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BACKGROUND Effacement of horizontal forehead lines (FHL) with onabotulinumtoxinA has not been investigated in prospective Phase 3 studies. OBJECTIVE To evaluate safety and efficacy of onabotulinumtoxinA treatment of FHL together with glabellar lines (GL). MATERIALS AND METHODS A 12-month, Phase 3 study randomized subjects with moderate-to-severe FHL and GL to onabotulinumtoxinA 40 U or placebo, distributed between the frontalis (20 U) and glabellar complex (20 U). After Day 180, subjects could receive up to 2 additional open-label onabotulinumtoxinA treatments. Efficacy was assessed using the Facial Wrinkle Scale (FWS) and Facial Line Outcomes questionnaire. RESULTS The intent-to-treat (ITT) population included 391 subjects, and the modified ITT (mITT) population (subjects with psychological impact) included 254 subjects. After 30 days, onabotulinumtoxinA significantly improved the investigator- and subject-assessed appearance of FHL severity by at least 2 FWS grades in 61.4% of ITT subjects versus 0% of placebo subjects (p < .0001). In the mITT population, 94.8% of onabotulinumtoxinA subjects and 1.7% of placebo subjects achieved investigator- and subject-assessed FWS ratings of none/mild (p = .0003). Patient-reported outcomes were consistent with FWS ratings. OnabotulinumtoxinA was well tolerated. CONCLUSION OnabotulinumtoxinA 40 U distributed between the frontalis and glabellar complex was safe and effective for treatment of moderate-to-severe FHL.

Although commonly practiced, simultaneous onabotulinumtoxinA injections to multiple facial areas have not been investigated in prospective studies.Evaluate safety and efficacy of onabotulinumtoxinA for treatment of forehead lines (FHL) distributed between the frontalis (20 U) and glabellar complex (20 U), with or without simultaneous lateral canthal areas (crow's feet lines [CFL], 24 U) treatment.Subjects with moderate to severe FHL were randomized (2:2:1) to onabotulinumtoxinA 40 U, onabotulinumtoxinA 64 U, or placebo. After 180 days, subjects could receive up to 2 additional open-label onabotulinumtoxinA 64 U treatments.The intent-to-treat (ITT) population comprised 787 subjects, and the modified ITT (mITT) population (subjects with psychological impact) comprised 568. After 30 days, onabotulinumtoxinA 40 U and 64 U significantly improved investigator- and subject-assessed FHL severity by at least 2 Facial Wrinkle Scale (FWS) grades in 45.6% and 53.0% of ITT subjects, respectively, versus 0.6% receiving placebo (both, p.0001). Significantly more mITT subjects receiving onabotulinumtoxinA achieved investigator- and subject-assessed FWS ratings of none/mild versus placebo (p.0001). OnabotulinumtoxinA was well tolerated.OnabotulinumtoxinA distributed between the frontalis and glabellar complex, with or without additional CFL injections, was safe and effective for treatment of moderate to severe FHL.

A number of prognostic factors have been identified as risk factors for chemotherapy-induced emesis. This post-hoc analysis addressed whether: (1) these prognostic factors can identify a low-risk group for whom ondansetron plus dexamethasone alone provide a high level of protection (≥80% no emesis); (2) the NK1 receptor antagonist aprepitant improves antiemetic outcome regardless of emetic risk. Breast cancer patients in a phase III double-blind, placebo-controlled trial were randomized to antiemetic regimens including ondansetron and dexamethasone, or aprepitant, ondansetron, and dexamethasone. Multivariate logistic regression models were used to assess the impact on emesis (but not nausea) of the regimen with aprepitant, and previously reported risk factors, including age (

Trans fatty acids have long been used in food manufacturing due in part to their melting point at room temperature between saturated and unsaturated fats. However, increasing epidemiologic and biochemical evidence suggest that excessive trans fats in the diet are a significant risk factor for cardiovascular events. A 2% absolute increase in energy intake from trans fat has been associated with a 23% increase in cardiovascular risk. Although Denmark has shown it is possible to all but eliminate commercial sources of trans fats from the diet, total elimination is not possible in a balanced diet due to their natural presence in dairy and meat products. Thus, the American Heart Association recommends limiting trans fats to

Background Little information exists on how facial aesthetic treatments are incorporated into aesthetic regimens. Objective Assess the evolution of facial aesthetic treatments in patients receiving long-term continuous onabotulinumtoxinA treatment. Methods This international retrospective chart review included patients with ≥5 years of continuous onabotulinumtoxinA treatments including ≥1 glabellar lines treatment/year. Charts were reviewed for facial areas treated, number of treatments, doses/treatment visit, concomitant aesthetic procedures, and onabotulinumtoxinA-related adverse events. Results Data were collected from 5,112 onabotulinumtoxinA treatment sessions for 194 patients over an average of 9.1 years. Dosing was relatively stable over time; however, interinjection intervals increased. Glabellar lines' treatment temporally preceded crow's feet lines and forehead lines' treatment. A majority of patients (85%) also received treatment with fillers. Cumulative increases in onabotulinumtoxinA treatments occurred over time and by facial area corresponding with increases in treatments with injectable fillers, energy-based devices, and prescription topical creams. The longer the patients were treated, the younger they perceived themselves to look. Rates of adverse events were low. Conclusion OnabotulinumtoxinA treatment evolved over time, coinciding with growth of the facial aesthetics market. Additional treatment modalities were added as complements to onabotulinumtoxinA. Long-term continuous onabotulinumtoxinA injections are an important component of contemporary facial aesthetic treatment regimens.

Background Although millions of aesthetic procedures are performed annually, few patient-reported outcome (PRO) measures have been used in this setting. Objective To evaluate the impact of onabotulinumtoxinA treatment for crow's feet lines (CFL) on relevant psychological variables and self-perception of age/appearance in subgroup populations. Materials and methods Facial Lines Outcomes (FLO-11) Questionnaire, Self-Perception of Age (SPA), and Subject Global Assessment of Change in CFL (SGA-CFL) were PRO measures administered in 2 Phase 3, double-blind placebo-controlled trials for the treatment of CFL alone or CFL/glabellar lines (GL). Patient-reported outcome measures were analyzed by subgroups (age, gender, and baseline CFL severity). Subject satisfaction with appearance was also analyzed. Results Most subgroups receiving onabotulinumtoxinA demonstrated significant improvements in psychological impact (FLO-11 Items 2, 5, and 8) versus placebo at Day 30 (p ≤ .05). OnabotulinumtoxinA-treated subjects consistently rated themselves as looking younger on SPA versus placebo in all subgroups at Day 30 (p ≤ .05) and showed significant improvements in CFL appearance versus placebo at all time points on SGA-CFL. Overall, subjects were satisfied with their appearance. Conclusion OnabotulinumtoxinA-treated subjects experienced significant improvements in perceived appearance, attractiveness, tiredness, age, and satisfaction versus placebo. Subjects treated for CFL and GL experienced even greater effects.

Objective: To investigate the relationship between viral load suppression and baseline viral load as well as that between viral load suppression and baseline CD4 + cell count. Design: Meta-analysis of published and presented studies. Methods: Trials of two nucleoside analogs plus nevirapine, indinavir, nelfinavir, or efavirenz as therapy for antiretroviral treatment-naive patients with HIV infection or AIDS who were followed-up for at least 6 months were included in the meta-analysis. The proportion of patients with viral loads of

Phospholipid extracts were made of a murine mammary adenocarcinoma implanted in the dorsum of the foot of C3H/He mice before and 96 h after 17 Gy irradiation or 150 mg/kg cyclophosphamide. Extracts of untreated tumors, which had grown for a further 96 h, were also studied. Although previous studies have shown significant changes in the precursors and catabolites of phosphatidylcholine and phosphatidylethanolamine following therapy, 31P nuclear magnetic resonance analysis of extracts showed no changes in these membrane constituents and other observed phospholipid species. A significant decrease in 1-alkyl-2-acyl-sn-glycero-3-phosphocholine, however, was observed 96 h following cyclophosphamide treatment.

The effect of 5-fluorouracil (5FU) on the 31P nuclear magnetic resonance (NMR) profile of a mouse mammary carcinoma, implanted on the foot of CH3/He mice, was studied both in vivo and in perchloric acid extracts. In vivo, significant increases in the ratios, nucleotide triphosphate:inorganic phosphate (Pi) (p0.02) and phosphocreatine:Pi (p0.005), were observed 48 h after 5FU, relative to control. Two readily resolvable peaks were observed in the phosphomonoester region of the in vivo NMR spectrum, phosphocholine (PC) and a peak (denoted PME') comprised of mainly phosphoethanolamine (PE). PME':PC was significantly elevated relative to control from 24 h to 168 h (p0.0001 at 48 h). Perchloric acid extract data indicate that the change in this ratio was due to an increase in the PE concentration rather than a decrease in PC. PE increased from 0.56 +/- 0.11 micromol/g tissue in controls to 0.95 +/- 0.29 micromol/g tissue 48 h after 5FU (p0.006). Perchloric acid extracts also revealed a significant increase in phosphodiesters. Glycerophosphocholine increased from 0.82 +/- 0.24 micromol/g tissue in controls to 1.82 +/- 0.61 micromol/g tissue in 5FU treated tumors after 48 h (p0.002), and glycerophosphoethanolamine increased from 0.25 +/- 0.06 micromol/g tissue in controls to 0.36 +/- 0.10 micromol/g tissue in treated tumors (p0.004). These changes suggest that ethanolamine and choline containing metabolites in this tumor may be metabolized via different pathways. Cell cycle analysis showed only relatively small changes in cell cycle distribution and apoptotic fraction following 5FU.

6-aminonicotinamide (6AN) has been shown to enhance radiosensitivity in vitro, although previous in vivo studies failed to show an effect. 31P NMR spectra were obtained by using a one-dimensional chemical shift imaging technique on a first generation transplant of the CD8FI spontaneous mammary carcinoma tumor model. Spectra were obtained both before and 10 h after treatment with 6AN (20 mg/kg). Changes in pH, nucleoside triphosphate/inorganic phosphate, and phosphocreatine/ inorganic phosphate measured at 10 h post-6AN were not significant. A new peak was detected 10 h post-6AN, which was assigned to 6-phosphogluconate (6PG), indicating inhibition of the pentose phosphate pathway (PPP). Based on the spectral data demonstrating inhibition of the PPP at 10 h post-6AN, tumor-bearing mice were irradiated (15 Gy x 3 fractions) on Days 1, 10 or 11, and 21 10 h after administration of 6-aminonicotinamide (20 mg/kg). Tumor-bearing mice receiving 6AN alone (20 mg/kg x 3), radiation alone (15 Gy x 3), or saline were also studied. Tumor growth delay studies indicated that 6AN alone induced a small but significant tumor growth delay (4.3 +/- 0.8 days). Radiation alone induced a tumor growth delay of 34.5 +/- 2.7 days. Treatment with 6AN followed by radiation induced a tumor growth delay of 57.0 +/- 3.8 days. This was significantly greater than the TGD values for treatment with 6AN alone or radiation (P < 0.01). No complete regressions were noted after treatment with 6AN or radiation alone. Concomitant therapy with 6AN plus radiation yielded 6/28 complete regressions (21%), which was significantly greater than radiation (P < 0.05) or 6AN alone (P < 0.01) on this mammary carcinoma.

The chemotherapeutic regimen of N-(phosphonacetyl)-L-aspartate (PALA) followed 17 h later by 6-methylmercaptopurine riboside (MMPR) and 6-aminonicotanamide (6AN) has been shown to be a potent sensitizer of anti-neoplastic therapy. We undertook this study to compare the therapeutic and metabolic effects of this triple drug combination vs one of its components, 6AN, in a murine mammary carcinoma. After treatment with PALA, MMPR and 6AN, a new peak was detected which was assigned to 6-phosphogluconate (6PG), which is a marker of inhibition of the pentose phosphate pathway at the 6-phosphogluconate dehydrogenase step. Treatment with PALA, MMPR and 6AN also induced a decrease in the ratios of nucleoside triphosphate/inorganic phosphate (NIP/P i ) and phosphocreatine/inorganic phosphate (PCr/P i ) similar to previous results with a different tumor model. These effects were most pronounced at 6 and 10 h. In addition, an increase in PME'/phosphocholine (PME'=downfield peak in the phosphomonoester region) was detected, which was expected because of the cytotoxic effect of this regimen. Treatment with 6AN alone also resulted in the detection of 6PG with a maximum intensity at 6 h post-6AN. Treatment with 6AN alone induced a smaller change in PME'/PC and failed to cause a decrease in PCr/P i or NTP/P i at 6 and 10 h. The enhanced response to the combination of PALA, MMPR and 6AN vs 6AN alone, both with regard to cytotoxicity and radiosensitization, may be due to energy depletion.

The effect of 6-aminonicotinamide on the metabolism of RIF-1 tumor cells was investigated using 13C and 31P NMR spectroscopy. 6-Aminonicotinamide can be metabolized to 6-amino-NAD(P), a competitive inhibitor of NAD(P)-requiring processes. 40 microM 6-aminonicotinamide led to an inhibition of 6-phosphogluconate dehydrogenase and an accumulation of 6-phosphogluconate. A subsequent accumulation of the 6-phosphogluconate precursor 6-phosphoglucono-delta-lactone was observed in the 13C NMR spectrum. These metabolites were shown to be intracellular, although a small amount of leakage of 6-phosphoglucono-delta-lactone occurred. The intracellular concentrations of 6-phosphogluconate and 6-phosphoglucono-delta-lactone were 1.9 +/- 0.8 micromol/108 cells (+/-1 standard deviation) and 0.8 +/- 0.4 micromol/10(8) cells, respectively, after 15 h. Glucose utilization and lactate production were significantly inhibited by 6-aminonicotinamide (both p < 0.05), indicating inhibition of glycolysis. 31P NMR data showed that phosphocreatine was significantly depleted in cells exposed to 6-aminonicotinamide (p < 0.05). Exposure of RIF-1 cells to 6-aminonicotinamide prior to 3- or 6-Gy x-irradiation induced a supra-additive cell kill, indicating that 6-aminonicotinamide is acting as a radiosensitizer. There was no effect of 6-aminonicotinamide alone or when the drug was given postradiation, suggesting that its mechanism of action may be by inhibition of radiation-induced repair.

1. Human cytochrome P450 2A6 is expressed in Chinese hamster lung fibroblasts. The isozyme hydroxylates coumarin at the 7-position.2. Metabolism of coumarin in these lung fibroblasts was monitored using 1H-nmr. Media samples were taken from cells grown in flasks and also in a fluidized bed bioreactor. In each case 7-hydroxycoumarin was readily observable by nmr in crude extracts of the medium.3. The rate of formation of 7-hydroxycoumarin observed in the acute bioreactor experiments on a per cell basis was found to be much higher than that obtained under chronic monolayer conditions, and correlated with glucose consumption rates.

The effect of cyclophosphamide on the metabolic profile of a mammary carcinoma implanted on the foot of mouse was studied by 31P NMR spectroscopy both in vivo and in perchloric acid extracts. The ratio nucleotide triphosphate:P(i) was significantly elevated in cyclophosphamide treated tumours relative to untreated tumours after 96 h in vivo (p < 0.05). Phosphocreatine:P(i) was similarly elevated from 48 to 168 h (p < 0.01). Resolution of the phosphomonoester peak into two distinct resonances allowed us to estimate the ratio of PME' to phosphocholine (PC), where PME' is a composite peak consisting, in part, of phosphoethanolamine (PE). PME':PC was found to be significantly higher in treated animals relative to control animals in vivo (p < 0.01 from 48 to 168 h). Perchloric acid extract spectra suggest that the increase in PME':PC was in part due to a decrease in PC concentration and also due to an increase in a previously unidentified resonance which was coresonant with PE. Extract data show that there was a significant increase in the concentration of the phosphodiesters, glycerophosphocholine (p < 0.01) and glycerophosphoethanolamine (p < 0.05) in treated relative to control tumours. The changes in the phosphomonoester resonances are qualitatively similar to previously described changes following radiation and suggest that they may be a marker of cell kill or lack of cell growth after antineoplastic therapy.

Cisplatin-based highly emetogenic chemotherapy (HEC) displays a biphasic pattern of emesis with both an early and delayed period. In contrast, moderately emetogenic chemotherapy (MEC) has a monophasic pattern. The objective of this analysis was to further investigate the impact of the NK1-receptor antagonist aprepitant on these patterns. Three phase III HEC (patients scheduled to receive cisplatin-based chemotherapy) and one phase III MEC (breast cancer patients scheduled to receive anthracycline plus cyclophosphamide (AC)) trials of aprepitant were included. In all studies, patients were randomized in a 1:1 ratio to an aprepitant regimen (aprepitant plus ondansetron plus dexamethasone) or the standard regimen (ondansetron plus dexamethasone). The exact dosing regimen for ondansetron and dexamethasone was different in each study. In a post hoc analysis, multivariate logistic regression models were used to assess the impact on first emesis at different time intervals after chemotherapy. One thousand five hundred twenty-seven patients and 856 patients were randomized and assessed for efficacy in the HEC and MEC trials, respectively. For HEC, aprepitant reduced the risk of first emesis by 38–77% vs. standard regimen, beginning 15–18 h after cisplatin and extending to 60 h. For MEC, aprepitant reduced the risk of first emesis by 38–61% vs. active control, beginning 3 h after AC and for up to 12 h. Time of onset and duration of enhanced control of emesis with the addition of aprepitant differed between HEC and MEC. This suggests that the pattern of NK1-sensitive mechanisms may vary for different chemotherapy regimens.

The results of an initial study on the feasibility of using the phosphonium analog of choline to follow the metabolism of phosphatidylcholine in tumors in vivo using 31 P NMR are reported. C3H/He mice bearing a mammary carcinoma tumor on the foot pad were fed a choline-free diet supplemented with the phosphonium analog of choline. Metabolites of this compound, including the phosphonium analogs of phosphatidylcholine, phosphocholine, glycerophosphocholine, and betaine were observed noninvasively in vivo in tumors by 31 P NMR after 2-3 weeks of feeding. Clearance of these phosphonium-labeled metabolites from tumors was measured after a change to a choline-containing diet. Significant decreases were seen in the levels of the analogs of betaine (P < 0.003) and phosphatidylcholine (P < 0.004) by Day 4. A significant increase in the level of authentic phosphocholine (P < 0.003) occurred over the same time period.

e20502 Background: Age, alcohol use, and history of sickness associated with pregnancy or motion have been identified as risk factors for chemotherapy-induced emesis. This post hoc analysis addressed two questions: 1) Can prognostic factors identify a low risk group for whom ondansetron (OND) plus dexamethasone [D] alone provide a high level of protection (≥80% no emesis)? 2) Does the NK1 receptor antagonist aprepitant improve antiemetic outcome regardless of emetic risk? Methods: The analysis was based upon outcomes in patients with breast cancer enrolled in a Phase III double-blind, placebo-controlled trial randomized to Day 1 OND 8 mg and D 20 mg before chemotherapy and OND 8 hours later and OND 8 mg bid Days 2–3 vs. Day 1 aprepitant 125 mg PO, OND 8 mg, and D 12 mg before chemotherapy and OND 8 mg 8 hours later and aprepitant 80 mg PO qd Days 2–3. Multivariate logistic regression models were used to assess the impact on emesis of the regimen with aprepitant, and previously reported risk factors, including age ( [Table: see text] [Table: see text]

9629 Background: Cisplatin-based HEC displays a biphasic pattern of emesis with both an early and delayed period. In contrast, MEC has a monophasic pattern. The objective of this analysis was to investigate the time course of action of the 5-HT3antagonist ondansetron (OND) and the NK1 antagonist aprepitant (APR) in trials with HEC and MEC. Methods: Phase III HEC and MEC trials of APR were included. In 2 HEC studies, patients (pts) scheduled to receive cisplatin- based chemotherapy were randomized to an active-control group (OND + dexamethasone [DEX] Day 1, DEX bid Days 2–4) or an APR group (APR + OND + DEX Day 1; APR + DEX qd Days 2–3; and DEX Day 4). In a third HEC study, control pts also received OND on Days 2- 3. For the MEC study, breast cancer pts receiving anthracycline + cyclophosphamide-based chemotherapy were randomized to an active- control group (OND + DEX pre chemotherapy and OND 8 hours (h) later; OND bid Days 2–3) or an APR group (APR + OND + DEX pre chemotherapy and OND 8 h later; APR qd Days 2–3). In a post-hoc analysis, multivariate logistic regression models were used to assess the impact on emesis at different time intervals using a modified intent-to-treat approach. No multiplicity adjustment was planned, so nominal p-values are reported. Results: 1,527 pts and 856 pts were randomized and assessed for efficacy in the HEC and MEC trials respectively. For HEC, APR reduced risk of emesis beginning 15–18 h after cisplatin and extending to 48 h by 45–77% compared to control and by 45–67% compared to the OND control. For MEC, APR markedly reduced emesis from 6–9 h by 61% compared to control (p=0.0012). Conclusions: Time of onset (15 h vs. 6 h) and time course (15–48 h vs. 6–9 h) for the enhanced control of emesis with the addition of APR differs between HEC and MEC respectively. With HEC these results suggest that 5-HT3 dependent mechanisms are most important in the first 12 h after HEC with NK1-dependent mechanisms having a key role later. With MEC both 5-HT3 and NK1 mechanisms appear to be important early and the greatest impact of the NK1 antagonist occurs in the first 9 h. These results provide a rationale for maximizing NK1-antagonist exposure early on with MEC as a means to improve emesis control. [Table: see text]