-sparing effect was detected.

Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD)

Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18–70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = −0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.

Inhibitory effect of single and repeated doses of nilotinib on the pharmacokinetics of CYP3A substrate midazolam.

Effects of single and repeated doses of nilotinib on the pharmacokinetics of midazolam, a cytochrome P450 3A (CYP3A) substrate, were assessed in 2 separate studies. In the single-dose nilotinib study, 18 healthy subjects were randomized to 6 treatment sequences to receive single dose of nilotinib 600 mg, midazolam 4 mg, and coadministration of both in a crossover manner. In the repeated-dose nilotinib study, 19 chronic myeloid leukemia patients took a single dose of midazolam 2 mg on days 1 and 13, and nilotinib 400 mg twice daily from days 2-13. In the single-dose study, the geometric mean ratio of the area under the plasma concentration time curve extrapolated to infinity (AUC(inf)) of midazolam plus nilotinib vs. midazolam was 1.3 (90%CI, 1.2-1.5) and the maximum observed serum concentration (C(max)) was 1.2 (90%CI, 1.0-1.4). In the repeated-dose study, the values for AUC(inf) and C(max) were 2.6 (90%CI, 2.1-3.3) and 2.0 (90%CI, 1.7-2.4), respectively. These results indicate that single-dose and repeated-dose administration of nilotinib results in weak and moderate inhibition of CYP3A, respectively. Therefore, appropriate monitoring and dose adjustment may be needed for drugs that are mainly metabolized by CYP3A, and have narrow therapeutic index, when coadministered with nilotinib.

The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects

Lersivirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with a unique resistance profile that exhibits potent antiretroviral activity against wild-type human immunodeficiency virus and clinically relevant NNRTI-resistant strains. Results from in vitro and in vivo investigations suggest that lersivirine is a cytochrome P450 (CYP3A4) inducer that is metabolized by CYP3A4 and uridine diphosphate glucuronosyltransferase (UGT) 2B7. In order to formally assess the effects of lersivirine on CYP3A4 metabolism and/or glucuronidation, we performed studies aimed at investigating the effects of lersivirine co-administration on the pharmacokinetics (PK) of midazolam, ethinylestradiol and levonorgestrel. Two drug-drug interaction studies were performed. Healthy subjects were co-administered (1) single dose midazolam, a prototypical CYP3A4 substrate, followed by 14 days of lersivirine twice daily with single dose midazolam on the final day of lersivirine dosing or (2) 10 days of once-daily (QD) lersivirine and QD oral contraceptives (OCs; ethinylestradiol and levonorgestrel), substrates for CYP3A4, UGT2B7, and/or P-glycoprotein. The effects of co-administration on the PK parameters of midazolam and OCs were assessed. At clinically relevant lersivirine doses (500-1,000 mg total daily dose), the mean plasma exposure of midazolam was reduced in a dose-dependent manner by 20-36 %. Co-administration of lersivirine 1,000 mg QD with OCs had minor PK effects, increasing ethinylestradiol exposure by 10 % and reducing levonorgestrel exposure by 13 %. These data further support previous observations that lersivirine is a weak CYP3A4 inducer, a weak inhibitor of glucuronidation, and a P-glycoprotein inhibitor. In both studies, lersivirine appeared to have a good safety and tolerability profile.

Safety, Pharmacokinetic, and Pharmacodynamic Phase I Dose-Escalation Trial of PF-00562271, an Inhibitor of Focal Adhesion Kinase, in Advanced Solid Tumors

PF-00562271 is a novel inhibitor of focal adhesion kinase (FAK). The objectives of this study were to identify the recommended phase II dose (RP2D) and assess safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF-00562271. Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients. Ninety-nine patients (median age, 60 years; 98% with Eastern Cooperative Oncology Group performance status of 0 or 1) were treated in 12 fasting and three fed cohorts. The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose (MTD) and RP2D. Grade 3 dose-limiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). PF-00562271 exposure increased with increasing dose; serum concentration-time profiles showed characteristic nonlinear disposition. Steady-state exposures were reached within 1 week. On coadministration, geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration-time curve increased by 60% and more than two-fold, respectively. Of 14 patients evaluable by [(18)F]fluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles. The MTD and RP2D of PF-00562271 is 125 mg twice per day with food. PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor. This first-in-class study supports further investigation of FAK as a promising therapeutic target.

The use of oral midazolam for perioperative anxiolysis of healthy patients undergoing Mohs surgery: Conclusions from randomized controlled and prospective studies

Anxiety can complicate any outpatient procedure by causing elevation in blood pressure and heart rate with resultant increase in intraoperative and postoperative bleeding. Anxiety may also reduce patient satisfaction with the surgical experience. Midazolam is an efficacious short-acting benzodiazepine with an excellent safety record. However, little experience is documented on the use of midazolam in outpatient dermatologic surgery. To establish the safety and efficacy of oral midazolam in healthy patients undergoing Mohs micrographic surgery. Patients undergoing outpatient Mohs surgery were randomized in a double-blind, placebo-controlled study of single-dose midazolam for efficacy and safety in producing anxiolysis of short duration. Asubpopulation of patients was evaluated prospectively in a nonrandomized arm of the study. Data on vital signs, anxiety, adverse events, and overall satisfaction were collected and compared using analysis of covariance model. Forty-four patients were randomized and 31 patients were enrolled in the prospective arm. Socioeconomic and surgical characteristics were similar among the groups. At 60 minutes, there was a clinically and statistically significant reduction in anxiety and alertness in both randomized and prospective arms. There were no major adverse events. Patients in all 3 groups were equally satisfied with their experience. Few patients with high perioperative anxiety were willing to participate in a randomized controlled trial of anxiolytic medication. Midazolam is safe and efficacious in perioperative anxiolysis for healthy patients undergoing outpatient Mohs micrographic surgery. Midazolam offers the benefits of amnesia, reduced alertness, and reduced blood pressure with no clinically significant adverse effects.

Balanced propofol sedation administered by nonanesthesiologists: The first Italian experience

To assess the efficacy and safety of a balanced approach using midazolam in combination with propofol, administered by non-anesthesiologists, in a large series of diagnostic colonoscopies. Consecutive patients undergoing diagnostic colonoscopy were sedated with a single dose of midazolam (0.05 mg/kg) and low-dose propofol (starter bolus of 0.5 mg/kg and repeated boluses of 10 to 20 mg). Induction time and deepest level of sedation, adverse and serious adverse events, as well as recovery times, were prospectively assessed. Cecal intubation and adenoma detection rates were also collected. Overall, 1593 eligible patients were included. The median dose of propofol administered was 70 mg (range: 40-120 mg), and the median dose of midazolam was 2.3 mg (range: 2-4 mg). Median induction time of sedation was 3 min (range: 1-4 min), and median recovery time was 23 min (range: 10-40 min). A moderate level of sedation was achieved in 1561 (98%) patients, whilst a deep sedation occurred in 32 (2%) cases. Transient oxygen desaturation requiring further oxygen supplementation occurred in 8 (0.46%; 95% CI: 0.2%-0.8%) patients. No serious adverse event was observed. Cecal intubation and adenoma detection rates were 93.5% and 23.4% (27.8% for male and 18.5% for female, subjects), respectively. A balanced sedation protocol provided a minimalization of the dose of propofol needed to target a moderate sedation for colonoscopy, resulting in a high safety profile for non-anesthesiologist propofol sedation.

Investigation of the Pharmacokinetic Interactions of Deferasirox, a Once‐Daily Oral Iron Chelator, With Midazolam, Rifampin, and Repaglinide in Healthy Volunteers

Deferasirox, a newly developed iron chelator, was coadministered orally with either a known inducer of drug metabolism or with cosubstrates for cytochrome P450 (CYP) to characterize the potential for drug-drug interactions. In the induction assessment, single-dose deferasirox pharmacokinetics were obtained in the presence and absence of a repeated-dose regimen of rifampin. In the CYP3A interaction evaluation, midazolam and its active hydroxylated metabolite were assessed after single doses of midazolam in the presence and absence of steady-state concentrations of deferasirox. To test for interaction at the level of CPY2C8, single-dose repaglinide pharmacokinetics/pharmacodynamics were determined with and without repeated-dose administration of deferasirox. After rifampin, a significant reduction (44%) in plasma exposure (AUC) to deferasirox was observed. Upon coadministration of midazolam, there was a modest reduction of up to 22% in midazolam exposure (AUC, C(max)), suggesting a modest induction of CYP3A4/5 by deferasirox. Def erasirox caused increases in repaglinide plasma C(max) and AUC of 1.5-fold to over 2-fold, respectively, with little change in blood glucose measures. Specific patient prescribing recommendations were established when coadministering deferasirox with midazolam, repaglinide, and rifampin. These recommendations may also apply to other substrates of CYP3A4/5 and CYP2C8 or potent inducers of glucuronidation.

The Effect of Multiple‐Dose, Oral Rifaximin on the Pharmacokinetics of Intravenous and Oral Midazolam in Healthy Volunteers

To evaluate the potential of rifaximin, an oral nonabsorbed (< 0.4%) structural analog of rifampin, to induce human hepatic and/or intestinal cytochrome P450 (CYP) 3A enzymes, with use of a known CYP3A probe, midazolam. Prospective, randomized, open-label, two-period, crossover study. Clinical research center. Twenty-seven healthy adult volunteers. During the first treatment period, subjects received a single dose of either intravenous midazolam 2 mg over 30 minutes or oral midazolam 6 mg on day 0. From days 3-10, they received rifaximin 200 mg every 8 hours. On days 6 (after the 9th dose of rifaximin) and 10 (after the 21st dose of rifaximin), subjects received a concomitant single dose of intravenous or oral midazolam. After a 15-day washout period, subjects were crossed over to the other formulation of midazolam, and the treatment schedule was repeated, with the second treatment period starting on day 26 and single-dose administration of midazolam on days 26, 32, and 36. Serial plasma samples were collected for pharmacokinetic analyses. The pharmacokinetic parameters of single-dose intravenous or oral midazolam were determined alone and after coadministration of rifaximin for 3 and 7 days. Rifaximin coadministration did not alter the measured pharmacokinetic parameters for midazolam or its major metabolite, 1'-hydroxymidazolam. The 90% confidence intervals for the maximum concentration and area under the concentration-time curve from time zero extrapolated to infinity (bioavailability) were all within 80-125% for intravenous and oral midazolam. Therefore, no drug interaction was observed between rifaximin and midazolam. Coadministration of midazolam and rifaximin was well tolerated. Overall, 3-7 days of rifaximin 200 mg 3 times/day did not alter single-dose midazolam pharmacokinetics. Rifaximin also does not appear to induce intestinal or hepatic CYP3A activity.

Lack of a pharmacokinetic interaction between steady-state roflumilast and single-dose midazolam in healthy subjects.

The aim of this study was to investigate the effects of roflumilast, an investigational PDE4 inhibitor for the treatment of COPD and asthma, on the pharmacokinetics of the CYP3A probe drug midazolam and its major metabolites. In an open, randomized (for midazolam treatment sequence) study, 18 healthy male subjects received single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart) alone, repeated doses of roflumilast (500 microg once daily for 14 days) alone, and repeated doses of roflumilast together with single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart). A comparison of clearance and peak and systemic exposure to midazolam following administration of roflumilast indicated no effect of roflumilast dosed to steady state on the pharmacokinetics of midazolam. Point estimates (90% CI) were 0.97 (0.84, 1.13) for the AUC of i.v. midazolam and 0.98 (0.82, 1.17) for that of oral midazolam with and without roflumilast. Therapeutic steady state concentrations of roflumilast and its N-oxide do not alter the disposition of the CYP3A substrate midazolam in healthy subjects. This finding suggests that roflumilast is unlikely to alter the clearance of drugs that are metabolized by CYP3A4.

Drug-Metabolizing Enzyme Inhibition by Ketoconazole Does Not Reduce Interindividual Variability of CYP3A Activity as Measured by Oral Midazolam

Variable interindividual expression of cytochrome P450 3A presents a challenge in dosing drugs. The use of potent inhibitors of CYP3A such as ketoconazole has been explored to reduce the clearance of CYP3A substrates, thereby resulting in smaller dose requirements; however, the impact of CYP3A inhibition on interindividual variability has not been well characterized. Our objective was to examine the effect of ketoconazole inhibition on CYP3A metabolic variability as measured by the CYP3A biomarker oral midazolam. A single dose of midazolam (0.075 mg/kg) was administered to 19 healthy Caucasian adults (38.7 +/- 8.8 years, nine male/10 female) at baseline and concurrently with ketoconazole (400 mg daily for 10 days) on day 6 or 9 of ketoconazole. Plasma samples were collected over 6 to 30 h. A paired t test and percent coefficient of variation (CV%) were used to evaluate differences in midazolam clearance and interindividual variability during both phases. Monte Carlo simulation was performed to determine probability distribution of area under the concentration-time curves (AUCs). Midazolam apparent oral clearance decreased by 89% (p < 0.0001) during inhibition. Cmax increased from 23 ng/ml (95% CI 19-29 ng/ml) to 55 ng/ml (95% CI 46-66 ng/ml), p < 0.0001. CV% increased from 41 to 58% from baseline to ketoconazole inhibition. AUCs [median (range)] were 0.20 mg . min/ml (0.05-0.81 mg . min/ml) and 1.94 mg . min/ml (0.25-25.4 mg . min/ml) at baseline and inhibition phase, with CV% of 41 and 61%, respectively. Ketoconazole decreased CYP3A activity but did not reduce interindividual variability. Use of a CYP3A inhibitor to standardize dosing of CYP3A substrates may not be feasible in clinical practice.

Pediatric Cinnarizine Overdose and Toxicokinetics

Cinnarizine, a piperazine derivative, is a widely prescribed medication for the treatment of vestibular disorders and motion sickness. Cinnarizine has antihistaminic, antiserotoninergic, antidopaminergic, and calcium channel-blocking properties. We present the first report in the English literature of cinnarizine poisoning and toxicokinetics. A 30-month-old toddler ingested 225 mg of cinnarizine, 18 times the recommended dose for older children. Four hours later, she became jittery with a wide-based gait and vomited 3 times. She was examined by her family physician, who reported stupor and twitching in both hands. On admission to the hospital, 6 hours after the ingestion, she was stuporous and had 3 short, generalized tonic-clonic convulsions that were controlled with a single dose of midazolam. Full clinical recovery was seen 10 hours after ingestion. Serum cinnarizine levels were 7407, 2629, and 711 ng/mL on admission and at 4 and 12 hours thereafter, respectively, 26.9 times higher than the therapeutic levels in adults. Elimination rate constant, calculated by linear regression of the ln concentrations of the 3 data points, was 0.19. Half-life, calculated from the equation t(1/2) = 0.693/kel, where kel is the elimination rate constant, was 3.65 hours. The manufacturing company revealed that their database contains 23 reports of cinnarizine overdose (adult and children), received between 1972 and 2004. Clinically, these cases reflect mainly symptoms of alterations in consciousness ranging from somnolence to stupor and coma, vomiting, extrapyramidal symptoms, and hypotonia. In a small number of young children, convulsions developed; recovery was uneventful in 4 cases and not reported in 1. The neurologic complication may be explained by the antihistaminic effect of cinnarizine because central nervous system depression and convulsions are known complications of antihistaminic overdose. It is hypothesized that cinnarizine-induced convulsions also are related to the antidopaminergic effect of the drug. Apart from the convulsions, no other adverse effects related to calcium channel-blocking properties, such as bradycardia or hemodynamic instability, were observed. Pediatric patients with cinnarizine overdose need to be observed in a health care facility for potential neurologic complications and be treated symptomatically. The delay to onset of clinical effect should be considered in the observation period.

Cerebral and plasma kinetics of a high dose of midazolam and correlations with its respiratory effects in rats

Benzodiazepine poisoning causes coma and respiratory depression. Our objective was to determine whether, and to what extent, arterial blood gas disturbances correlated with blood or cerebral kinetics of midazolam. A 160 mg kg −1 single dose of midazolam was infused intravenously over 20 min in catheterized male Sprague–Dawley rats. Midazolam kinetics was simultaneously determined in plasma and brain using striatal microdialysis. Midazolam concentrations were measured using a high-performance liquid chromatographic assay with ultraviolet detection. Midazolam (160 mg kg −1) reproducibly induced deep coma with respiratory acidosis. Plasma midazolam kinetics was well described by a bi-exponential model, with an elimination half-life of 6.4 ± 1.8 h. The striatal dialysate concentration peaked at 50.0 ± 8.9 min after the end of infusion, with a significant delay to peak concentration compared to plasma. Respiratory depression, assessed by the elevation in PaCO 2, was more closely correlated with midazolam striatal dialysate rather than plasma kinetics. These results suggest a central mechanism for midazolam respiratory effects at toxic doses in rats. In conclusion, our study showed a delayed onset in peak PaCO 2 and pH effects after the slow infusion of a toxic dose of midazolam in rats. The effects on arterial blood gases were better correlated with midazolam striatal concentrations than with plasma concentrations. This study may contribute to better understanding of benzodiazepine-induced respiratory depression in poisonings.