Robert J. Noveck

Blocking of Responses to Endotoxin by E5564 in Healthy Volunteers with Experimental Endotoxemia

E5564 is a second-generation synthetic analogue of the lipid A component of endotoxin (lipopolysaccharide [LPS]). The ability of E5564 to block the toxic activity of LPS was assessed in a double-blind, placebo-controlled study. A bolus infusion of endotoxin (4 ng/kg) was administered to healthy subjects to induce a mild transient syndrome similar to clinical sepsis. Single E5564 doses of 50-250 microg ameliorated or blocked all of the effects of LPS in a dose-dependent manner. All E5564 dose groups had statistically significant reductions in elevated temperature, heart rate, C-reactive protein levels, white blood cell count, and cytokine levels (tumor necrosis factor-alpha and interleukin-6), compared with placebo (P<.01). In doses of > or = 100 microg, E5564 acted as an LPS antagonist and completely eliminated these signs. E5564 also blocked or ameliorated LPS-induced fever, chills, headache, myalgia, and tachycardia (P<.01). These results demonstrate that E5564 blocks the effects of LPS in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis.

Parecoxib Sodium does not Impair Platelet Function in Healthy Elderly and Non-Elderly Individuals

ObjectiveTo compare the effects of parecoxib sodium, an injectable prodrug of a cyclo-oxygenase-2—specific inhibitor, and ketorolac on platelet function and bleeding time in elderly individuals and non-elderly adults.Design and SettingDouble-blind, randomised, active- and placebo-controlled, parallel-group studies.Patients and ParticipantsHealthy men and women, between the ages of 65 and 95 years (62 elderly individuals) or 18 and 55 years (48 non-elderly individuals).MethodsParticipants received placebo or active medication: parecoxib sodium 40mg twice daily intravenously for 8 days (both studies), ketorolac 15mg four times daily intravenously for 5 days (elderly individuals) or 30mg four times daily intravenously for 5 days (non-elderly individuals). Ex vivo platelet aggregation responses to arachidonate, collagen and adenosine diphosphate (ADP), bleeding time and serum thromboxane B2 (TXB2) levels were measured.ResultsIn both studies, parecoxib sodium had little or no effect on arachidonate-induced platelet aggregation, whereas ketorolac caused statistically significant and sustained decreases in platelet aggregation throughout the entire drug administration period. Parecoxib sodium also had little or no effect on collagen- or ADP-induced aggregation compared with ketorolac. Although there was a high degree of variability in bleeding times, significant prolongation of bleeding times was observed only in the ketorolac groups in both studies. Parecoxib sodium had no effect on serum TxB2 concentrations in non-elderly individuals. In elderly individuals, ketorolac significantly and profoundly reduced TxB2 levels at all assessments, whereas parecoxib sodium showed less of a reduction.ConclusionAlthough a direct correlation has not been proven, patients with reduced platelet function do appear to be at a higher risk of experiencing increased bleeding during surgery. Thus, the absence of effect on platelet aggregation and bleeding time observed in these studies suggests that parecoxib sodium is less likely to be associated with excessive bleeding during surgery, and therefore is potentially safer than ketorolac for use in patients undergoing surgery, irrespective of age.

Differential effects of morning and evening dosing of nisoldipine ER on circadian blood pressure and heart rate

The time of administration of once-daily antihypertensive agents may have a significant impact on blood pressure control during awake and sleep periods. Using 24-h ambulatory monitoring, we compared the effects of morning and evening dosing of the long-acting dihydropyridine calcium channel blocker, nisoldipine extended-release (ER), on circadian blood pressure (BP) and heart rate in patients with mild-to-moderate hypertension. After completing a 3-week placebo run-in period, 85 patients were randomized to morning versus evening nisoldipine ER treatment at a fixed 20-mg dose. Patients were treated for 4 weeks, followed by crossover to the alternate dosing regimen for 4 additional weeks. Twenty-four-hour ambulatory monitoring was performed at baseline and at 4 and 8 weeks after randomization. Awake and sleep times were determined by electronic activity recorders (Actigraphy). Similar least-squares (+/-SE) mean changes from baseline in 24-h BP (systolic BP/diastolic BP: -11.9/-7.4 +/- 0.6/0.5 v -11.6/-6.5 +/- 0.6/0.5 mm Hg) and heart rate (1.0/1.7 +/- 0.4/0.4 beats/min) occurred with morning and evening administration, respectively. A significantly greater effect on awake diastolic BP (systolic BP/diastolic BP: -12.6/-8.1 +/- 0.7/0.4 v -11.3/-6.4 +/- 0.7/0.4 mm Hg; P = .16/.01) was observed with morning dosing compared with evening dosing. In addition, small increases in sleep and early morning heart rate were seen with evening compared with morning administration of nisoldipine (sleep, 3.1 +/- 0.4 v 0.4 +/- 0.4 beats/min; P < .001; early morning, 3.5 +/- 0.7 v 0.5 +/- 0.7 beats/min; P = .002). These differential effects on awake BP and sleep heart rate were also observed in patients who had normal (dippers) and elevated (nondippers) BP values during sleep. Appropriate evaluation of the efficacy and safety of long-acting antihypertensive agents is essential when evening administration is being considered. In the present study, the timing of nisoldipine ER administration had no effect on mean changes in BP and heart rate over a 24-h period. However, nisoldipine ER had some differential effects during sleep and awake periods with morning relative to evening dosing.

Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers.

Celecoxib is a novel cyclooxygenase‐2‐specific inhibitor for the management of acute pain, primary dysmenorrhea, and the signs and symptoms of arthritis. This double‐blind, placebo‐controlled study in 16 healthy volunteers evaluated whether celecoxib alters the effect of concomitant aspirin on platelet function. Volunteers received celecoxib (400 mg/day) or placebo for 4 days. On day 5, they also received a single 325 mg dose of aspirin with either 200 mg celecoxib or placebo. Thromboxane and platelet aggregation response to adenosine 5′‐diphosphate (ADP), collagen, and arachidonic acid were measured before the first dose of celecoxib or placebo (baseline) and before dosing and 2 and 8 hours postdose on day 5. There was no significant difference in thromboxane inhibition between the two groups (percent inhibition: placebo 99.4%, celecoxib 99.0%; p = 0.555). There was also no significant difference in the effect of aspirin on platelet aggregation due to ADP, collagen, or arachidonic acid between the groups. Therefore, these data indicate that celecoxib does not alter the effects of aspirin on platelet function.

Dose-ranging analgesic study of Prosorb diclofenac potassium in postsurgical dental pain.

BACKGROUND ProSorb diclofenac potassium (K) is a novel, liquid-filled rapid-dispersion formulation of the nonsteroidal anti-inflammatory drug diclofenac, placed into soft gelatin capsules. Its time to maximal plasma drug concentration has been shown to be approximately half, and its maximal plasma drug concentration nearly twice, that of immediate-release diclofenac K tablets. OBJECTIVE This study compared the analgesic dose-response relationship and tolerability of 3 doses of ProSorb diclofenac K and placebo in the treatment of pain after dental impaction surgery. METHODS This randomized, double-blind, double-dummy, placebo-controlled parallel-group study was conducted at 6 centers across the United States. Patients aged 18 to 65 years with moderate or severe pain after the removal of > or =1 impacted mandibular third molar were randomly assigned to receive a single dose of ProSorb diclofenac K 25, 50, or 100 mg or placebo. Pain intensity and relief were assessed up to 6 hours after dosing. Rescue treatment was allowed after 1 hour. Efficacy end points included the summed pain intensity difference over 3 and 6 hours (SPID3 and 6); total pain relief at 3 and 6 hours (TOTPAR3 and 6); median times to onset of perceptible and meaningful relief (analgesic onset) and rescue medication use (analgesic duration); and cumulative percentage of patients using rescue medication. Tolerability was assessed using vital sign measurements and spontaneous reporting of adverse events. RESULTS A total of 265 patients (154 women, 111 men; mean age, 23.3 years) were enrolled. All 3 ProSorb diclofenac K groups showed higher SPID6 and TOTPAR6 scores and longer median times to rescue medication use than the placebo group (all, P < 0.001). For these end points, a dose-response relationship was evident between the 100-mg dose and the 25- and 50-mg doses (P < or = 0.05); the 25- and 50-mg doses were similar. In the diclofenac groups, median onset times for first perceptible (< or =22.5 min) and meaningful (< or =53.0 min) relief were significantly more rapid than placebo (P < or = 0.01). Proportions of patients requiring rescue analgesic were < or =50.8% with diclofenac compared with 79.4% with placebo. Proportions of patients assigning a global evaluation of good or better was > or =68% with diclofenac compared with 21% for placebo. Tolerability was similar across all treatment groups. CONCLUSION In this study of patients treated for pain following dental impaction surgery, single doses of ProSorb diclofenac K 25, 50, and 100 mg were more efficacious than placebo with respect to reduction of pain. All 3 doses provided a rapid analgesic onset and were well tolerated.

Dose-Proportional and Stereospecific Pharmacokinetics of Methylphenidate Delivered Using an Osmotic, Controlled-Release Oral Delivery System

Methylphenidate hydrochloride (HCl) is frequently used for the treatment of attention deficit/hyperactivity disorder (ADHD). A study was conducted in healthy subjects to evaluate the dose‐ranging pharmacokinetics of 18, 36, and 54 mg methylphenidate HCl delivered using an oral, osmotic, controlled‐release formulation (OROS®). Plasma concentrations of l‐methylphenidate were 40‐fold lower than those of d‐methylphenidate, whereas plasma concentrations of d‐α‐phenyl‐2‐piperidine acetic acid (d‐PPA) and l‐PPA, the major metabolite of methylphenidate, were comparable. Mean AUCinf values for d‐methylphenidate were 42.2, 80.9, and 120 ng•h/mL for the 18, 36, and 54 mg doses, respectively, increasing dose proportionally. AUCinf values for l‐methylphenidate were only ∼1% of d‐methylphenidate (0.43, 0.96, and 1.82 ng•h/mL for the 18, 36, and 54 mg dose groups, respectively). In contrast, AUCinf values of d‐ and l‐PPA were comparable. The dose‐normalized d‐ and l‐methylphenidate plasma concentration‐time profiles for the three treatment groups were superimposable. Similarly, dose‐normalized plasma concentrations of d‐ and l‐PPA were superimposable. Methylphenidate metabolism, measured as the ratio of d‐methylphenidate AUCinf to d‐PPA AUCinf and as l‐methylphenidate AUCinf to l‐PPA AUCinf, was similar for the three dose groups, indicating that methylphenidate metabolism was not affected by increasing dose. OROS® (methylphenidate HCl) exhibits dose‐proportional and linear pharmacokinetics.

Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban

Summary Of the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation reversal of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10–30 minutes of administration and sustained for at least 24 hours. Institution where the work was performed: Duke University Clinical Research Unit, Duke University Medical Center, Durham, NC USA

Percutaneous absorption and pharmacokinetics of eflornithine HCl 13.9% cream in women with unwanted facial hair

This article reports the results of an open‐label, multiple‐dose study to determine percutaneous absorption and pharmacokinetics of eflornithine following topical treatment with eflornithine HC®l 13.9% cream (Vaniqa™). Ten women with excessive facial hair were treated with two 0.5 g single doses of [14C]‐labeled eflornithine HC®l 13.9% (w/w) cream (periods A and C) separated by twice‐daily application of 0.5 g unlabeled eflornithine HC113.9% cream for 7 days (period B). Analysis of radioactivity excreted in urine and feces indicated that percutaneous absorption was minimal. Comparison with urinary excretion of eflornithine in period A suggested that most of absorbed eflornithine was excreted in urine without being metabolized. Radioactivity was not detectable in blood or plasma, but eflornithine concentrations were measurable, with peak concentrations of 4.96 ng/ml in period A and 10.44 ng/ml in period C. Eflornithine was eliminated from plasma with a mean terminal half‐life of 11 hours (first application) and 8 hours (final application). Trough plasma concentrations reached steady state (4.61‐5.50 ng/ml) after 4 days of twice‐daily topical treatment, and multiple dosing had no apparent effect on disposition kinetics. The low degree of percutaneous absorption and low systemic exposure to eflornithine offer a favorable clinical safety profile of eflornithine HC®l 13.9% cream.

Pharmacokinetics of pantoprazole in patients with moderate and severe hepatic dysfunction

BACKGROUND Patients with impaired hepatic function usually require gastric acid-suppressant therapy but are at increased risk for drug interactions and may require dosage adjustments. The proton pump inhibitor pantoprazole is rapidly absorbed and eliminated, primarily by cytochrome P450 (CYP) 2C19 isozymes. OBJECTIVE This study sought to determine whether dosage adjustment of pantoprazole is required in patients with moderate or severe hepatic impairment by comparing the pharmacokinetic profile of pantoprazole in such patients with that in healthy slow metabolizers of pantoprazole, in whom no dosage adjustment is required. METHODS Patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment received oral pantoprazole 40 mg once daily on days 1 through 4 and then on alternate days (days 6 and 8). Serial blood samples were collected on days 4 and 8 for analyses of plasma pantoprazole concentrations. Pharmacokinetic data were compared between the 2 groups with hepatic impairment and against historical data from 17 healthy subjects who were genetically slow CYP2C19 metabolizers of pantoprazole. RESULTS Twenty-two patients participated in the study, 13 in the Child-Pugh class B group and 9 in the Child-Pugh class C group. No clinically significant differences in pantoprazole pharmacokinetics were noted between the patients with hepatic impairment and the healthy slow metabolizers of pantoprazole on days 4 and 8. Pantoprazole was well tolerated. Four Child-Pugh class B patients and 3 Child-Pugh class C patients reported > or = 1 adverse event. Adverse events were generally mild or moderate, and were similar to those reported in healthy subjects. Two patients discontinued the study because of severe events related to their underlying disease. CONCLUSIONS The pharmacokinetics and tolerability of pantoprazole were similar in patients with moderate hepatic impairment, patients with severe hepatic impairment, and healthy slow metabolizers of pantoprazole, in whom no dosage adjustment is required. Thus, no dosage adjustment of pantoprazole is required in patients with hepatic impairment, regardless of its severity. However, caution should be exercised when giving pantoprazole to patients with severe hepatic impairment.

American Society for Clinical Pharmacology and Therapeutics position statement on dietary supplement safety and regulation.

Jason D. Morrow, MD, Chair, Timi I. Edeki, MD, PhD, Mohamed El Mouelhi, MD, PhD, Raymond E. Galinsky, PharmD, Rose Kovelesky, RPh, PhD, Robert J. Noveck, MD, PhD, and Charles Preuss, RPh, PhD, American Society for Clinical Pharmacology and Therapeutics Task Force on Dietary Supplements Nashville, Tenn, Waukegan, Ill, Mason, Ohio, Indianapolis, Ind, Emeryville, Calif, New Orleans, La, and West Palm Beach, Fla