Changes In Laboratory Values Research Articles

P3-11-03: A Phase I Trial of D-Limonene in Newly Diagnosed Breast Cancer Patients: A Chemoprevention Study.

Abstract Background: D-limonene (DL) is a highly lipophilic monoterpene found naturally in citrus that has been demonstrated in preclinical studies to have anticancer properties. Early phase clinical trials support the investigation of DL in the chemoprevention of breast cancer. We sought to evaluate whether DL and its presumed active metabolite perillic acid (PA) would distribute extensively to the breast tissue and reach an effective drug concentration. We hypothesized that the mechanism of DL is related to the induction of apoptosis in cancer cells. Materials and Methods: We enrolled 40 patients with newly diagnosed Stage 0–2 breast cancer to take 2 grams daily of oral DL for 2–6 weeks prior to planned surgical intervention. Blood was drawn pre/post intervention to assess for toxicity and plasma concentration of DL and PA. Adverse effects related or possibly related to the study drug were noted. A small piece of breast tissue adjacent to the tumor mass was used to measure drug concentration for each patient. DL and PA levels in breast tissue were analyzed by gas chromatography and liquid chromatography, respectively, in tandem with mass spectrometry. Analysis of variance testing was used to determine if DL or PA preferentially concentrated in the breast tissue compared to plasma. We tested for a possible modulation of the biomarkers estrogen receptor (ER), progesterone receptor, HER2, Ki67 or grade pre/post treatment by comparing results from the core biopsy to the surgical pathology and applying pairwise Student's T tests. The caspase 3 and the annexin V assays were performed by plating 10,000 cells per well for the cell lines MCF7, MDA-231, BT474, and T47D and separately administering DL and PA acid in serial dilutions in their treatment concentration ranges in triplicate and read by microplate. Results: DL was found to preferentially concentrate in breast tissue versus plasma (tissue/plasma concentration ratio (TPCR) of 1297, p<0.001) while PA did not concentrate (TPCR of 1.4, p=0.9). 20 patients (50%) reported Grade 1 eructation, which was the most common adverse effect. A slight decrease in white count from a mean of 7.1 to 6.6 (p=0.03) and a slight increase in ALT from a mean of 22.5 to 26.9 (p=0.03) were noted. No other statistically significant changes in laboratory values related to serum complete blood count, renal, hepatic or other studies were noted. No change in tissue biomarkers were noted post-treatment. DL produced a dose dependent increase in the apoptotic markers cleaved caspase 3 and annexin V for the ER positive cell lines MCF7, BT474, and T47D, however, no such response was noted for the triple negative cell line MDA-231. A PA dose response trend was noted with the annexin V but not the caspase 3 assay for each cell line. Discussion: D-limonene preferentially concentrates in the breast tissue and is a candidate chemopreventive agent based on its favorable side effect profile. PA does not readily concentrate in the breast when administered as oral DL. Our correlative studies establish that DL induces apoptosis in ER positive breast cancer cell lines; no definite relationship between PA and apoptosis was found. Further clinical trials of DL are necessary to establish its potential role as a chemopreventive agent in breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-11-03.

Evolution of Laboratory Values in Patients With Kawasaki Disease

As outlined in the 2004 American Heart Association guidelines, the diagnosis of Kawasaki disease (KD) is supported by results of clinical laboratory studies. However, detailed information regarding the evolution of these results during illness has not been previously reported. The goals of this project were to characterize the evolution of clinical laboratory values in KD before and after treatment with intravenous immunoglobulin (IVIG). Laboratory values from 380 unselected, consecutive KD patients were analyzed at 3 times: acute (illness day, 2-10; illness day 1 = first day of fever and before IVIG), subacute (illness day, 11-21), and convalescent (illness day, 22-60). Results were stratified by IVIG response and coronary artery outcome. Although white blood cell count, percentage bands, erythrocyte sedimentation rate, and C-reactive protein values were highest and age-adjusted hemoglobin was lowest in the acute phase before IVIG, platelet count was highest in the subacute phase, and percentage lymphocytes and eosinophils were highest in the convalescent phase after IVIG. KD patients with coronary artery aneurysms had a higher white blood cell count in the subacute phase and higher erythrocyte sedimentation rate in the subacute and convalescent phases compared with those with dilated or normal coronary arteries. A consistent evolution of laboratory values is associated with KD before and after treatment. Understanding the dynamic changes in laboratory values can assist physicians in using laboratory criteria to diagnose KD following the American Heart Association guidelines.

Benign convulsions in newborns and infants: Occurrence, clinical course and prognosis

Background During early development severe epilepsies may appear, some with well established occurrence. Benign non-epileptic and epileptic paroxysmal syndromes with excellent prognosis occur in the same period. There are no exact data on their occurrence. Aim We have reviewed medical histories of children with benign non-epileptic or benign epileptic events: benign myoclonus of early infancy, benign neonatal sleep myoclonus, benign sleep myoclonus in infancy, benign partial epilepsy in infancy (BPEI) and benign infantile familial convulsions (BIFC) were established. The occurrence, clinical characteristics and prognosis of these syndromes were evaluated. Methods Inclusion criteria were met in 31 children. Research included retrospective analysis of clinical characteristics, laboratory values, neuroimaging and neurophysiological assessments, followed by evaluation of psychosocial development with the use of the Strengths and Difficulties Questionnaire (SDQ), fulfilled by parents. Results In our group the incidence of benign non-epileptic convulsions was 6.69 per 10 000 live births and the incidence of benign epileptic convulsions was 1.35 per 10 000. Male/female ratio in the group of children with non-epileptic events was 2.1:1. Among non-epileptic group 5 out of 23 children and among epileptic group 3 out of 8 children had minimal, mild or moderate abnormalities at neurological assessment at the time of the first clinical examination. Nonspecific changes in laboratory values were seen in 6 out of 23 in the non-epileptic and in 1 out of 8 children in the epileptic group. Neurophysiological assessments showed subtle changes in 4/23 in the non-epileptic and 6/8 in the epileptic group. Neuroimaging was not optimal in 5/23 with non-epileptic and 3/8 with epileptic events. Analysis of SDQ did not show significant deviations in psyhosocial development. Statistically significant deviation was observed only in relations with peers ( p = 0.009). Conclusions Benign neonatal and infantile convulsions are more frequent than severe epilepsies of the same age period. Results show higher proportion of males with benign non-epileptic conditions. No deviations in further development was found. Laboratory values, neuroimaging and neurophysiological assessments were normal or nonspecifically changed.

Effect of adalimumab on clinical laboratory parameters in patients with Crohnʼs disease: Results from the CHARM trial

Nutritional deficiencies and anemia are common in Crohn's disease (CD). We evaluated the effect of adalimumab on changes in laboratory values using data from CHARM, in which patients were randomized to adalimumab 40 mg every other week (eow), adalimumab 40 mg weekly, or placebo for 56 weeks. Mean changes in laboratory values from baseline to Weeks 26 and 56 were compared between adalimumab and placebo using analysis of covariance models. Percentages of patients with suboptimal laboratory values at Weeks 26 and 56 were compared between treatment groups using Cochran-Mantel-Haenszel (CMH) tests. Pearson correlation coefficients for associations between changes in Crohn's Disease Activity Index (CDAI) score and changes in laboratory values were estimated at Weeks 4, 26, and 56. The intention-to-treat analysis included 778 patients randomized to adalimumab eow (N = 260), adalimumab weekly (N = 257), or placebo (N = 261). Baseline abnormalities in laboratory values were common across treatment groups. CMH tests revealed significantly lesser rates of suboptimal laboratory values with adalimumab vs. placebo at Week 26, including hypoalbuminemia, calcium deficiency, low hemoglobin, low hematocrit, low red blood cell count, elevated platelet count, and elevated C-reactive protein concentration (all P < 0.05). These improvements persisted at Week 56. Improvements in CDAI from baseline to Weeks 4, 26, and 56 were significantly correlated with changes from baseline for albumin, hemoglobin, and C-reactive protein (all P < 0.001). Adalimumab therapy for moderately to severely active CD was associated with significant improvements in nutritional, hematologic, and inflammatory markers.

P01.8 Serum S100B levels in children with simple febrile seizures

Results: The incidence of benign convulsion is 8,046/10,000 live births. 65% of included children were male, 26% had minimal, mild or moderate abnormalities in neurological evaluation at the time of first clinical examination. For a similar percentage we found nonspecific changes in laboratory values (23%), neurophysiological assessments (32%) and neuroimaging (26%). Spontaneous remission of seizures were observed in 38% of children with BPEI/BIFC. Analysis of SDQ did not show significant deviations in psyhosocial development. Statistically significant deviation was observed only in relations with peers (p=0.009). Conclusions: Benign neonatal and infantile convulsions are more frequent than severe epilepsies. Results show higher proportion of males with these conditions and no deviations in further development. Laboratory values, neuroimaging and neurophysiological assessments are normal or nonspecifically changed. Antiepileptic treatment is justified in a portion of children diagnosed with BPEI/BIFC.

Sodium Iodide Symporter SPECT Imaging of a Patient Treated With Oncolytic Adenovirus Ad5/3-Δ24-hNIS

Sodium Iodide Symporter SPECT Imaging of a Patient Treated With Oncolytic Adenovirus Ad5/3-Δ24-hNIS

Biochemical and Hematologic Changes after Percutaneous Radiofrequency Ablation of Liver Tumors: Experience in 83 Procedures

Purpose To determine the frequency and severity of various abnormal laboratory tests after percutaneous radiofrequency (RF) ablation of liver tumors and to estimate the correlation between laboratory test values and volumes of tumor and ablated tissue. Materials and Methods Biochemical and hematologic laboratory values of 83 computed tomography-guided RF ablations of liver tumors were reviewed retrospectively at baseline, 0–6, 6–12, 12–24 hours, and 1–2 weeks, assessed for significant changes, and correlated with tumor, total ablation, and ablative margin (consisting of ablated nontumoral liver parenchyma and calculated by subtracting tumor volume from ablation volume). Results Mean total ablation volume was 26.6 mL (range, 3.14–1020.5 mL). Aspartate aminotransferase (AST) values exceeded normal range after 78 (93.9%) procedures and peaked at 12–24 hours (mean, 321 U/L). Alanine aminotransferase (ALT) values exceeded normal range after 58 (69.9%) procedures and peaked at 12–24 hrs (mean, 220 U/L). Bilirubin levels increased after 34 (41%) procedures (mean maximal increase, 1.1 mg/dL) and peaked at 12–24 hours in 13 (36%). Peak AST (r = 0.3), peak ALT (r = 0.3), and peak bilirubin (r = 0.3) levels correlated only with ablation margin volume. Three patients with severely elevated bilirubin and alkaline phosphatase levels had biliary complications. Platelets decreased below 100,000/μL ( n = 5) only when the preprocedural level was < 120,000/μL. Severe myoglobinemia occurred once and was treated successfully with serum alkalinization. Conclusions Changes in laboratory values after percutaneous RF ablation of liver tumors are common and usually mild and self-limited. Peak aminotranferase levels and bilirubin values correlate with ablative margin volume and, along with elevated alkaline phosphatase, when severe, may be a harbinger of biliary complications.

FC13-11 - Effectiveness of mazindol in children with ADHD : open-label study

Mazindol is a central nervous system stimulant, which blocks reuptake of dopamine and norepinephrine. Mazindol (1–6 mg/d) has previously been studied in the treatment of excessive daytime sleepiness with relative therapeutic benefit. Our hypothesis suggests that mazindol may be effective for the treatment of Attention Deficit Hyperactivity Disorder symptoms.Based on clinical assessments after oral administration of mazindol to 24 children (9–12 years) with ADHD (according to DSM-IVTR criteria), this open-label study evaluates the efficacy, safety and tolerability of mazindol (1 mg/d, 7 days). Safety evaluations included routine hematology, electrocardiograms, blood pressure, and pulse rate. Efficacy rating measurements included ADHD-RS score (primary outcome measure), CPRS-R:L, CGI-S and CGI-I (secondary outcome measures). This clinical trial reports data obtained from 21 boys (10 ± 1 years).Based on primary outcome (ADHD-RS), change in ADHD-RS mean total score after one week of mazindol was −24.6 (p &lt; 0.0001) ; greater than a 90% improvement from baseline. Change in CPRS-R:L (80 items) mean total score after one week of mazindol was −55.5 (p &lt; 0.0001); CGI-S after one week of mazindol was -3,02 (p&lt; 0.01). Adverse events were mild to moderate in severity and decreased appetite, weight loss, headache, and abdominal pain were most common (95%).Changes in laboratory values, ECG, blood pressure, pulse rate and body weight were not clinically meaningful. Blood pressure and pulse rate were unchanged (p &gt; 0.05) after one week of treatment.This preliminary investigation suggests that mazindol is still a new well-tolerated and active psychostimulant for the treatment of ADHD in children.

Prevalence of Hyponatremia, Renal Dysfunction, and Other Electrolyte Abnormalities Among Runners Before and After Completing a Marathon or Half Marathon

Background:Prior reports on metabolic derangements observed in distance running frequently have small sample sizes, lack prerace laboratory measures, and report sodium as the sole measure.Hypothesis:Metabolic abnormalities—hyponatremia, hypokalemia, renal dysfunction, hemoconcentration—are frequent after completing a full or half marathon. Clinically significant changes occur in these laboratory values after race completion.Study Design:Observational, cross-sectional study.Methods:Consenting marathon and half marathon racers completed a survey as well as finger stick blood sampling on race day of the National Marathon to Fight Breast Cancer (Jacksonville, Florida, February 2008). Parallel blood measures were obtained before and after race completion (prerace, n = 161; postrace, n = 195).Results:The prevalence of prerace and postrace hyponatremia was 8 of 161 (5.0%) and 16 of 195 (8.2%), respectively. Hypokalemia was not present prerace but was present in 1 runner postrace (1 of 195). Renal dysfunction occurred prerace in 14 of 161 (8.7%) and postrace in 83 of 195 (42.6%). Among those with postrace renal dysfunction, 45.8% (38 of 83) were classified as moderate or severe. Hemoconcentration was present in 2 of 161 (1.2%) prerace and 6 of 195 (3.1%) postrace. The mean changes in laboratory values were (postrace minus prerace): sodium, 1.6 mmol/L; potassium, −0.2 mmol/L; blood urea nitrogen, 2.8 mg/dL; creatinine, 0.2 mg/dL; and hemoglobin, 0.3 g/dL for 149 pairs (except blood urea nitrogen, n = 147 pairs). Changes were significant for all comparisons (P < 0.01) except potassium (P = 0.08) and hemoglobin (P = 0.01).Conclusions:Metabolic abnormalities are common among endurance racers, and they may be present prerace, including hyponatremia. The clinical significance of these findings is unknown.Clinical relevance:It is unclear which runners are at risk for developing clinically important metabolic derangements. Participating in prolonged endurance exercise appears to be safe in the majority of racers.

Long-Term Safety of OROS Methylphenidate in Adults With Attention-Deficit/Hyperactivity Disorder

To evaluate the long-term safety of OROS methylphenidate in the management of attention-deficit/hyperactivity disorder (ADHD) in adults. This multicenter, open-label, dose-titration, flexible dose study enrolled adults with ADHD for 6 or 12 months of treatment with OROS methylphenidate. Dosing began at 36 mg/d, with titration in 18-mg increments every 7 days until a predefined outcome (efficacy threshold, maximum dosage of 108 mg/d, or limiting adverse event). Dose reduction occurred for prespecified reasons, and the subjects discontinued if unable to tolerate 36 mg/d. Assessments included ADHD symptoms, adverse events, vital signs, and laboratory results. A total of 550 subjects received treatment (52% were men; mean age, 39 years; range, 18-65 years), and 57% (146/258) and 44% (129/292) completed their 6 or 12 months of treatment with mean durations of 128 and 213 days, respectively. The final prescribed dosages were 36 mg/d (22.4%), 54 mg/d (25.1%), 72 mg/d (22.0%), 90 mg/d (17.1%), and 108 mg/d (13.5%). Modest increases from baseline to final visit were observed in mean systolic (2.6 mm Hg) and diastolic (1.9 mm Hg) blood pressure and pulse (4.1 beats per minute). The mean weight decreased by 2.3 kg. No clinically meaningful changes in laboratory values or electrocardiogram parameters were observed other than increased heart rate. Most common adverse events included decreased appetite (26.7%), headache (24.0%), and insomnia (20.7%). No serious adverse event was considered related to study medication. Several measures of efficacy indicated improvement during the study. OROS methylphenidate, in the flexible dosage range from 36 to 108 mg/d, was well tolerated for up to 1 year in adults with ADHD.

ベンズブロマロン（ユリノーム&amp;reg;錠）の製造販売後調査 ー使用実態下における副作用発現状況ならびに安全性および有効性に関連する臨床検査値の推移ー

ベンズブロマロン（ユリノーム®錠）の使用実態下における安全性および有効性を再確認する目的でプロスペクティブに使用成績調査を行った．安全性解析対象4,659症例中，113症例に144件の副作用が発現し，副作用発現症例率は2.43％であった．主な副作用は，臨床検査値異常が48症例（62件）で，この内，AST増加，ALT増加など肝機能関連の検査値異常が40症例（51件）であった．また，肝障害などの「肝胆道系障害」が 21症例（21件），発疹などの「皮膚および皮下組織障害」が18症例（21件），下痢などの「胃腸障害」が12症例（13件）認められた．副作用発現症例の層別解析において，副作用発現頻度に影響を及ぼす背景因子は特に認められなかった．ベンズブロマロン投与開始前に比べて投与後のALT，血清クレアチニン値，eGFR値に特段の変化は認められなかった．ベンズブロマロン投与後，血清尿酸値はベンズブロマロンの投与量に応じて低下した．また，投与開始前のeGFR値が30mL／min／1.73m2以上の群において，ベンズブロマロン投与後，血清尿酸値は治療目標値である6mg／dL以下に維持されていた．

A Clinical Pharmacokinetic Drug-Drug Interaction Study of Arbaclofen Placarbil, a Novel Reflux Inhibitor, With Esomeprazole

Purpose: Arbaclofen placarbil (AP), a novel reflux inhibitor, is an actively transported prodrug of the R isomer of baclofen (RB). AP is currently under investigation as an adjunct to proton pump inhibitors (PPI) for the treatment of gastroesophageal reflux disease (GERD) in patients who remain symptomatic on PPIs. The purpose of this study was to assess the potential for pharmacokinetic (PK) drug-drug interaction between AP and esomeprazole. Methods: In this open-label, 2-treatment, 2-period, sequential design study, 15 healthy adult subjects were treated with sustained-release AP 60 mg qd for 5 days, followed by AP 60 mg + esomeprazole 40 mg qd for 5 days. There was a 3-day titration period and a 5-day tapering period for AP. Steady-state AP and RB concentrations were determined on days 8 and 13, using LC/MS/MS methods. PK parameters were estimated using noncompartmental analysis and compared for AP and AP + esomaprazole (days 8 and 13) using ANOVA. Results: Fifteen subjects completed the study. AP was well absorbed and rapidly converted to RB. Mean RB Css,max and AUCss,24 values were 144 ng/mL and 1480 ng*h/mL, respectively, for AP alone, and were 124 ng/mL and 1270 ng*h/mL, respectively, when AP was dosed with esomeprazole. Mean Css,max and AUCss,24 of RB were each decreased by approximately 14% when AP was coadministered with esomeprazole. Statistical analysis showed no significant treatment effect on the PK parameters at level α=0.05. The 90% confidence intervals of ratio of means included 1. Levels of the intact prodrug were low and transient for both treatments (Mean of % [AP AUClast to RB AUClast] of ≤ 10). There was no effect on AP exposure when AP was coadministered with esomeprazole. Both AP and AP+ esomaprazole treatments were generally safe and well tolerated. There were no clinically significant changes in laboratory values, vital signs, or ECG parameters. Conclusion: There was no clinically relevant or statistically significant drug-drug interaction when AP was administered with esomeprazole. The results of this study suggest that no AP dose adjustment is needed with coadministration of PPIs. Disclosure: All authors are employees of XenoPort, Inc. The study was funded by XenoPort, Inc.

EFFICACY AND TOLERABILITY OF A FIXED LOW-DOSE COMBINATION PERINDOPRIL/INDAPAMIDE AS INITIAL TREATMENT IN PRIMARY ARTERIAL HYPERTENSION: THE START STUDY: PP.16.108

Objective: The objective of the study was to determine the efficacy and tolerability of once-daily administration of a fixed low-dose combination of perindopril 2 mg / indapamide0.25 mg as initial treatment in patients with primary hypertension, naïve of any previous therapy. Design and Method: This prospective, multi-centre, open label, national trial enrolled consecutive outpatients >18 years old, with BP >140/90mmHg, naïve of any previous antihypertensive therapy over 5 month. The follow-up lasted 12 weeks with monthly visits. Patients were included to receive once daily, 1 tablet of fixed dose combination of perindopril 2 mg/indapamide 0.625 mg, in addition to lifestyle modifications. If necessary, at the follow-up visits, the dose could be gradually increased to 3 mg/0.937 mg and 4 mg/1.25 mg. Results: The study population consisted of 714 patients included and followed-up in 49 study centres. At baseline, more than half (60%, n = 434) of the patients had grade 2, a quarter (26.5%, n = 189) grade 1, and only 12.7% (n = 91) grade 3 hypertension. No significant gender differences related to severity of hypertension were noted. The primary endpoint (BP control rate at 3 months) was 69%, slightly higher in women (p = 0.002). As expected, time to BP control was shorter in patients with moderate hypertension at baseline (p < 0.001), with approximately one month delay for each supplemental grade of hypertension. 91.6% of the controlled patients needed only one tablet of fixed perindopril 2 mg /indapamide 0.625 mg combination, in addition to lifestyle modifications. The main secondary endpoint (average BP reduction over 3 months of treatment) was 31.2 and 16.6 mmHg in sitting systolic and diastolic BP respectively. Compliance was good, 98.47% of the patients completing the study. At 90 days, adverse effects were less than 1%, with 5 withdrawals because of them. No significant changes in laboratory values were noted. Conclusion: Initial therapy with the fixed low-dose combination perindopril 2 mg / indapamide 0,625 mg is safe and effective to control mild to moderate hypertension.

Association between positional changes in laboratory values and severity in subjects with obstructive sleep apnea syndrome.

The aim of the study was to investigate the association between the difference (defined as the remainder, Rm) in laboratory values determined in the upright and supine positions and the severity of obstructive sleep apnea syndrome (OSAS). Thirty-three Japanese male subjects with OSAS [apnea/hypopnea index (AHI: the number of apneas and hypopneas per hour) > or =5] underwent cephalometric analysis and measurements of nasal resistance in the upright and supine positions. Several parameters in a dental model and physical features were also analyzed. Significant associations of the logarithmic AHI, with neck depth, Rm for the facial axis, and the minimum airway behind the tongue in the supine position were found in multiple linear regression analysis. Our results suggest that neck depth, Rm for the facial axis and the minimum airway behind the tongue in the supine position may be determinants of the severity of OSAS.

A randomised, multicentre, double-blind, placebo-controlled trial of etanercept in adults with refractory heel enthesitis in spondyloarthritis: the HEEL trial

ObjectiveInflammation at the entheses is a distinguishing feature of spondyloarthritis (SpA). Enthesitis at the heel is the most common location and is often chronic, refractory to standard treatment and may...

Long‐Term, Open‐Label Safety Study of Oral Almotriptan 12.5 mg for the Acute Treatment of Migraine in Adolescents

This study evaluated the long-term safety of oral almotriptan 12.5 mg for the treatment of multiple migraine episodes in adolescents over a 12-month period. Efficacy outcomes were assessed as a secondary objective. Adolescent migraineurs aged 12-17 years were enrolled in this 12-month, open-label study (Study ID CR002827). Patients were instructed to record their assessments on paper headache records whenever they experienced a migraine headache that they treated with study medication. Safety was assessed descriptively and assessments included adverse event (AE) recording, change in laboratory values, vital signs, and electrocardiogram parameters. Efficacy outcomes were assessed descriptively and outcomes included rates for 2- and 24-hour pain relief and sustained pain relief, 2- and 24-hour pain-free and sustained pain-free, and presence of migraine-associated symptoms of photophobia, phonophobia, nausea and vomiting. Overall, 67.1% of patients reported >or=1 AE over the course of the trial, 7.6% had an AE judged by the study investigator to be related to treatment with almotriptan, 2.4% discontinued because of an AE, and 1.9% reported serious AEs. The most commonly reported treatment-related AEs (occurring in >or=1% of patients) were nausea (1.4%) and somnolence (1.4%). Pain relief responses for treated migraines of moderate or severe intensity at baseline were 61.7% and 68.6%, at 2 and 24 hours, respectively; the sustained pain relief rate was 55.5%. Pain-free responses were reported for 40.5% of all treated migraines at 2 hours and 65.9% of treated migraines at 24 hours; the sustained pain-free rate was 38.4%. The proportion of migraines that achieved the pain relief, sustained pain relief, pain-free and sustained pain-free endpoints were similar in the 12- to 14-year and 15- to 17-year age groups. Treating with almotriptan 12.5 mg when headache pain was mild was associated with higher rates of pain relief and pain-free at 2 and 24 hours, and sustained pain relief and sustained pain-free, compared with treatment initiated when pain was severe. Almotriptan 12.5 mg was well tolerated in this adolescent population over a 12-month period. No unexpected safety or tolerability concerns were revealed over the course of this study. The results are consistent with almotriptan 12.5 mg being effective for the acute treatment of pain and symptoms associated with migraine in both younger and older adolescents.

Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, in healthy subjects

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y(12) receptor antagonist in development for reduction of clinical thrombotic events in patients with acute coronary syndromes. The purpose of our studies was to determine the effect of single-ascending doses of ticagrelor in healthy subjects. In two randomised, double-blind, placebo-controlled single ascending dose studies, healthy subjects received oral doses of 0.1-100 mg or placebo (n = 25) and 30-400 mg or placebo (n = 13). Absorption of ticagrelor was rapid [median time to peak plasma concentration (t(max)) 1.3-2 h], as was the formation of its main (active) metabolite, AR-C124910XX (t(max) 1.5-3 h). For both ticagrelor and AR-C124910XX, the peak plasma concentration (C(max)) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) increased in an apparently dose-proportional manner over the dose range studied, indicating linear pharmacokinetics. The mean terminal-phase half-life (t(1/2)) was approximately 7-8.5 h for ticagrelor and 8.5-10 h for AR-C124910XX; AR-C124910XX exposure was approximately one third that of ticagrelor. Inhibition of platelet aggregation (IPA) was dose related and was nearly complete at 2 h (mean 88-95%; final extent, with 20 microM adenosine diphosphate ADP) at doses of 100-400 mg. Linear and predictable pharmacokinetics of ticagrelor and AR-C124910XX were observed. A consistent and high IPA was maintained over 2-12 h, gradually decreasing with declining plasma concentration starting around 12 h post-dose, indicating that the IPA is reversible. Ticagrelor was well tolerated, with no serious or dose-related adverse events or notable changes in laboratory values observed.

Safety and Tolerability of Rufinamide in Children With Epilepsy: A Pooled Analysis of 7 Clinical Studies

Rufinamide is a novel antiepileptic agent recently approved in the United States for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. To help inform clinical decision making, the authors analyzed safety and tolerability data from the entire pediatric population in the rufinamide epilepsy clinical development program. The analysis population comprised 212 rufinamide-treated (age range 3-16 years) and 197 placebo patients (age range 4-17 years) in the double-blind studies, and 391 patients receiving rufinamide in the double-blind and/or open-label extensions. The most common adverse effects observed in rufinamide-treated patients in the double-blind studies were somnolence, vomiting, and headache. Changes in laboratory values, vital signs, and weight were generally clinically insignificant. This pooled analysis of data from pediatric patients in clinical studies of rufinamide for the treatment of seizures, mainly as adjunctive therapy, suggests a favorable safety and tolerability profile in this patient population.

Adalimumab Therapy is Associated with Improvements in Clinical Laboratory Parameters in Patients with Moderately to Severely Active Crohnʼs Disease

Purpose: Clinical complications such as nutritional deficiencies and anemia are common in patients with Crohn's disease (CD). We assessed the effect of adalimumab treatment in reducing the severity and incidence of CD-related clinical complications/abnormalities indicated by clinical laboratory outcomes. Methods: Data were from CHARM, a double-blind, Phase III trial in which patients with moderate to severe CD were randomized at Week 4 to adalimumab every other week (eow), adalimumab weekly, or placebo. Demographics and disease-related data were similar for all 3 arms of the study. Laboratory outcomes evaluated in this analysis included indicators of nutritional deficiencies (albumin, calcium, total protein, and potassium), hematologic problems (hemoglobin, hematocrit, red blood cell [RBC] count, and platelet count), and inflammatory response (C-reactive protein [CRP]). The analysis included randomized patients with an observation at baseline and at least 1 observation after Week 4. Standard reference ranges were used to determine abnormalities and normal values. Mean changes in laboratory values from baseline to Weeks 26 and 56 were compared between adalimumab and placebo using analysis of covariance models. Cochran-Mantel-Haenszel (CMH) tests compared the percentage of patients with complications indicated by suboptimal laboratory values at Weeks 26 and 56 between treatment groups, controlling for baseline presence of complications. Patients who discontinued the trial or switched to open-label adalimumab had their last value carried forward.Table: Patients with suboptimal laboratory values: percentages at baseline/week 56Results: The intention-to-treat sample included 778 patients randomized to adalimumab (N=517) or placebo (N=261). CMH tests revealed significantly lesser rates of several clinical complications with adalimumab vs. placebo at Weeks 26 and 56 (table provides Week-56 assessments). Conclusion: Significant improvements in nutritional, hematologic, and inflammatory markers were observed with adalimumab therapy in patients with moderate to severe CD. These findings have important implications for clinical practice. Disclosure: Dr Rubin - Consulting fees - Abbott; Speakers bureau - Abbott. Procter & Gamble - Consulting fees, research support; Salix - Consulting fees, research support; Prometheus - Consulting fees, research support; UCB - Consulting fees, Advisory board; Centocor - Consulting fees, Advisory board; Elan - Consulting fees, Advisory board; Shire - Consulting fees, Advisory board A. Bensimon - Employee: Analysis Group Inc. Dr Yu - Employee: Analysis Group Inc. Dr Wu - Employee: Analysis Group Inc. Dr Pollack - Employee: Abbott Laboratories; Stockholder: Abbott, Johnson & Johnson (Janssen), Human Genome Sciences Dr Chao - Employee, stocks: Abbott Dr Mulani - Employee, stocks: Abbott. This research was funded by Abbott Laboratories, Abbott Park, IL.

Safety and pharmacokinetics of panitumumab in Japanese patients with advanced solid tumors

Panitumumab is a fully human, monoclonal antibody against the epidermal growth factor receptor. Previous studies in non-Japanese patients with solid tumors showed that panitumumab exhibited nonlinear pharmacokinetics, was well tolerated (skin toxicities were the most common treatment-related adverse events), and had antitumor activity in some patients. This open-label, phase 1 study investigated panitumumab safety and pharmacokinetics in Japanese patients. Japanese patients with advanced solid tumors were enrolled into one of three sequential panitumumab dose cohorts (cohort 1, 2.5 mg/kg weekly; cohort 2, 6.0 mg/kg every 2 weeks; and cohort 3, 9.0 mg/kg every 3 weeks) and received panitumumab until disease progression or drug intolerability. Safety endpoints included the incidence of adverse events, changes in laboratory values, and the appearance of anti-panitumumab antibodies. Serial pharmacokinetic samples were collected after the first and third doses of panitumumab. Tumors were assessed at week 8 and every 8 weeks thereafter. Eighteen patients (6 per cohort) were enrolled. No dose-limiting toxicities, investigator-reported infusion reactions, or deaths occurred. Seven patients had grade-3/4 adverse events; fatigue and anorexia were most common. The most common skin toxicities were rash and acneiform dermatitis. No neutralizing anti-panitumumab antibodies were detected. Panitumumab exhibited nonlinear pharmacokinetics, and antitumor activity was observed in 31% (4/13) of the patients with colorectal cancer. In Japanese patients with solid tumors, panitumumab was well tolerated, demonstrated pharmacokinetic and safety profiles similar to those observed previously in non-Japanese patients, and exhibited encouraging antitumor activity in patients with colorectal cancer.