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Introduction The satisfactory safety/tolerability profile of V117957, an investigational NOP receptor partial agonist, has been previously established in ~200 healthy subjects with maximum doses at 30mg following a single oral administration and 10mg once daily for 2 weeks. V117957 exhibited linear plasma exposures at doses up to 10mg. In patients with insomnia disorder, V117957 demonstrated dose-dependent improvement in sleep efficiency and sleep maintenance between 0.5mg and 10mg as measured by polysomnography and patient diaries. The current study evaluated the abuse potential and safety of V117957 in healthy, nondependent recreational polydrug users with a history of central nervous system (CNS) depressant use. Methods The abuse potential of V117957 (1mg, 6mg, 10mg), placebo, and triazolam (0.5mg, 1mg) were assessed in a randomized, double-blind, double-dummy, placebo- and positive-controlled crossover study. Triazolam was utilized as a positive control based on its comparable pharmacokinetic and pharmacodynamic characteristics. V117957 doses (1mg, 6mg, 10mg) were selected to represent therapeutic, mid-range supratherapeutic, and maximum-tolerated supratherapeutic doses, respectively. Subjects were qualified based on pharmacodynamic responses following a single oral 0.75mg triazolam dose. Drug liking was measured through 24 hours, including the primary endpoint of maximum “at the moment” Drug-Liking Visual Analog Scale, as recommended by FDA. Secondary endpoints included Divided Attention Test (DAT) and Choice Reaction Time (CRT). Results The positive control (triazolam 0.5mg, 1mg) produced statistically significant greater abuse potential and cognitive/motor impairment versus placebo, which demonstrated study validity. In contrast, V117957 at 1mg was not statistically significantly different from placebo. At the supra-therapeutic doses of 6 and 10mg, V117957 was associated with abuse potential and cognitive/motor impairment greater than placebo, yet similar to those of triazolam 0.5 and 1mg. Conclusion Overall, in this valid study, V117957 1mg and placebo were associated with statistically significant lower potential for abuse and reduced cognitive/motor impairment compared with the two supratherapeutic doses of V117957 (6mg, 10mg), and triazolam (0.5mg, 1mg). V117957 1mg met FDA’s statistical criterion for similarity to placebo. Support Funded by Imbrium Therapeutics, a subsidiary of Purdue Pharma L.P.

This study was a 14-day, outpatient, open-label randomized crossover trial of lyophilized black raspberries (BRBs) in older overweight or obese males to determine whether BRB consumption affects postprandial inflammation associated with consumption of a high-fat high-calorie (HFHC) meal. Ten study participants consumed 45 g/d of lyophilized BRBs for 4 days, followed by a HFHC breakfast plus BRBs on day 6 or consumed the HFHC breakfast on day 6 without previous consumption of BRBs and then crossed over to the other treatment after a 2-day washout period. Blood samples were obtained before and 1, 2, 4, 8, and 12 hours after consumption of the HFHC breakfast. The primary study outcomes were changes in area under the concentration-time curve (AUC) for interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α). The secondary outcomes were safety and tolerability of lyophilized BRB powder. The chronology and values of measured serum concentrations for IL-6, TNF-α, and CRP were consistent with those described previously by other investigators. The AUC of serum IL-6 was lowered significantly (P = 0.03, n = 10) with BRB consumption (34.3 ± 7.6 pg·mL⁻¹·h⁻¹ compared with 42.4 ± 17.9 pg·mL⁻¹·h⁻¹ for consumption of the HFHC meal alone). However, no significant differences (change in AUC) were calculated for serum CRP and TNF-α. The findings of this pilot study suggest that consumption of lyophilized BRBs may attenuate postprandial inflammation in overweight or obese males consuming a HFHC meal. Further investigation of BRBs is warranted to better elucidate their inflammomodulatory potential.

Introduction V117957 is an investigational nociceptin/orphanin-FQ peptide (NOP) receptor partial agonist designed to treat insomnia by promoting sleep onset and maintenance with minimal residual next-day somnolence or psychomotor impairment. The satisfactory safety/tolerability profile of V117957 has been previously established in ~200 healthy subjects with maximum doses at 30mg following a single oral administration and 10mg once daily for 2 weeks. The present study was conducted to assess the safety/tolerability and pharmacokinetics (PK) of V117957 with co-administered alcohol. Methods A randomized, double-blind, double-dummy, placebo-controlled, balanced six-period crossover design was employed. Single doses (2mg, 6mg) of V117957 and placebo were administered orally to healthy subjects in the morning with and without alcohol (0.7g/kg). Pharmacodynamic (PD) effects of V117957 were assessed, and safety/tolerability and PK interactions were also characterized. The primary PD endpoints (body sway, Digit Vigilance Test, and numeric working memory) were measured through 12 hours postdosing. Results Forty-eight subjects were enrolled and randomized; 46 completed. Compared with placebo, alcohol alone showed an impairment on psychomotor/cognitive performances through 2 hours postdose. V117957 alone showed a dose-dependent impairment. Compared with V117957 alone and alcohol alone, co-administration of alcohol and V117957 showed greater impairment until 8 hours postdose. No subject discontinued due to an adverse event (AE). No clinically meaningful treatment-emergent (TE) changes in clinical laboratory values, vital signs, SpO2 measurements, or 12-lead ECG results were observed. The most common TEAE was somnolence. All plasma and urine PK parameters for V117957 and alcohol were comparable when V117957 or alcohol was administered alone or in combination. Conclusion Single oral doses of V117957, 2mg or 6mg, administered alone or in combination with alcohol in healthy subjects resulted in no notable PK interaction between V117957 and alcohol. A dose-effect relationship in the magnitude and duration of impairment was observed for most psychomotor/cognitive performance parameters. Greater effects of V117957 with alcohol were observed for most psychomotor/cognitive performance parameters up to 8 hours post-dose. Support Funded by Imbrium Therapeutics, a subsidiary of Purdue Pharma L.P.

Context Transdermal formulations of buprenorphine offer controlled delivery of buprenorphine for sustained analgesic efficacy with reduced adverse events (AEs) compared with the other modes of administration. A buprenorphine transdermal system (BTDS) delivering 5, 10, or 20 mcg/hour for seven days is now marketed in the U.S. as Butrans ® (Lohmann Therapie-System AG, Andernach Germany), a Schedule III single-entity opioid analgesic indicated for the management of moderate and chronic pain in patients requiring continuous around-the-clock analgesia for an extended period. Objectives This was a randomized open-label study in healthy subjects to characterize the steady-state buprenorphine pharmacokinetics after the delivery of three consecutive seven-day BTDS applications. Methods Thirty-seven subjects were randomized to receive three consecutive BTDS 10 mcg/hour (BTDS 10) patches applied to the deltoid or upper back for seven days each. Blood samples for buprenorphine concentration measurements were taken. Safety was assessed using recorded AEs, clinical laboratory test results, vital signs, pulse oximetry, physical examinations, and electrocardiograms. Patch adhesion assessments were taken. Results Analysis of C min demonstrated that steady state was reached during the first BTDS 10 application. No significant difference in C min was observed across the three applications. Total and peak plasma buprenorphine exposures were similar after each of the seven-day administrations of BTDS. Conclusion Three consecutive once-weekly applications of BTDS 10 provided consistent and sustained delivery of buprenorphine. Steady-state plasma concentrations were reached within 48 hours of the first application of BTDS 10. Patch adhesion analysis confirmed the appropriateness of the seven-day application period. Overall, BTDS 10 was safe and well tolerated.

Background and Objective Reformulated OxyContin® (oxycodone-HCl controlled release) tablets (ORF) became available in the United States in August 2010. The original formulation of OxyContin® (oxycodone-HCl controlled release) tablets (OC) used a delivery system that did not provide inherent resistance to crushing and dissolving. The objective of this study was to compare the pharmacokinetics, tolerability, and safety of finely crushed ORF tablets, coarsely crushed ORF tablets, and finely crushed OC tablets. Methods This randomized, single-blind, single-dose, single-center, six-sequence, triple-treatment, triple-period crossover study enrolled eligible healthy adults (aged 18–55 years inclusive). The study evaluated the pharmacokinetics, tolerability, and safety of intranasally administered ORF, both finely crushed and coarsely crushed, as well as finely crushed OC tablets. Plasma oxycodone concentrations were quantified and analyzed to determine the maximum observed plasma concentration (Cmax), time to maximum plasma concentration (tmax), area under the plasma concentration–time curve from hour 0 to the last measurable plasma concentration (AUClast), and area under the plasma concentration–time curve extrapolated to infinity (AUC∞). The abuse quotient (AQ), calculated as Cmax/tmax, served as an index of the average rate of increase in drug concentration from dosing to tmax. Intranasal tolerability rating scales (discomfort, itching, burning, pain, runny nose, and stuffiness) and intranasal endoscopy were conducted. Safety assessments included adverse events, vital signs, pulse oximetry (SpO2), and electrocardiograms. Results Of 83 subjects screened and enrolled, 30 were randomized to period 1, with 1 subject subsequently discontinuing due to the subject’s choice. Mean Cmax values for finely crushed ORF (17.1 ng/mL) and coarsely crushed ORF (15.5 ng/mL) were lower than that for finely crushed OC (22.2 ng/mL). Median tmax for finely crushed OC (1.0 h) was shorter than that for either finely crushed ORF (2.0 h) or coarsely crushed ORF (3.0 h). Mean AQ values were approximately 66 and 80 % lower, respectively, for finely crushed ORF and coarsely crushed ORF than that for finely crushed OC. Finely crushed ORF, coarsely crushed ORF, and finely crushed OC demonstrated similar total oxycodone exposures (AUC∞). Insufflation of ORF produced greater nasal discomfort and stuffiness than finely crushed OC, although the latter produced higher runny nose scores. No significant difference was found in other nasal tolerability measures. The overall safety profile was as expected following opioid administration in healthy subjects. Conclusions In contrast to OC, both finely and coarsely crushed ORF retained some control of oxycodone release. Reduced Cmax and increased tmax for ORF resulted in lower AQ scores for ORF compared with OC. ORF was associated with greater intranasal irritation than OC. These data suggest that ORF has a lower intranasal abuse potential than OC.

Early clinical trials rely upon paid healthy volunteers. Concern has been raised regarding the characteristics of these individuals, how well they understand their rights and the risks of clinical research, and how they may be influenced by manipulation or coercion. Therefore, we investigated (1) the motivations of subjects in clinical trials, (2) how well these individuals comprehend a consent form they sign, and (3) the effect of the stipend on the reliability of information reported by volunteers in clinical trials. Thirty healthy subjects (age, 21-45 years) in a long-duration clinical trial were administered a questionnaire gathering demographic information and testing their comprehension of the consent form. In a separate chart review of 10 clinical trials, 374 subjects were studied to determine their reliability in reporting abnormalities in their medical history and in reporting adverse events, and an association was examined between the incidence of unreliable reporting and the stipend paid to them for participating in the clinical trial. A large percentage of subjects who were enrolled in the long-duration clinical trial failed to comprehend a variety of basic concepts related to the consent form and their participation in the drug study. The chart review demonstrated that subjects who are paid larger stipends may not be more likely to report abnormalities on their medical history. Further studies should be undertaken with larger numbers of subjects enrolled in clinical trials, and possible associations between demographic data (eg, income, level of education, number of previous studies) and the reliability of information provided by normal healthy research volunteers should be examined.

Observations of predose spikes in transaminases from a phase I study prompted our review of other clinical trials, including 250 healthy participants from 4 studies at 3 sites. Six of these participants (2.4%) displayed elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels immediately predose despite normal values

Casopitant, an antiemetic, is a neurokinin-1 receptor antagonist metabolized primarily by cytochrome P450 3A4 (CYP3A4). Three phase 1 studies with 131 healthy subjects examined the impact of a strong CYP3A inhibitor (ketoconazole) and inducer (rifampin) on the pharmacokinetics and safety of casopitant. Oral casopitant was administered alone (study 1, 100-mg single dose; study 2, 150 mg on day 1, 50 mg on days 2 and 3; study 3, 150-mg single dose) with either 400 mg daily of oral ketoconazole or 600 mg daily of oral rifampin. Ketoconazole increased the maximum observed plasma concentration (C(max)) and area under the plasma concentration time curve to the last sampling time, t (AUC(0-t)) of single-dose casopitant 2.7-fold and 12-fold and increased the C(max) of 3-day casopitant 2.5-fold on day 1 and 2.9-fold on day 3, whereas AUC((0-tau)) increased 4.3-fold on day 1 and 5.8-fold on day 3. Neither safety signals nor prolongation of Fredericia-corrected QT was observed at these increased exposures in study 2. Repeat-dose rifampin reduced the C(max) and AUC((0-t)) of casopitant 96% and 90%, respectively. These clinical studies confirmed the role of CYP3A in the metabolism and disposition of casopitant. Coadministration of casopitant with strong inhibitors of CYP3A is likely to increase plasma exposure of casopitant, whereas coadministration with strong inducers of CYP3A is likely to decrease casopitant exposure and compromise efficacy.

Background Vaginal atrophy (VA) is a prevalent disorder in postmenopausal women that is characterized by decreased epithelial thickness, reduced vaginal maturation index (VMI) and increased vaginal pH. Current medical therapy consists of local or systemic replacement of estrogens. Objective The goal of this study was to understand, at a molecular level, the effect of estradiol (E2) on the vaginal epithelium. Methods Nineteen women were treated with E2 delivered through a skin patch at a dose of 0.05 mg/day for 12 weeks. The diagnosis of VA was confirmed by a VMI with ≤5% superficial cells and vaginal pH > 5.0. Vaginal biopsy samples were collected at baseline and after treatment. Differentially expressed mRNA transcripts in these biopsies were determined by microarray analysis. Results All 19 subjects had increased VMI (>5%) and/or reduced pH (≤5) following treatment. Most subjects also had increased serum E2 levels and reduced serum FSH levels. Transcriptional profiling of vaginal biopsies identified over 3000 E2-regulated genes, including those involved in several key pathways known to regulate cell growth and proliferation, barrier function and pathogen defense. Conclusions E2 controls a plethora of cellular pathways that are concordant with its profound effect on vaginal physiology. The data presented here are a useful step toward understanding the role of E2 in vaginal tissue and the development of novel therapeutics for the treatment of VA.

Eleven subjects completed a clinical trial to determine the safety/tolerability of freeze-dried black raspberries (BRB) and to measure, in plasma and urine, specific anthocyanins-cyanidin-3-glucoside, cyanidin-3-sambubioside, cyanidin-3-rutinoside, and cyanidin-3-xylosylrutinoside, as well as ellagic acid. Subjects were fed 45 g of freeze-dried BRB daily for 7 days. Blood samples were collected predose on days 1 and 7 and at 10 time points postdose. Urine was collected for 12 hours predose on days 1 and 7 and at three 4-hour intervals postdose. Maximum concentrations of anthocyanins and ellagic acid in plasma occurred at 1 to 2 hours, and maximum quantities in urine appeared from 0 to 4 hours. Overall, less than 1% of these compounds were absorbed and excreted in urine. None of the pharmacokinetic parameters changed significantly between days 1 and 7. In conclusion, 45 g of freeze-dried BRB daily are well tolerated and result in quantifiable anthocyanins and ellagic acid in plasma and urine.

In phase I clinical trials intended for healthy volunteers, testing for human immunodeficiency virus (HIV) is often times part of a routine screening procedure to determine eligibility. The rationale is to safeguard volunteers, to protect the scientific integrity of a clinical trial, and/or to facilitate the process of drug development. Asymptomatic HIV-positive individuals are at increased risk for adverse events, and participating in a phase I clinical trial could also interfere with effective treatment for their disease. Although the Food and Drug Administration has not established a policy regarding HIV testing in clinical trials, some institutional review boards (IRBs) impose restrictions. The role of an IRB is to protect the rights and welfare of human subjects in clinical trials. Restricting testing does not protect subjects and may in fact harm them; therefore, an IRB should not restrict testing proposed by a pharmaceutical sponsor in agreement with a clinical investigator.

GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25–800 mg; n = 45) or multiple doses (100–600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼five-fold compared with placebo, reaching peak concentrations of ∼50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides. Trial Registration: Clinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621

Variations in hormone levels during different phases of the menstrual cycle have been shown to alter the pharmacokinetics of some medications and are known to exert significant effects on seemingly unrelated physiologic parameters. Numerous studies have been undertaken to examine the effects of different phases of the menstrual cycle on leukocyte and differential counts, but results have often been inconclusive and contradictory. This study endeavored to reexamine these parameters, measured by standard laboratory assays, in healthy ovulating females to determine whether the menstrual cycle may have clinically relevant effects on leukocyte counts. Twenty-one women, aged 18 to 35 years and not taking hormonal contraception, were enrolled in an outpatient study within 12 hours after the onset of normal menses. The women reported to the clinical pharmacology unit for a complete blood count with differential on days 1, 2, 7, 10 through 17, 22, and 25 through 32. Blinded duplicate samples were obtained on day 2 to assess variability at the analytic site, and levels of luteinizing hormone and estradiol were measured on days 11 through 16 to determine the day of ovulation. Eighteen women completed the study, with cycle lengths ranging from 24 to 31 days (28.2 +/- 1.9 days, mean +/- SD). Evaluations of the data revealed a trend toward higher leukocyte counts and absolute neutrophil counts at the onset of menses but no significant or clinically relevant effects of different phases of the menstrual cycle on these parameters. Some split samples showed considerable variation in the assays (eg, a 42% increase in absolute neutrophil counts), suggesting that errors at the analytic facility may be a more important consideration than hormonal effects.

Aims To assess the potential of ziprasidone to alter the renal clearance and steady-state serum levels of lithium. Methods Healthy subjects who had stable serum lithium levels during the first 7 days of treatment with lithium 900 mg day− 1, given as two divided daily doses, were randomized to receive concomitant treatment with either ziprasidone, 40 mg day− 1, given as two divided daily doses, on days 9–11 followed by 80 mg day− 1, given as two divided daily doses on days 12–15 (n = 12), or placebo twice daily (n = 13). Ziprasidone or placebo was administered 2 h before each dose of lithium. Results Ziprasidone administration was associated with a 0.07 mmol l− 1 (13%) mean increase in steady-state serum lithium levels compared with a mean increase of 0.06 mmol l− 1 (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h− 1 (5%) in the ziprasidone group and by 0.14 l h− 1 (9%) in the placebo group. None of these differences between the two groups was statistically or clinically significant. Conclusions Ziprasidone does not alter steady-state serum lithium concentrations or renal clearance of lithium.

Aims To evaluate the pharmacokinetics and tolerability of single and multiple oral doses of ziprasidone in healthy male volunteers, and to determine the influence of ziprasidone on serum prolactin levels.

Aims To determine whether ziprasidone alters the metabolizing activity of the 2D6 isoenzyme of cytochrome P450 (CYP2D6).

The efficacy of gallium (Ga) nitrate was examined in a murine model of sepsis. Male Balb/c mice (6–8 weeks) were randomized into 3 groups: 1) vehicle-treated controls 2) mice with sepsis induced by treatment with 0.3 mg iv of Propionibacterium acnes followed one week later by 0.01 μg lipopolysaccharide (LPS) and 10 mg of D-galactosamine (GalN) 3) mice with sepsis injected with 45 mg/kg s.c. of gallium nitrate (calculated as elemental Ga) 24 hours prior to LPS/GalN. Two hours after LPS/GalN or vehicle, plasma concentrations of tumor necrosis factor (TNF-α) in groups 1, 2 and 3 were 54 ± 31 (n = 6), 21390 ± 5139 (n = 4), and 21909 ± 943 (n = 5) pg/ml, respectively. After 6 hours, plasma concentrations of gamma interferon (IFN-γ) were < 10 (n = 8), 4771 ± 1078 (n = 6), and 1622 ± 531 (n = 15) pg/ml, respectively, and of nitratenitrite (products of nitric oxide) were 64 ± 8 (n = 7), 146 ± 118 (n = 8), and 57 ± 8 (n = 15) μM. At 18 hours, serum chemistries were; SGOT 171 ± 46 (n = 13), 10986 ± 3062 (n = 7), and 1078 ± 549 (n = 8) IU/L; SGPT 165 ± 59, 17214 ± 4340, and 2088 ± 1097 IU/L; and total bilirubin 0.2 ± 0.0, 0.9 ± 0.4, and 0.2 ± 0.0 mg/dl for groups 1, 2, and 3 respectively. Blinded histologic evaluation of livers at 18 hours revealed inflammatory infiltrate scores (x [range], 0 = none, 1 = minimal, 2 = mild, 3 = moderate, and 4 = severe) of 0.1 [0–1] (n = 8), 3.0 [2–4] (n = 15), and 2.0 [0–3] (n = 10), and necrosis scores of 0.0, 2.8 [0–4], and 0.9 [0–4]. Although Ga did not affect production of TNF-α, it ameliorated hepatocellular injury and protected against necrosis. Based on this model of sepsis, Ga may have a role in treating the human disease.

This study was performed to examine the effect of the coadministration of azithromycin on the pharmacokinetics of the protease inhibitor indinavir (Crixivan®). In an open-label, parallel-design study, 32 healthy male and female volunteers were given indinavir (800 mg tid) for 5 days. One hour prior to the first dose of indinavir on day 5, 18 subjects received 1200 mg azithromycin (Zithromax®), and 14 subjects received matching placebo. Serial samples ofplasma were obtained for 8 hours following the morning dose of indinavir on days 4 and 5 and assayed for indinavir by HPLC/UV. Twenty-seven subjects completed the study. Following coadministration of azithromycin with indinavir, there was no significant change between day 5 and day 4 in AUC (20.7 mg○hr/ml and 23.1 mg○hr/ml; 90% CI on the ratio 81%-100%) or C max (9.88 mg/ml and 10.3 mg/ml; 90% CI 86%-108%). The day 5 to day 4 difference in indinavir concentrations following coadministration with azithromycin was not significantly different from the day 5 to day 4 difference with placebo (AUC p = 0.68; C max p = 0.074). Therefore, azithromycin does not significantly alter the kinetics of indinavir.

Aims CP-105,696, (+)-1-(3S,4R)-[3-(4-phenylbenzyl)-4-hydroxy-chroman-7-yl] cyclopropane carboxylic acid is a potent, novel LTB4 receptor antagonist advanced to clinical trials to determine its efficacy in inflammatory diseases. The pharmacokinetics and pharmacodynamics of CP-105,696 were investigated in healthy male volunteers following oral administration of single doses of 5 to 640 mg. Methods Forty-eight subjects participated in a randomized, double-blind, parallel group study. Plasma and urine concentrations of CP-105,696 were determined at intervals after drug administration. As an indication of LTB4 receptor antagonism following oral administration of CP-105,696, the inhibiton of LTB4-induced upregulation of the neutrophil cell surface complement receptor (CR3), CD11b/CD18, was monitored at 4 h following drug administration using an ex vivo whole blood flow cytometry assay. Results Cmax and AUC(0,∞) increased in a dose-related manner. Respective mean Cmax values were 0.54 to 30.41 μg ml−1 following doses of 5 to 640 mg. Respective mean AUC(0,∞) values were 1337 to 16819 μg ml−1 h for the 40 to 640 mg dose groups. Plasma concentrations declined in a monoexponential manner, with terminal elimination half-lives ranging from 289 to 495 h. Group mean terminal elimination half-lives were dose-independent. Urinary excretion of unchanged drug accounted for

Gallium (Ga) nitrate, a drug which prevents a variety of experimental autoimmune diseases, was investigated in a murine model of systemic lupus erythematosus (SLE). In one experiment, female MRL/Mp lpr/lpr (MRL/lpr) mice were randomized into 2 groups of 6: 1) vehicle (trisodium citrate) and 2) Ga. Subcutaneous injections began at 3 weeks of age and continued weekly until the mice were euthanized a week after the thirteenth injection. The loading dose of Ga (calculated as elemental Ga) was 45 mg/kg, followed by 15 mg/kg/week. In another experiment (n = 18) with 3 males and 3 females per group, mice received 1) vehicle, 2) Ga x 1 (one 45 mg/kg dose), and 3) Ga x 13. In the experiment with 12 mice, axillary lymph nodes from Ga-treated mice were significantly smaller than those from vehicle-treated mice (91+/-42 and 360+/-358 mg respectively, mean+/-SD), and spleens as well as lymph nodes from the former showed significantly less lymphoid infiltrate. In the experiment with 18 mice, prescapular lymph nodes weighed 312+/-98, 217+/-52, and 42+/-34 mg, and spleens weighed 732+/-492, 409+/-164, and 192+/-93 mg in the groups which received vehicle, Ga x 1, and Ga x 13 respectively. Control mice had significantly more lymphoid infiltrates in the lungs, spleen, and lymph nodes and, unlike Ga x 13 mice, exhibited glomerulitis and renal vasculitis. Within groups, females developed more severe disease than males. The Ga x 13 group had increased percentages of CD4-bearing and CD8-bearing lymphocytes in lymph nodes and increased CD4-bearing lymphocytes in the spleen, with an increased proliferative response to mitogen stimulation in vitro in lymph nodes, although not in the spleen. The Ga x 13 group also gained less weight and developed osteosclerosis. Although preliminary, our findings suggest that clinical trials with Ga in SLE are merited.

BACKGROUND/OBJECTIVE Bupivacaine liposome injectable suspension is a novel, prolonged-release formulation of bupivacaine. The time to onset of analgesia following an injection of liposome bupivacaine compared with placebo (normal saline) was investigated using a novel incisional pain model. Bupivacaine HCl was used as a positive control, compared with placebo to verify the validity of the study. MATERIALS AND METHODS In this Phase 1, single-blind, crossover study, healthy volunteers (n = 132) were randomized to four sequential cohorts to receive subcutaneous normal saline in one arm and either liposome bupivacaine 40 mg or bupivacaine HCl 7.5 mg in the other. At 30, 15, 5, and 2 minutes after study drug administration for Cohorts 1 - 4 respectively, an incision was made in each arm and 18% acetic acid solution was applied to elicit pain. The primary outcome measure was a subject's assessment of pain intensity on a 100 mm visual analog scale. RESULTS Statistically significant differences in pain intensity scores between liposome bupivacaine and normal saline were observed at 30, 15, 5, and 2 minutes postdose; similar findings were reported for bupivacaine HCl vs. normal saline. Both liposome bupivacaine and bupivacaine HCl were well tolerated and achieved > 30% pain reduction, normalized to placebo, within 5 minutes. CONCLUSIONS These results indicate that liposome bupivacaine offers time to onset characteristics similar to traditional bupivacaine HCl: clinically meaningful analgesia within 2 minutes after administration and substantial analgesia by 5 minutes.

Gallium nitrate (GN) was evaluated for its ability to interfere with a cute rejection of DBA/2-->C57BL/6 heterotopic cardiac allografts, in comparison with the depleting anti-CD4 mAb, GK1.5. The administration of GN for 30 days (s.c. 30 mg/kg elemental gallium on days 0 and 3, 10 mg/kg every third day) resulted in >60-day graft survival in 78% (25 of 32) of the graft recipients, whereas 2 perioperative injections of anti-CD4 monoclonal antibody (mAb) resulted in >60-day graft survival in 58% (24 of 41) of the graft recipients. Serum gallium levels peaked at about 2000 ng/ml after 2-3 weeks of treatment and decreased to about 300 ng/ml by day 60, a level that was maintained for at least 30 more days. During the early posttransplant period, 25% of GN-treated grafts, but not anti-CD4 mAb-treated grafts, exhibited an unusual, transient reduction in graft impulse strength, suggesting a transient rejection response. Macroscopically, the long-surviving (>60 days) grafts from either treatment group exhibited none of the features of rejecting allografts. Histologically, they exhibited minor edema and rare epicardial inflammation but no tissue necrosis. However, there were vascular changes in allografts from GN-treated mice, including altered endothelial morphology, associated with moderate intimal hyperplasia and mild perivascular leukocytic infiltration. Allografts from anti-CD4 mAb-treated mice exhibited prominent neointimal hyperplasia associated with endothelial morphologic changes and prominent vascular and perivascular leukocytic infiltration. In general, both GN and anti-CD4 mAb promoted long-term allograft survival, but these allografts displayed the histopathologic signs of ongoing inflammation and chronic allograft rejection.

Activation of neutrophils by phorbol-12-myristate-13-acetate (PMA) causes rapid production of superoxide radical (O 2 − ), leading to the formation of additional reactive oxygen species, including hydrogen peroxide (H 2 O 2 ), hypochlorous acid (HOCl), and possibly hydroxyl radical (·OH). These reactive oxygen species have been associated with the oxidation of some drugs. We investigated the metabolism of phenytoin (5,5-diphenylhydantoin) and the covalent binding of reactive intermediates to cellular macromolecules in activated neutrophils. In incubations with 100 μM phenytoin, PMA-stimulated neutrophils from six human subjects produced p -, m -, and o -isomers of 5-(hydroxyphenyl)-5-phenylhydantoin (HPPH) in a ratio of 1.0:2.1:2.8, respectively, as well as unidentified polar products. Analysis of cell pellets demonstrated that phenytoin was bioactivated to reactive intermediates that bound irreversibly to macromolecules in neutrophils. Glutathione, catalase, Superoxide dismutase, azide, and indomethacin all diminished the metabolism of phenytoin and the covalent binding of its reactive intermediates. The iron-inactivating chelators desferrioxamine and diethylenetriaminepentaacetic acid had little or no effect on the metabolism of phenytoin by neutrophils, demonstrating that adventitious iron was not contributing via Fenton chemistry. In an ·OH-generating system containing H 2 O 2 and Fe 2+ chelated with ADP, phenytoin was oxidized rapidly to unidentified polar products and to p -, m -, and o -HPPH (ratio 1.0:1.7:1.5, respectively). Reagent HOCl and human myeloperoxidase (MPO), in the presence of Cl − and H 2 O 2 , both formed the reactive dichlorophenytoin but no HPPH. However, no chlorinated phenytoin was detected in activated neutrophils, possibly because of its high reactivity. These findings, which demonstrated that activated neutrophils biotransform phenytoin in vitro to hydroxylated products and reactive intermediates that bind irreversibly to tissue macromolecules, are consistent with phenytoin hydroxylation by ·OH generated by a transition metal-independent process, chlorination by HOCl generated by MPO, and possibly cooxidation by neutrophil hydroperoxidases. Neutrophils activated in vivo may similarly convert phenytoin to reactive intermediates, which could contribute to some of the previously unexplained adverse effects of the drug.

1. An open-label, randomised study was performed to assess the effect of tenidap sodium on the pharmacodynamics and plasma protein binding of warfarin. 2. Fourteen healthy male volunteers received either a single oral dose of 120 mg tenidap sodium or matching placebo capsules from days 11 to 36. A single oral dose of 0.75 mg kg-1 warfarin was administered on days 1 and 32. 3. The mean prothrombin AUC(1,120h) value between baseline and day 32 increased from 1692.4 +/- 234.5 s h to 1769.3 +/- 218.0 s h in the group given tenidap, and decreased from 1747.6 +/- 289.4 s h to 1708.1 +/- 236.8 s h in the placebo group. 4. Tenidap caused a slight delay in the normalisation of prothrombin times following the second dose of warfarin on day 32 compared with the first dose on day 1. This was significant at 36, 48, 72 and 96 h but not at 120 h after administration of warfarin. 5. The mean percentage of unbound warfarin in the tenidap group (0.08% +/- 0.09) was significantly different (P = 0.047) from that in the placebo group (-0.03% +/- 0.10) but this was not considered to be clinically meaningful. 6. These data indicate that prothrombin times should be monitored during concomitant administration of tenidap and warfarin.

The effects of gallium nitrate (GN) were evaluated on osteopenia induced by ovariectomy (OVX) and a low-calcium diet (LCD) in Sprague-Dawley rats. Twenty-five rats (300–400 g) were randomized into four groups of 5–7 animals: (I) OVX LCD treated with GN for 22 weeks; (II) OVX LCD treated with GN for 10 weeks; (III) OVX LCD treated with saline; and (IV) sham-operated (SO), normal diet, treated with saline. GN-treated rats received a 30-mg/kg subcutaneous single dose of elemental gallium, followed by 10 mg/kg per week, whereas control animals received an equal volume of saline. All animals were euthanized at 22 weeks. Measurements of bone density and histomorphometry, performed on the proximal portion of the tibia, indicated significant bone loss in all OVX LCD animals. GN-treated rats in group I gained significantly less weight than those in the other groups, and their blood urea nitrogen increased, suggesting a nephrotoxic effect. After discontinuation of GN, rats in group II gained weight at the same rate as those which had received only saline. Bone formation rates in the GN-treated rats were double those of the saline-treated OVX animals and more than 10 times those of SO controls. Although the bone formation rate in GN-treated rats increased, GN had no effect in preventing the loss of bone surface, density and volume induced by OVX LCD. These findings suggest that although GN may enhance osteoblastic activity, this agent alone does not appear effective in the prevention of bone loss induced by OVX LCD.

An open-label, placebo-controlled study was conducted to determine the effects of sertraline on the steady-state levels and renal clearance of lithium in 20 healthy volunteers. Subjects received 600 mg of lithium twice daily for 9 days. On the evening of day 8, subjects received orally either placebo or 100 mg of sertraline; these were administered twice, 8 hours apart, beginning 2 hours after the evening dose of lithium. In a comparison of day 8 with day 9 (before administration of the morning doses of lithium), sertraline was associated with only a 0.01 mEq/L (1.4%) decrease in steady-state levels and a 0.11 L/hour (6.9%) increase in the renal clearance of lithium. Neither change was statistically significant relative to placebo. Four subjects were excluded from analysis because of protocol violations or laboratory abnormalities unrelated to sertraline. Seven subjects who received lithium plus sertraline experienced side effects, mainly tremors, possibly related to treatment, whereas none of those administered lithium plus placebo experienced side effects. No sertraline-related laboratory abnormalities were observed.

1. Hexobarbital (100 mg/kg i.p.) sleeping times in male CD-1 mice pretreated (-1 h) with a single i.p. injection of 150 mumol/kg of psoralen or coumarin analogues were increased, most markedly (6-fold) by linear, methoxy-substituted psoralens. 2. Hexobarbital sleeping times of mice which received three daily injections (231 mumol/kg; 50 mg/kg) of 8-methoxypsoralen (8-MOP) were 44% of controls (corn oil). 3. The whole-body half-life of caffeine (1 mg) in mice was 10.2, 1.2, and 0.37 h following 8-MOP (50 mg/kg per day) x 1, vehicle, and 8-MOP x 3 respectively. 4. The whole-body concentrations of hexobarbital (100 mg/kg dose) in mice 30 min after dosing were 14.3 +/- 0.9, 8.4 +/- 0.3, and 5.2 +/- 0.5 micrograms/ml (1 mouse = 150 ml) following 8-MOP (50 mg/kg per day) x 1, vehicle, and 8-MOP x 3 respectively. 5. It is concluded that, administered acutely, psoralen analogues inhibit hexobarbital metabolism in mice; and 8-MOP administered acutely inhibits the metabolism of caffeine and hexobarbital, but administered repeatedly increases their metabolism.

Most new drug development in Phase I clinical trials relies on the use of "normal healthy research volunteers" (NHRVs); however, little is known about the personality functioning of these volunteers. Determining whether NHRVs are similar to or different from individuals with "normal" personalities can impact participant recruitment, group assignment, and statistical interpretation of study results. This pilot study was undertaken to gain insight into the demographics, personality functioning, and potential psychopathology of the volunteers who participated in a Phase I confinement clinical drug trial. NHRVs (N=28) in an all-male, Phase I clinical trial completed a battery of questions, including the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and a sociodemographic questionnaire. Fifty percent of the sample showed clinically significant elevations on at least one of the scales. Current findings need to be replicated and expanded through future research. Results must be interpreted with caution because of the small, all-male sample. This preliminary study suggests that there is a difference in personality functioning between NHRVs and the general population. In addition, NHRVs may purposefully distort or conceal self-report information when participating in studies.

The effects of gallium nitrate on bone turnover were evaluated in four patients with active Paget's disease. Treatment with gallium nitrate (100 mg/m2 daily for 5 days, intravenously in 5% glucose) significantly reduced serum calcium, serum phosphate, urinary calcium, and the ratio of maximum tubular reabsorption of phosphate to glomerular filtration rate in each patient. Serum parathyroid hormone levels rose. The findings suggest that the fall in serum calcium caused secondary hyperparathyroidism, resulting in a fall in serum phosphate. Serum alkaline phosphatase and urinary hydroxyproline levels fell substantially, showing that gallium effectively suppressed bone turnover. The fall in hydroxyproline excretion preceded that in serum alkaline phosphatase, suggesting that suppression of bone resorption by osteoclasts preceded that of bone formation by osteoblasts. Alkaline phosphatase levels remained low throughout follow-up (85-141 days), so the effect of gallium seems to be long-lasting.

First-time-in-humans studies of drugs (phase I) typically exclude unsuitable volunteers by testing for recreational drugs. However, volunteers are usually not screened for cotinine, a metabolite of nicotine, even though tobacco products may alter pharmacokinetic and pharmacodynamic parameters and withdrawal from tobacco may cause additional adverse events. The accuracy of personal histories as a means of excluding smokers was examined prospectively in three phase I units in the northeastern, midwestern, and southwestern United States. In studies intended for nonsmokers, 45 of 282 purported nonsmokers screened before enrollment tested positive for cotinine. This suggests that personal histories are unreliable in determining tobacco use in clinical trials designated for nonsmokers.

Gallium nitrate, a drug shown to have efficacy in Paget's disease of bone, hypercalcemia of malignancy, and a variety of experimental autoimmune diseases, also inhibits the growth of some types of cancer. We examined dose and timing of administration of gallium nitrate on limb regeneration in the Mexican axolotl, Ambystoma mexicanum. Administered by intraperitoneal injection, gallium nitrate inhibited limb regeneration in a dose-dependent manner. Gallium nitrate initially suppressed epithelial wound healing and subsequently distorted both anterior-posterior and proximo-distal chondrogenic patterns. Gallium nitrate given at three days after amputation severely inhibited regeneration at high doses (6.25 mg/axolotl) and altered the normal patterning of the regenerates at low doses (3.75 mg/axolotl). Administration of 6.25 mg of gallium nitrate at four or 14 days prior to amputation also inhibited regeneration. In amputated limbs of gallium-treated axolotls, the chondrocytes were lost from inside the radius/ulna. Limbs that regenerated after gallium treatment was terminated showed blastema formation preferentially over the ulna. New cartilage of the regenerate often attached to the sides of the existing radius/ulna proximally into the stump and less so to the distal cut ends. J. Exp. Zool. 293:384–394, 2002. © 2002 Wiley-Liss, Inc.

Joseph P Kitzmiller,1,4 Mitch A Phelps,2 Marjorie V Neidecker,3 Glen Apseloff41Center for Pharmacogenomics, Colleges of Medicine and of Engineering, The Ohio State University Medical Center, 2Colleges of Pharmacy and Medicine, Pharmacoanalytic Shared Resources Laboratory, The Ohio State University, 3Colleges of Medicine, Nursing, and Pharmacy, The Ohio State University, 4Department of Pharmacology, The Ohio State University College of Medicine, Columbus, OH, USAAbstract: Studying the effect of drugs on humans, clinical pharmacologists play an essential role in many academic medical and research teams, within the pharmaceutical industry and as members of government regulatory entities. Clinical pharmacology fellowship training programs should be multidisciplinary and adaptable, and should combine didactics, applied learning, independent study, and one-on-one instruction. This article describes a recently developed 2 year clinical pharmacology fellowship program – one of only nine accredited by the American Board of Clinical Pharmacology – that is an integrative, multi faceted, adaptable method for training physicians, pharmacists, and scientists for leadership roles in the pharmaceutical industry, in academia, or with regulatory or accreditation agencies. The purpose of this article is to provide information for academic clinicians and researchers interested in designing a similar program, for professionals in the field of clinical pharmacology who are already affiliated with a fellowship program and may benefit from supplemental information, and for clinical researchers interested in clinical pharmacology who may not be aware that such training opportunities exist. This article provides the details of a recently accredited program, including design, implementation, accreditation, trainee success, and future directions.Keywords: clinical pharmacology education, clinical pharmacology fellowship

Injectable gallium (Ga) nitrate, approved in the United States for the treatment of hypercalcemia of malignancy, has been known for more than 2 decades to have immunosuppressive properties. At therapeutic doses, it has few adverse effects, although high-dose infusions may result in severe nephrotoxicity, particularly in patients who are not adequately hydrated, and severe anemia. In animal models, Ga has been shown to have efficacy in the treatment of adjuvant arthritis, type 1 diabetes, experimental autoimmune encephalomyelitis, experimental pulmonary inflammation, cardiac allograft rejection, experimental autoimmune uveitis, endotoxic shock, and systemic lupus erythematosus. Clinical trials have demonstrated efficacy in Paget's disease of bone and activity against some malignancies, including epithelial ovarian carcinoma, non-squamous cell carcinoma of the cervix, bladder cancer, and non-Hodgkin's lymphoma. Other clinical trials underway include studies of sarcoidosis and rheumatoid arthritis. Future studies should be conducted not only in other autoimmune diseases, such as multiple sclerosis, but also in graft-versus-host disease, leprosy, and acquired immunodeficiency syndrome (AIDS).

The effect of sertraline on the plasma protein binding of warfarin was investigated in a nonblinded randomised placebo-controlled parallel trial in 12 healthy male volunteers. The study participants received single doses of warfarin before administration of sertraline or placebo and again after sertraline or placebo had been administered for 22 days. Treatment with sertraline for 26 days increased the area under the mean prothrombin time vs time curve by 145 sec *h (7.9%), compared with a decrease of 17 sec *h (-1.0%) in the placebo group. Although statistically significant (p = 0.02), this difference was not felt to be clinically meaningful. There appeared to be a slight delay in the normalisation of the prothrombin time in the sertraline-treated group after the second dose of warfarin, which also would not be expected to be clinically significant. After 22 days, a statistically significant (p = 0.02) increase in unbound warfarin was observed in the sertraline group compared with the placebo-treated individuals. Neither the change in prothrombin time nor the change in plasma protein binding were considered to have any clinical relevance; however, good clinical practice dictates that prothrombin time should be monitored in patients treated concurrently with warfarin and sertraline to ensure that the integrity of coagulation response is maintained. The metabolism of warfarin is principally mediated by the cytochrome P450 (CYP) isoenzyme CYP2C9/10. Thus, sertraline appears to have a minimal effect on the CYP2C9/10 isoenzyme.

1. An open-label, randomised placebo-controlled study was conducted to determine the effects of tenidap sodium, a novel, cytokine-modulating anti-rheumatic drug, on the steady-state concentrations and renal clearance of lithium carbonate. 2. Eighteen healthy male volunteers received 450 mg lithium carbonate twice daily for 15 days and once on day 16. On days 9-16 subjects also received either placebo or 120 mg day-1 tenidap 2 h prior to the morning dose of lithium. 3. Following a single dose of tenidap, the renal clearance of lithium decreased significantly by 0.36 l h-1 (-23%) compared with the clearance in the placebo group, which increased by 0.18 l h-1 (+14%). Steady-state serum lithium levels increased after a single dose of tenidap by 0.069 mEq l-1 (+13%), and in the placebo group levels increased by 0.003 mEq l-1 (+0.5%); this difference was not significant. 4. After 7 days' continuous administration of tenidap, the renal clearance of lithium had decreased by 0.38 l h-1 (-25%), compared with the placebo group in which clearance had increased by 0.16 l h-1 (+12%). The steady-state serum concentration of lithium increased by 0.208 mEq l-1 (+39%) in the tenidap group and by 0.063 mEq l-1 (+10%) in the placebo group. Both of these differences were significant. 5. Two subjects who received lithium plus tenidap experienced gastrointestinal side effects, compared with none of those who were administered lithium plus placebo. 6. It is recommended that serum lithium levels be monitored when tenidap and lithium are administered concomitantly.

A 15-year-old boy died during a vaso-occlusive sickle cell crisis after having received a prolonged infusion of morphine. Even in therapeutic doses, narcotics may cause significant respiratory acidosis and hypoxemia, enhancing polymerization of hemoglobin SS and thereby promoting sickling and vaso-occlusion. When narcotics are used during a sickle cell crisis, the best method is pharmacokinetically based patient-controlled analgesia.