A Pooled Analysis Evaluating Renal Safety in Placebo- and Active Comparator-Controlled Phase III Trials of Multiple-Dose Injectable HPßCD-Diclofenac in Subjects with Acute Postoperative Pain.

OBJECTIVE : While injectable nonsteroidal anti-inflammatory drugs (NSAIDs) are a key component of postoperative multimodal analgesia, renal safety concerns may limit use in some patients. This study examined the renal safety of injectable HPßCD-diclofenac when given for ≤ 5 days following orthopedic or abdominal/pelvic surgery. METHODS : Pooled analysis of data from two randomized, placebo- and active comparator-controlled phase III trials in 608 total patients was conducted. Renal safety was assessed by examining treatment-emergent adverse events (AEs) and postoperative blood urea nitrogen (BUN) and serum creatinine shifts. RESULTS : There were three renal AEs each in the HPßCD-diclofenac (n = 318 patients) and placebo (n = 148 patients) groups, and two renal AEs in the ketorolac group (n = 142 patients). No significant difference in renal AE risk was detected for patients receiving HPßCD-diclofenac (RR: 1.40 [0.15,13.3]; P = 0.75) or ketorolac (RR: 2.08 [0.19,22.7]; P = 0.56) versus placebo. All renal AEs were mild or moderate in severity, and a single renal AE (acute renal failure in a patient receiving HPßCD-diclofenac) was treatment-related. One incidence of postoperative shift to high (> upper limit of normal) serum creatinine occurred in the HPßCD-diclofenac group (n = 2 in the ketorolac group). Mean changes in serum creatinine or BUN did not differ significantly between patients receiving HPßCD-diclofenac and placebo. CONCLUSIONS : While this analysis examined relatively brief exposure typical for parenterally administered analgesics in the postoperative setting in patients with largely normal renal function, the results suggest that HPßCD-diclofenac use for acute postoperative pain may not be associated with added renal safety risks over placebo in this patient population.

Safety of a novel parenteral formulation of diclofenac after major orthopedic or abdominal/pelvic surgery in a population including anticoagulated, elderly or renally insufficient patients: an open-label, multiday, repeated dose clinical trial.

OBJECTIVE: Decisions to use or avoid nonsteroidal anti-inflammatory drugs (NSAIDs) for postsurgical pain are often influenced by concerns about bleeding and renal adverse effects. The objective of this study was to evaluate the safety of a novel parenteral NSAID, hydroxypropyl-ß-cyclodextrin (HPßCD) diclofenac, in a large postsurgical patient population, with particular focus on bleeding and renal effects. METHODS: This was a large open-label study in adult patients with acute moderate-to-severe pain following major surgery. Patients received ≥2 days of continuous treatment with HPßCD diclofenac, administered as a small-volume bolus injection every 6 hours. Few exclusion criteria were applied in order to reflect surgical patient populations commonly managed in clinical practice. Adverse events (AEs) were recorded throughout the study. The incidences of bleeding- and renal-related AEs were examined in patient subpopulations with known risk factors for NSAID-induced complications: advanced age, pre-existing renal insufficiency, concomitant anticoagulant use, prolonged exposure, elevated dosage, and major surgeries. RESULTS: Of the total 971 patients studied, 38% were ≥65 years old (12% >75 years), 62% received concomitant anticoagulants, and 6% had pre-existing renal insufficiency. HPßCD diclofenac was well tolerated by the patient population. AE rates are presented by risk factor to enable clinicians to better describe renal- or bleeding-related AEs. CONCLUSIONS: In addition to its previously demonstrated efficacy, this study provides evidence of HPßCD diclofenac's safety in a large postsurgical population including anticoagulated, elderly or renally insufficient patients. Because study exclusion criteria were minimal, these findings may be broadly generalizable to populations commonly treated in clinical practice.

Safety of Injectable HPßCD-Diclofenac in Older Patients with Acute Moderate-to-Severe Postoperative Pain: A Pooled Analysis of Three Phase III Trials.

BACKGROUND: Hydroxypropyl-ß-cyclodextrin-diclofenac (HPßCD-diclofenac) is an NSAID used to treat acute moderate-to-severe postoperative pain. This post hoc analysis investigated the safety of HPßCD-diclofenac in patients aged ≥ 65 years. METHODS: Data from three phase III trials of HPßCD-diclofenac in adult patients with acute moderate-to-severe postoperative pain were pooled (NCT00448110, NCT00507026, and NCT00726388). Patients who received one or more dose of HPßCD-diclofenac or placebo were included and stratified according to age: < 65, 65-74, or ≥ 75 years. Numerical and categorical variables were compared across the groups using ANOVA and Cochran-Mantel-Haenszel tests, respectively. Cochran-Mantel-Haenszel relative risks compared with placebo were calculated, adjusted by study. RESULTS: Overall, 1289 patients were included: 878, 282, and 129 in the < 65, 65-74, and ≥ 75-years groups, respectively. Overall incidence of treatment-emergent adverse events (TEAEs) was similar in the three groups (p = 0.4360). Incidences of postoperative anemia (p < 0.0001), constipation (p = 0.0017), and hypotension (p = 0.0003) increased significantly across the age groups, whereas headache (p = 0.0008) and flatulence (p = 0.0118) decreased significantly. Relative risks for all System Organ Class categories and preferred terms investigated were similar among the groups and similar to placebo. CONCLUSIONS: Overall incidence of TEAEs in patients aged 65-74 or ≥ 75 years was similar to patients aged < 65 years. The groups displayed similar relative risks for the most frequent TEAEs, which were all similar to placebo. The TEAE profiles of the groups showed differences, all of which may be anticipated due to age-related differences in susceptibility and the types of surgery most commonly performed in each group. CLINICALTRIALS. GOV IDENTIFIERS: NCT00448110, NCT00507026, and NCT00726388.

Pharmacokinetics of Diclofenac and Hydroxypropyl-ß-Cyclodextrin (HPßCD) Following Administration of Injectable HPßCD-Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment.

Given their established analgesic properties, nonsteroidal anti-inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl-ß-cyclodextrin (HPßCD) following administration of the injectable NSAID HPßCD-diclofenac; and (2) the PK of HPßCD following administration of HPßCD-diclofenac and intravenous itraconazole formulated with HPßCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (Vz ) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between Vz (but not CL or elimination half-life, t½ ) and renal function. HPßCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t½ . There were no significant differences in diclofenac or HPßCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPßCD in healthy subjects following HPßCD-diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (<5% without adjustment). With respect to PK properties, these results suggest that HPßCD-diclofenac might be administered to patients with mild or moderate renal insufficiency or mild hepatic impairment without dose adjustment (NCT00805090).

Postoperative opioid sparing with injectable hydroxypropyl-ß-cyclodextrin-diclofenac: pooled analysis of data from two Phase III clinical trials.

PURPOSE: Use of nonopioid analgesics (including nonsteroidal anti-inflammatory drugs) for postoperative pain management can reduce opioid consumption and potentially prevent opioid-related adverse events. This study examined the postoperative opioid-sparing effect of repeated-dose injectable diclofenac formulated with hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac. PATIENTS AND METHODS: Pooled data from two double-blind, randomized, placebo- and active comparator-controlled Phase III trials were analyzed. Patients received HPßCD-diclofenac, placebo, or ketorolac by intravenous injection every 6 hours for up to 5 days following abdominal/pelvic or orthopedic surgery. Rescue opioid use was evaluated from the time of first study drug administration to up to 120 hours following the first dose in the overall study population and in subgroups defined by baseline pain severity, age, and HPßCD-diclofenac dose. RESULTS: Overall, 608 patients received ≥1 dose of study medication and were included in the analysis. While 93.2% of patients receiving placebo required opioids, the proportion of patients requiring opioids was significantly lower for patients receiving HPßCD-diclofenac (18.75, 37.5, or 50 mg) or ketorolac (P<0.005 for all comparisons). Mean cumulative opioid dose and number of doses were significantly lower among patients receiving HPßCD-diclofenac versus placebo for the 0-24 through 0-120 hour time periods (P<0.0001), as well as versus ketorolac for the 0-72 through 0-120 hour time periods (P<0.05). HPßCD-diclofenac significantly reduced opioid consumption versus placebo in subgroups based on baseline pain severity (moderate, severe) and age (<65 years, ≥65 years) from the 0-24 hour period onward. When compared to ketorolac, HPßCD-diclofenac also significantly reduced cumulative opioid consumption among patients with moderate baseline pain (0-72 through 0-120 hours) and opioid dose number among patients ≥65 years old (0-24 through 0-120 hours). CONCLUSION: HPßCD-diclofenac can reduce postoperative opioid requirements. As this analysis was not powered to compare opioid-related adverse event rates, follow-up studies examining the clinical impact of HPßCD-diclofenac's opioid sparing are warranted.

A Phase I study evaluating the effect of age and weight on the pharmacokinetics of an injectable formulation of diclofenac solubilized with hydroxypropyl-ß-cyclodextrin.

PURPOSE: The analgesic and opioid-sparing effects of nonsteroidal anti-inflammatory drugs can be beneficial in postoperative populations. Hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac is an injectable formulation of diclofenac solubilized with HPßCD that is administered as a low-volume intravenous bolus. This open-label, single-dose study examined the effects of age and weight on the pharmacokinetic (PK) profile of HPßCD-diclofenac. METHODS: Eighty-eight adult volunteers were enrolled. An age-based cohort included 34 subjects 55-82 years old stratified into three groups and receiving HPßCD-diclofenac 18.75 mg. A weight-based cohort included 54 subjects stratified into five groups based on body weight and body mass index and receiving HPßCD-diclofenac 37.5 mg. PK analysis was performed on blood samples collected predosing and at predefined intervals (5, 10, 20, 30, and 45 minutes; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 18 hours) postdosing. Diclofenac PK parameters were examined in the individual cohorts, and regression analyses of the relationship between age, weight, and PK parameters were performed on pooled data from all enrolled subjects. RESULTS: Examination of the age-based cohort revealed similar diclofenac PK parameters across age groups. PK parameters were likewise similar across weight groups in the weight-based cohort. Regression analysis on pooled data from the age- and weight-based cohorts revealed that increasing body weight was associated with a significant increase in diclofenac clearance (CL), suggesting decreased exposure in high-weight patients. Analysis of the pooled population also demonstrated an inverse relationship between age and elimination half-life (t1/2), likely due to a decrease in the volume of distribution (Vz) with increased age, not a change in CL. There were no deaths, serious adverse events, or adverse events that led to discontinuation. CONCLUSION: This study suggests that the CL of diclofenac is not dependent on age in elderly subjects receiving HPßCD-diclofenac but indicates that diclofenac CL increases with increasing body weight.

Cardiovascular safety of hydroxypropyl-ß-cyclodextrin-diclofenac in the management of acute postsurgical pain: a pooled analysis of 2 randomized, double-blind, placebo- and active comparator-controlled phase III clinical trials.

STUDY OBJECTIVE: Long-term use of nonsteroidal anti-inflammatory drugs, including selective and nonselective cyclooxygenase inhibitors, has been suggested to be associated with cardiovascular (CV) safety risks. Data are limited regarding CV risks associated with short-term nonsteroidal anti-inflammatory drug use, including injectable formulations, although it has been suggested that even a single dose may increase CV adverse event (AE) risk. The objective of this study was to examine the CV safety of an injectable diclofenac formulation solubilized with hydroxypropyl-ß-cyclodextrin (HPßCD) when given for ≤5days postoperatively. DESIGN: A pooled analysis of CV AEs from 2 pivotal phase III clinical trials examining the efficacy and safety of intravenous (IV) HPßCD-diclofenac vs placebo and the active comparator ketorolac was conducted. SETTING: Postoperative, with treatment initiated in the postanesthesia care unit ≤6hours postsurgery. PATIENTS: Overall, 608 abdominal/pelvic and orthopedic surgery patients met inclusion criteria and received ≥1 study medication dose. INTERVENTIONS: Patients received either HPßCD-diclofenac, ketorolac, or placebo via IV bolus injection every 6hours, for ≤5days postsurgery. MEASUREMENTS: CV AEs, reported by study investigators, were evaluated through the treatment period and follow-up (≤37days after last study medication dose), and relative CV AE risks were estimated. MAIN RESULTS: IV HPßCD-diclofenac was not associated with increased treatment-emergent CV AE incidence vs placebo (11.6% vs 12.2%; relative risk, 0.96 [95% confidence interval, 0.56-1.62]). Serious CV AEs as well as treatment-related AEs were uncommon, and there were no reports of myocardial infarction or cerebrovascular accident. CV AEs were uncommon during the follow-up period, occurring in 1.3%, 0%, and 1.4% of patients in the HPßCD-diclofenac, ketorolac, and placebo groups, respectively. CONCLUSIONS: Although a longer duration follow-up study in a larger patient population would expand our understanding of potential CV risks, the present analysis suggests that postoperative use of HPßCD-diclofenac does not present an added CV safety risk over placebo.

Single-dose and multiple-dose pharmacokinetics and dose proportionality of intravenous and intramuscular HPßCD-diclofenac (Dyloject) compared with other diclofenac formulations.

STUDY OBJECTIVE: To evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. DESIGN: Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. SETTING: Clinical research center. SUBJECTS: Healthy adult volunteers. INTERVENTION: Study 1: Subjects received HPßCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPßCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods. MEASUREMENTS AND MAIN RESULTS: Study 1: IV HPßCD-diclofenac had a higher peak plasma concentration (Cmax ) and earlier time to reach maximum plasma concentration (Tmax ), but equivalent plasma exposure (area under the curve from time zero to t [AUC0-t ]) to IV Voltarol. The geometric mean ratio of HPßCD-diclofenac (IV) to Voltarol (IV) for AUC0-t was 106.27%. The geometric mean ratio of HPßCD-diclofenac (IM) to Voltarol (IM) for AUC0-t was 110.91%. The geometric mean ratio of HPßCD-diclofenac (IV) to HPßCD-diclofenac (IM) for AUC0-t was 101.25%. The geometric mean ratio of HPßCD-diclofenac (IM) to Voltarol (IV) for AUC0-t was 104.96%. Study 2: Cmax for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPßCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ng·hour/ml) and 37.5 mg (1843 ng·hour/ml) IV HPßCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ng·hour/ml). CONCLUSIONS: Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPßCD-diclofenac compared with Voltarol and after IM administration of HPßCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPßCD-diclofenac was equivalent to IV administration of HPßCD-diclofenac and IV administration of Voltarol. Study 2: HPßCD-diclofenac showed dose proportionality after single- and multiple-dose administration and no accumulation of HPßCD-diclofenac. HPßCD-diclofenac was safe and well tolerated following IV and IM administration.

Effects of injectable HPßCD-diclofenac on the human delayed rectifier potassium channel current in vitro and on proarrhythmic QTc in vivo.

BACKGROUND: Novel formulations and administration routes of established drugs may result in higher maximum concentrations or total exposures and potentially cause previously unrecognized adverse events. OBJECTIVE: This study evaluated the proarrhythmic potential of hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac, a novel injectable diclofenac formulation solubilized with hydroxypropyl-ß-cyclodextrin (HPßCD), on ventricular electrical conduction in preclinical and clinical models. METHODS: We assessed the effects of diclofenac, HPßCD, and HPßCD-diclofenac on the human delayed rectifier potassium channel (IKr) using human embryonic kidney (HEK) 293 cells transfected with a human ether-à-go-go-related gene (hERG) using whole-cell patch-clamp. In a single-dose, active- and placebo-controlled, 4-period crossover, thorough QT in vivo study, 70 healthy volunteers (mean age, 23.3 years; range, 18-49 years; 55.75% male) received HPßCD-diclofenac at 37.5- and 75-mg doses, inactive vehicle (placebo), and an active control (moxifloxacin). RESULTS: In vitro, diclofenac produced no statistically significant effect on IKr. Significant, non-dose-dependent effects were observed in the presence of HPßCD or HPßCD-diclofenac of similar magnitude across the 300-fold dose range of concentrations tested, suggesting an artifact due to the detergent effect of HPßCD in this in vitro model. In vivo, neither HPßCD-diclofenac dose resulted in QTc prolongation ≥2 ms (≥5 ms is the threshold of clinical concern). No correlation was evident between changes in QTc and plasma concentrations of diclofenac or HPßCD. Confirming study sensitivity, moxifloxacin produced a mean QTc prolongation >10 ms. CONCLUSIONS: The findings from the present study suggest that HPßCD-diclofenac does not have a dose-dependent effect in the in vitro hERG assay system and does not produce proarrhythmic QTc prolongation in vivo. ClinicalTrials.gov identifier: NCT01812538.

A multicenter, open-label, exploratory dose-ranging trial of intranasal hydromorphone for managing acute pain from traumatic injury.

UNLABELLED: We conducted a prospective multicenter, open-label, escalating dose-range trial to compare, across patients, single intranasal doses (2, 4, 6, 8, and 10 mg) of hydromorphone HCl in the treatment of acute trauma pain The main outcome measure of pain-intensity reduction was derived from serial Numerical Pain-Rating Scores and calculated as the summed pain-intensity difference over 3 hours (SPID 3). Nasal examinations, vital signs, and adverse events were reported as safety outcomes. The mean decrease in pain intensity from baseline to 30 minutes was 39 to 44% for the 4-, 6-, 8- and 10-mg doses (n = 19, 33, 28, and 19 per group) and only 24% reduction for the 2-mg dose (n = 14). SPID 3 for the 2-mg dose was 40 to 50% below all other doses. There were no clinically meaningful changes in vital signs or nasal examinations. Adverse events (nausea, vomiting, pruritus, oxygen desaturation, bad taste, dizziness) were of mild to moderate intensity, increased with dose, and expected, based on route of administration and opioid pharmacology. Intranasal hydromorphone provides a component of rapid pain relief in the care of emergency department patients suffering from acute trauma pain. PERSPECTIVE: This article presents a pilot dose-ranging study of intranasally administered hydromorphone, administered in the emergency department to patients suffering from acute trauma pain. This study demonstrates research success in this setting and noninjection-based delivery and certain doses of intranasal hydromorphone may be effective in treating acute trauma pain.

The dose response and effects of dexamethasone on bupivacaine microcapsules for intercostal blockade (T9 to T11) in healthy volunteers.

Biodegradable microcapsules containing bupivacaine/dexamethasone produce an anesthetic duration of 7-11 days in animal models. In this investigation, we explored the effect of increasing doses (Part 1) and the effect of including dexamethasone (Part 2) on the onset, density, and duration of analgesia and anesthesia produced by bupivacaine microcapsules. Concentrations ranging from 0.3125% to 5.0% in microcapsules were compared with 0.25% aqueous bupivacaine (bilateral injection, three intercostal nerves, 2 mL per nerve) (Part 1). Part 2 compared 2.5% microcapsules with or without the inclusion of dexamethasone by unilateral blockade. Sensory block was assessed by pinprick, temperature sensation, and subjective numbness (0, not numb; 10, totally numb). Pharmacodynamic assessments and plasma drug concentrations of bupivacaine and dexamethasone were measured for 96 h. The onset time was reduced and the duration of analgesia increased over the 0.3125%-5.0% dose range (P < 0.02). Onset with 2.5% microcapsules approximated that of 0.25% aqueous bupivacaine. Microcapsule block duration increased to at least 96 h and was significantly longer than aqueous bupivacaine (P < 0.001). Inclusion of dexamethasone increased the duration of pinprick anesthesia in 2.5% microcapsules (P = 0.03). We conclude that bupivacaine/dexamethasone microcapsules are well tolerated and demonstrate a dose-related effect in onset and duration of intercostal blockade. Inclusion of dexamethasone increases intercostal block anesthesia.

Dexamethasone prolongs local analgesia after subcutaneous infiltration of bupivacaine microcapsules in human volunteers.

BACKGROUND: The addition of small amounts of dexamethasone to extended-release formulations of bupivacaine in microcapsules has been found to prolong local analgesia in experimental studies, but no clinical data are available. METHODS: In a double-blinded study, 12 healthy male volunteers were randomized to receive simultaneous subcutaneous injections of bupivacaine microcapsules with dexamethasone and bupivacaine microcapsules without dexamethasone in each calf. Local analgesia was assessed with a validated human pain model; main parameters evaluated were thermal, mechanical, and pain detection thresholds and suprathreshold responses to heat and mechanical stimulation. Measurements were performed every 2 h for the first 8 h and daily for the week after injection. Primary endpoints were evaluation of maximal analgesic effect, time of onset, and duration of analgesia. Summary measures (area under curve [AUC]) were considered best estimate of analgesia. Safety evaluations were performed daily for the first week and at 2 weeks, 6 weeks, and 6 months after injection. RESULTS: The addition of dexamethasone significantly prolonged local analgesia of bupivacaine microcapsules without influence on maximal analgesic effect. AUC in all thermal measurements and the sensory mechanical threshold were significantly increased between 1-7 days after drug injection in the group given dexamethasone compared with the group not given dexamethasone. No serious side effects were observed. CONCLUSIONS: Addition of small amounts of dexamethasone to bupivacaine incorporated in microcapsules prolonged local analgesia compared with microcapsules with plain bupivacaine after subcutaneous administration in humans.

Bupivacaine in microcapsules prolongs analgesia after subcutaneous infiltration in humans: a dose-finding study.

In this study, we examined the onset and duration of local analgesic effects of bupivacaine incorporated into biodegradable microcapsules (extended-duration local anesthetic; EDLA) administered as subcutaneous infiltrations in different doses in humans. In 18 volunteers, the skin on the medial calf was infiltrated with 10 mL of EDLA, and the opposite calf was infiltrated with 10 mL of aqueous bupivacaine (5.0 mg/mL) in a double-blinded, randomized manner. Three different concentrations of EDLA were tested (6.25, 12.5, and 25 mg/mL), with 6 subjects in each group. Pain responses to mechanical and heat stimuli and sensory thresholds (touch, warm, and cold detection thresholds) were examined by von Frey hairs and contact thermodes. Assessments were made before and 2, 4, 6, 8, 24, 48, 72, 96, and 168 h after the injections. Safety evaluations were performed daily for the first week and at 2 wk, 6 wk, and 6 mo after the injections. The time to maximum effects was significantly shorter for aqueous bupivacaine (2-6 h) than for EDLA (4-24 h), but there were no significant differences between the maximum effects of EDLA and aqueous bupivacaine. From 24 to 96 h after the injections, EDLA was significantly more efficient than aqueous bupivacaine for all variables, and significant effects of EDLA were demonstrated for at least 96 h for all variables. In general, a dose-response gradient was seen in the EDLA group for 5 of 7 variables when the curves expressing effect over time for the different concentrations were evaluated. No serious side effects were observed for up to 6 mo after administration. In conclusion, bupivacaine incorporated in microcapsules provided analgesia for 96 h after subcutaneous infiltration.

Thiopental and propofol affect different regions of the brain at similar pharmacologic effects.

Propofol has a greater amnesic effect than thiopental. In this study we tested whether different brain regions were affected by propofol and thiopental at similar drug effects. Changes in regional cerebral blood flow (rCBF) were identified by using SPM99 analysis of images obtained with positron emission tomography with (15)O water. Ten right-handed male volunteers (age, 35 +/- 10 yr; weight, 74.1 +/- 7.5 kg; mean +/- sd) were randomized to receive thiopental (n = 4) or propofol (n = 6) to target sedative and hypnotic concentrations with bispectral index (BIS) monitoring. Four positron emission tomography images were obtained during various tasks at baseline and with sedative and hypnotic effects. Two participants receiving propofol were unresponsive at sedative concentrations and were not included in the final analyses. Median serum concentrations were 1.2 and 2.7 microg/mL for sedative and hypnotic propofol effects, respectively. Similarly, thiopental concentrations were 4.8 and 10.6 microg/mL. BIS decreased similarly in both groups. The pattern of rCBF change was markedly different for propofol and thiopental. Propofol decreased rCBF in the anterior (right-sided during sedation) brain regions, whereas thiopental decreased rCBF primarily in the cerebellar and posterior brain regions. At similar levels of drug effect, propofol and thiopental affect different regions of the brain. These differences may help to identify the loci of action for the nonsedative effects of propofol, such as amnesia.

A model to evaluate the pharmacokinetic and pharmacodynamic variables of extended-release products using in vivo tissue microdialysis in humans: bupivacaine-loaded microcapsules.

UNLABELLED: Biodegradable microcapsules produce an ultra-long duration of local anesthesia. We hypothesized that this duration is caused by the sustained-release of bupivacaine from the microcapsules into the surrounding tissue. Previous studies investigated the pharmacokinetics (PKs) of bupivacaine after release from microcapsules and absorption into the systemic circulation. Microdialysis sampling can determine the PKs of any drug at its site of injection. This study was performed to characterize the PKs of bupivacaine and dexamethasone released from microcapsules at a subcutaneous injection site over a 96-h period in volunteers. Bupivacaine concentrations were compared with clinical variables of local anesthetic blockade. This study demonstrates that bupivacaine is released in a sustained manner from microcapsules, that bupivacaine concentrations increase for 24-34 h after microcapsule injection, and that analgesia parallels the tissue bupivacaine concentration obtained by microdialysis. Analgesia was equally rapid in onset with aqueous and microcapsule bupivacaine (P = 0.23). Analgesia was still present at 78% of microcapsule-injected sites after 96 h, significantly longer than for aqueous bupivacaine (P < 0.001). Mild pruritus was the most common side effect, occurring with 56% of the microcapsule injections. Dexamethasone-containing bupivacaine microcapsules are well tolerated and produce a prolonged duration of skin analgesia. Systemic absorption of bupivacaine produces higher peak plasma levels after aqueous injection than after microcapsule injection, despite the injection of a threefold larger load of bupivacaine in the latter. IMPLICATIONS: Microcapsules loaded with bupivacaine and dexamethasone and administered by subcutaneous injection produce prolonged cutaneous anesthesia and analgesia. Determination of local tissue pharmacokinetic variables of bupivacaine by microdialysis confirms that the prolonged duration of anesthesia is caused by the extended release characteristics of the microcapsules.