Di (2-ethylhexyl) phthalate alters neurobehavioral responses and oxidative status, architecture, and GFAP and BDNF signaling in juvenile rat's brain: Protective role of Coenzyme10.

Di-(2-ethylhexyl) phthalate (DEHP), a phthalate plasticizer, is widely spread in the environment, presenting hazards to human health and food safety. Hence, this study examined the probable preventive role of coenzyme10 (CQ10) (10 mg/kg.b.wt) against DEHP (500 mg/kg.wt) - induced neurotoxic and neurobehavioral impacts in juvenile (34 ± 1.01g and 3 weeks old) male Sprague Dawley rats in 35-days oral dosing trial. The results indicated that CQ10 significantly protected against DEHP-induced memory impairment, anxiety, depression, spatial learning disorders, and repetitive/stereotypic-like behavior. Besides, the DEHP-induced depletion in dopamine and gamma amino butyric acid levels was significantly restored by CQ10. Moreover, CQ10 significantly protected against the exhaustion of CAT, GPx, SOD, GSH, and GSH/GSSG ratio, as well as the increase in malondialdehyde, Caspas-3, interleukin-6, and tumor necrosis factor-alpha brain content accompanying with DEHP exposure. Furthermore, CQ10 significantly protected the brain from the DEHP-induced neurodegenerative alterations. Also, the increased immunoexpression of brain-derived neurotrophic factor, not glial fibrillary acidic protein, in the cerebral, hippocampal, and cerebellar brain tissues due to DEHP exposure was alleviated with CQ10. This study's findings provide conclusive evidence that CQ10 has the potential to be used as an efficient natural protective agent against the neurobehavioral and neurotoxic consequences of DEHP.

Bee venom (Apis mellifera L.) rescues zinc oxide nanoparticles induced neurobehavioral and neurotoxic impact via controlling neurofilament and GAP-43 in rat brain.

This study investigated the possible beneficial role of the bee venom (BV, Apis mellifera L.) against zinc oxide nanoparticles (ZNPs)-induced neurobehavioral and neurotoxic impacts in rats. Fifty male Sprague Dawley rats were alienated into five groups. Three groups were intraperitoneally injected distilled water (C 28D group), ZNPs (100 mg/kg b.wt) (ZNPs group), or ZNPs (100 mg/kg.wt) and BV (1 mg/ kg.bwt) (ZNPs + BV group) for 28 days. One group was intraperitoneally injected with 1 mL of distilled water for 56 days (C 56D group). The last group was intraperitoneally injected with ZNPs for 28 days, then BV for another 28 days at the same earlier doses and duration (ZNPs/BV group). Depression, anxiety, locomotor activity, spatial learning, and memory were evaluated using the forced swimming test, elevated plus maze, open field test, and Morris water maze test, respectively. The brain contents of dopamine, serotonin, total antioxidant capacity (TAC), malondialdehyde (MDA), and Zn were estimated. The histopathological changes and immunoexpressions of neurofilament and GAP-43 protein in the brain tissues were followed. The results displayed that BV significantly decreased the ZNPs-induced depression, anxiety, memory impairment, and spatial learning disorders. Moreover, the ZNPs-induced increment in serotonin and dopamine levels and Zn content was significantly suppressed by BV. Besides, BV significantly restored the depleted TAC but minimized the augmented MDA brain content associated with ZNPs exposure. Likewise, the neurodegenerative changes induced by ZNPs were significantly abolished by BV. Also, the increased neurofilament and GAP-43 immunoexpression due to ZNPs exposure were alleviated with BV. Of note, BV achieved better results in the ZNPs + BV group than in the ZNPs/BV group. Conclusively, these results demonstrated that BV could be employed as a biologically effective therapy to mitigate the neurotoxic and neurobehavioral effects of ZNPs, particularly when used during ZNPs exposure.

Palliative effect of Moringa olifera-mediated zinc oxide nanoparticles against acrylamide-induced neurotoxicity in rats.

Repeated acrylamide (ACR) exposure in experimental animals and humans causes variable degrees of neuronal damage. Because of its unique features, several green synthesized nanomaterials are explored for neuromodulatory activity. Hence, this study investigated the effect of green synthesized zinc oxide nanoparticles using Moriga olifera leaves extract (MO-ZnONP) against acrylamide (ACR)-induced neurobehavioral and neurotoxic impacts in rat. Forty male Sprague Dawley rats were distributed into four groups orally given distilled water, MO-ZnONP (10 mg/kg b.wt), ACR (20 mg/kg b.wt), or MO-ZnONP + ACR for 60 days. Gait quality and muscular, motor, and sensory function were assessed. Acetylcholinesterase (AChE), dopamine, catalase, malondialdehyde (MDA), and Zn brain contents were determined. Brain histopathology and immunohistochemical localization of the amyloid-ß protein and abnormal Tau were performed. The results revealed that MO-ZnONP significantly reduced ACR-induced sensory dysfunctions, hind limb abnormality, and motor deficits. Additionally, the ACR-induced increase in dopamine and AChE were significantly supressed by MO-ZnONP. Besides, MO-ZnONP significantly restored catalase and Zn content but reduced increased MDA brain content resulting from ACR. Furthermore, the ACR-induced neurodegenerative changes and increased amyloid-ß and phosphorylated Tau immunoexpression was significantly abolished by MO-ZnONP. Conclusively, MO-ZnONP could be used as a biologically effective compound for mitigating ACR's neurotoxic and neurobehavioral effects.

Removal of Cadmium, Copper, and Lead From Water Using Bio-Sorbent From Treated Olive Mill Solid Residue.

Olive Mill Solid Residue (OMSR) can be utilized as a bio-sorbent in wastewater treatment. Even though several studies on OMSR as a bio-sorbent were carried out, there is still a need to investigate a simple and relatively inexpensive OMSR treatment that increases pollutant removal. In this study; OMSR is used in batch experiments to remove toxic heavy metals from aqueous solutions including Cd2+, Cu2+, and Pb2+ ions. The effect of OMSR treatment (untreated; OMSR-U, treated with n-hexane; OMSR-H, and treated with water; OMSR-W) was investigated by chemical oxygen demand and cation exchange capacity. It was confirmed by both tests that OMSR-W was the best treatment. The same result was re-confirmed by batch uptake experiments of the heavy metal ions. Using OMSR-W as a bio-sorbent; the effect of several parameters such as pH, contact time, bio-sorbent concentration, metal ions concentration, and the presence of other metal species were studied to figure their influence on the metal ions uptake. The optimum conditions for single metal systems were found to occur at pH 5.5, an initial metal concentration of 50 mg/L, a shaking time of 60 minutes, a bio-sorbent concentration of 20 g/L. In binary metal ions solutions; Cd2+ uptake was increased in presence of Cu2+ or Pb2+. However, the uptake of Cu2+ and Pb2+ was decreased in presence of other metals. The equilibrium sorption data for single metal systems were described by the Langmuir isotherm model. The highest value of maximum uptake was found for Pb2+ (4.587 mg/g) followed by Cd2+ (4.525 mg/g) and Cu2+ (4.367 mg/g). These results show that OMSR-W, which has a very low economical value, could be used for the treatment of wastewater contaminated with heavy metals.

Neurobehavioral and immune-toxic impairments induced by organic methyl mercury dietary exposure in Nile tilapia Oreochromis niloticus.

Although substantial knowledge of mercury toxicity in fish has been assembled; until now, studies investigating the toxic impacts in Nile tilapia (Oreochromis niloticus) following dietary exposure to organic methyl mercury (MeHg) are less prolific. Accordingly, the current study aimed to evaluate the impacts of MeHg on neurobehavioral and immune integrity in Nile tilapia after dietary exposure. Two hundred and twenty-five juvenile Nile tilapia (19.99 ± 0.33 g) were allocated into five groups in triplicates (15 fish/replicate). G1, G2, G3, G4, and G5. O. niloticus were fed corresponding basal diets containing 0, 0.5, 1, 1.5, and 2 mg/kg diet MeHg chloride (MeHgCl) daily for 30 days, zero value represented the control G1 group. The results showed that MeHg induced significant alterations in O. niloticus behavior, the swimming behavior was significantly decreased, while scratching, biting, and fin tugging behaviors were significantly augmented. Moreover; chasing, mouth pushing, and butting behaviors were significantly increased in all the exposed groups. MeHg significantly decreased brain acetylcholine esterase (AChE) and serum immunoglobulin M (IgM) levels in all the exposed groups. Meanwhile, serum levels of lysozyme (LYZ), nitric oxide (NO), superoxide dismutase (SOD) malondialdehyde (MDA), protein carbonyl (PCO), and 8 hydroxy 2 deoxyguanosine (8OH2dG) were significantly elevated in all the exposed groups except for serum reduced glutathione (GSH) content was significantly decreased implying oxidative stress (OS), lipid peroxidation (LPO), protein, DNA damage and impaired immune response of the exposed tilapia. MeHg significantly altered transcriptional expression of immune-related genes including (TNF-α, IL-1ß, and IL-8, and IL-10) in all the exposed groups. From the obtained outcomes, the present research is the premier to investigate that dietary MeHg exposure in O. niloticus significantly induced neurobehavioral and immune defense impairments in a dose-related manner. This study exhibits that dietary MeHg may pose a potential threat to the O. niloticus populations.

Curcumin mitigates neurotoxic and neurobehavioral changes of gentamicin and sodium salicylate in rats by adjusting oxidative stress and apoptosis.

Currently, antibiotics and salicylates are the most highly consumed medications worldwide. The side effects of these pharmaceuticals on the nervous system have been little investigated. Thus, this study aimed to examine the influence of the gentamicin (GM) and sodium salicylates (SS) on neurobehavioral functions, including locomotors function, memory, and sensorimotor functions together with gamma-aminobutyric acid (GABA) neurotransmitter levels. Also, oxidative stress, lipid peroxidation, and apoptotic indicators of brain tissue were assessed. Additionally, the histopathological architecture of brain tissues was investigated. This study also evaluated the curcumin (CUR) efficacy to counteract the GM or SS induced neurotoxic impacts in rats. For this purpose, seven groups were administered physiological saline (1 ml/rat; orally), olive oil (1 ml/rat; orally), CUR (50 mg/kg bwt; orally), GM (120 mg/kg bwt; intraperitoneally), SS (300 mg /kg bwt; intraperitoneally), CUR + GM, or CUR + SS for consecutive 15 days. The results revealed that GM and SS exposure evoked impaired memory, sensorimotor deficit functions, and depressive-like behavior together with the depletion of GABA. GM and SS exposure elevated malondialdehyde and Caspase-3 levels, but total antioxidant capacity and Bcl-2 levels were reduced. Besides, GM and SS exposure induced distinct pathological perturbations in cerebral cortices and hippocampus tissues. CUR significantly reversed the GM and SS harmful impacts. In conclusion, these findings verified that CUR could be a biologically efficient protective intervention against GM and SS induced neurotoxic impacts and neurobehavioral aberrations.

Comparison of the pH-dependent formation of His and Cys heptapeptide complexes of nickel(II), copper(II), and zinc(II) as determined by ion mobility-mass spectrometry.

The analog methanobactin (amb) peptide with the sequence ac-His1 -Cys2 -Gly3 -Pro4 -Tyr5 -His6 -Cys7 (amb5A ) will bind the metal ions of zinc, nickel, and copper. To further understand how amb5A binds these metals, we have undertaken a series of studies of structurally related heptapeptides where one or two of the potential His or Cys binding sites have been replaced by Gly, or the C-terminus has been blocked by amidation. The studies were designed to compare how these metals bind to these sequences in different pH solutions of pH 4.2 to 10 and utilized native electrospray ionization (ESI) with ion mobility-mass spectrometry (IM-MS) which allows for the quantitative analysis of the charged species produced during the reactions. The native ESI conditions were chosen to conserve as much of the solution-phase behavior of the amb peptides as possible and an analysis of how the IM-MS results compare with the expected solution-phase behavior is discussed. The oligopeptides studied here have applications for tag-based protein purification methods, as therapeutics for diseases caused by elevated metal ion levels or as inhibitors for metal-protein enzymes such as matrix metalloproteinases.

Ion Mobility-Mass Spectrometry Techniques for Determining the Structure and Mechanisms of Metal Ion Recognition and Redox Activity of Metal Binding Oligopeptides.

Electrospray ionization (ESI) can transfer an aqueous-phase peptide or peptide complex to the gas-phase while conserving its mass, overall charge, metal-binding interactions, and conformational shape. Coupling ESI with ion mobility-mass spectrometry (IM-MS) provides an instrumental technique that allows for simultaneous measurement of a peptide's mass-to-charge (m/z) and collision cross section (CCS) that relate to its stoichiometry, protonation state, and conformational shape. The overall charge of a peptide complex is controlled by the protonation of 1) the peptide's acidic and basic sites and 2) the oxidation state of the metal ion(s). Therefore, the overall charge state of a complex is a function of the pH of the solution that affects the peptides metal ion binding affinity. For ESI-IM-MS analyses, peptide and metal ions solutions are prepared from aqueous-only solutions, with the pH adjusted with dilute aqueous acetic acid or ammonium hydroxide. This allows for pH dependence and metal ion selectivity to be determined for a specific peptide. Furthermore, the m/z and CCS of a peptide complex can be used with B3LYP/LanL2DZ molecular modeling to discern binding sites of the metal ion coordination and tertiary structure of the complex. The results show how ESI-IM-MS can characterize the selective chelating performance of a set of alternative methanobactin peptides and compare them to the copper-binding peptide methanobactin.

Weak Acid-Base Interactions of Histidine and Cysteine Affect the Charge States, Tertiary Structure, and Zn(II)-Binding of Heptapeptides.

Zinc fingers are proteins that are characterized by the coordination of zinc ions by an amino acid sequence that commonly contains two histidines and two cysteines (2His-2Cys motif). Investigations of oligopeptides that contain the 2His-2Cys motif, e.g., acetyl-His1-Cys2-Gly3-Pro4-Tyr5-His6-Cys7, have discovered they exhibit pH-dependent Zn(II) chelation and have redox activities with Cu(I/II), forming a variety of metal complexes. To further understand how these 2His-2Cys oligopeptides bind these metal ions, we have undertaken a series of ion mobility-mass spectrometry and B3LYP/LanL2DZ computational studies of structurally related heptapeptides. Starting with the sequence above, we have modified the potential His, Cys, or C-terminus binding sites and report how these changes in primary structure affect the oligopeptides positive and negative charge states, conformational structure, collision-induced breakdown energies, and how effectively Zn(II) binds to these sequences. The results show evidence that the weak acid-base properties of Cys-His are intrinsically linked and can result in an intramolecular salt-bridged network that affects the oligopeptide properties.

Changing dietary n-6:n-3 ratio using different oil sources affects performance, behavior, cytokines mRNA expression and meat fatty acid profile of broiler chickens.

Typical formulated broiler diets are deficient in n-3 poly-unsaturated fatty acids (PUFA) due to widening n-6:n-3 PUFA ratio which could greatly affect performance, immune system of birds and, more importantly, meat quality. This study was conducted to evaluate the effect of modifying dietary n-6:n-3 PUFA ratio from plant and animal oil sources on performance, behavior, cytokine mRNA expression, antioxidative status and meat fatty acid profile of broiler chickens. Birds (n = 420) were fed 7 diets enriched with different dietary oil sources and ratios as follows: sunflower oil in control diet (C); fish oil (FO); 1:1 ratio of sunflower oil to FO (C1FO1); 3:1 ratio of sunflower oil to fish oil (C3FO1); linseed oil (LO); 1:1 ratio of sunflower oil to linseed oil (C1LO1); 3:1 ratio of sunflower oil to linseed oil (C3LO1), resulting in dietary n-6:n-3 ratios of approximately 40:1, 1.5:1, 4:1, 8:1, 1:1, 2.5:1 and 5:1, respectively. The best final body weight, feed conversion ratio as well as protein efficiency ratio of broilers were recorded in the C1FO1 and C1LO1 groups. Compared with the control group, the dressing percentage and breast and thigh yield were highest in the C1FO1 and C1LO1 groups. Narrowing the dietary n-6:n-3 ratio increased (P < 0.05) n-3 PUFA content of breast meat. Moreover, the breast meat contents of eicosapentaenoic acid and docosahexaenoic acid increased (P < 0.05) with increasing dietary FO whereas α-linolenic acid content was higher with LO supplementation. Also, enriching the diets with n-3 PUFA from FO and LO clearly decreased (P < 0.05) serum total cholesterol, triglycerides and very low-density lipoproteins and enhanced antioxidative status. The feeding frequency was decreased (P < 0.05) in the C1FO1 and C1LO1 groups. Likewise, n-3 PUFA-enriched diets enhanced the frequency of preening, wing flapping and flightiness. Animal oil source addition, compared to plant oil, to broiler diets enhanced the relative mRNA expression of interferon gamma, interleukin-1 beta, interleukin-2 and interleukin-6 genes, especially at low n-6:n-3 ratios. This study has clearly shown that narrowing n-6:n-3 ratio through the addition of FO or LO improved performance and immune response of broilers and resulted in healthy chicken meat, enriched with long chain n-3 PUFA.

Characteristics of Immobilized Urease on Grafted Alginate Bead Systems

This study evaluated the biological importance of immobilized urease enzyme over the free urease. The support material used for urease immobilization was alginate. Generally, the immobilization of urease in alginate gel showed a marked increase in Km and Vmax. However, the immobilized urease showed higher thermal stability than that of free enzyme. The rate of thermal inactivation of the immobilized enzyme decreased due to entrapment in gel matrix. Also, the activity of the immobilized urease was more stable in retention than that of the free enzyme during the storage in solution, although the activity of the immobilized enzyme was lower in comparison with the free enzyme. A stable immobilized system and long storage life are convenient for applications that would not be feasible with a soluble enzyme system. These results highlighted the technical and biochemical benefits of immobilized urease over the free enzyme.

The use of opioids at the end-of-life and the survival of Egyptian palliative care patients with advanced cancer.

BACKGROUND AND AIM: One of the barriers to cancer pain control and palliative care (PC) development is the misconception that the use of opioids may hasten death. This concern is exaggerated when higher doses of opioids are used at the end-of-life. The aim of this study was to investigate the relationship between survival and the dose of opioids used at the end-of-life of patients with advanced cancer in an Egyptian PC setting. METHODS: Retrospective review of the medical records of 123 patients with advanced cancer managed in an Egyptian cancer center-based palliative medicine unit (PMU). Patients were classified according to the last prescribed regular opioid dose expressed in milligrams of oral morphine equivalent (OME) per day (mg OME/24 h) into three groups: no opioid or low-dose group (<120 mg OME/24 h), intermediate-dose group (120-<300 mg OME/24 h) and high-dose group (≥300 mg OME/24 h). Survival was calculated from the date of first referral to the PMU to death. RESULTS: The median age of patients was 53 years, breast cancer was the most common diagnosis (18%) and the majority (68%) died at home. Opioids were prescribed for pain control in 94% of patients and were prescribed on regular basis in 89%. The mean last prescribed opioid dose for the whole group of patients was 167 (±170) mg OME/24 h and it was highest among patients with pleural mesothelioma [245 (±258) mg OME/24 h]. The last prescription included no opioids or low-dose opioids in 57 (46%) patients, intermediate-dose in 42 (34%) and high-dose in 24 (20%). The estimated median survival was 45 days for the no opioid/low-dose group, 75 days for the intermediate-dose group and 153 days for the high-dose group (P=0.031). CONCLUSIONS: The results suggest that the dose of opioids has no detrimental impact on the survival of patients with advanced cancer in an Egyptian PC setting. Further research is needed to overcome barriers to cancer pain control especially in settings with inadequate cancer pain control.

Opioid consumption before and after the establishment of a palliative medicine unit in an Egyptian cancer centre.

Opioid consumption before and after the establishment of a palliative medicine unit (PMU) in an Egyptian cancer centre was reviewed. A comparison of consumption during the year before the PMU was established to consumption during the third year after the PMU's establishment revealed that morphine consumption increased by 698 percent, fentanyl by 217 percent, and tramadol by 230 percent. Expressed in defined daily dose (DDD) and adjusted for 1,000 new cancer patients, consumption increased by 460 percent, from 4,678 DDD/1,000 new patients to 26,175 DDD/1,000 new patients. Expressed in grams of oral morphine equivalent (g OME), consumption increased by 644 percent, from 233 g OME/1,000 new patients to 1,731 g OME/1,000 new patients. The establishment of the PMU was associated with an increase in opioid consumption, especially morphine, which is an indicator of improvement in cancer pain control. The expression of opioid consumption in OME in addition to DDD may provide further information, especially when weak opioids are included in the analysis.

Polyphenolic compounds from flowers of Hibiscus rosa-sinensis Linn. and their inhibitory effect on alkaline phosphatase enzyme activity in vitro.

Graded concentrations (0.1-100 mg/mL reaction mixture) of the methanolic extract of the flowers of Hibiscus rosa-sinensis Linn., its water-soluble fraction as well as compounds isolated from this fraction were tested for their inhibitory effect on alkaline phosphatase enzyme activity in vitro. Both the methanolic extract and its water-soluble fraction showed significant inhibitory effects on the enzyme activity in vitro. On screening the activity of the compounds isolated from the water-soluble fraction, its high inhibitory activity was attributed to the presence of quercetin-7-O-galactoside which showed a high potent inhibition of the enzyme activity reaching 100% at 100 mg/mL reaction mixture. Phytochemical investigations of the water-soluble fraction were also carried out and afforded ten polyphenolic compounds including two new natural compounds, namely kaempferol-7-O-[6'''-O-p-hydroxybenzoyl-beta-D-glucosyl-(1-->6)-beta-D-glucopyranoside] and scutellarein-6-O-alpha-L-rhamnopyranoside-8-C-beta-D-glucopyranoside). The chemical structure of the isolated compounds was elucidated on the basis of chemical and spectral data.

Naproxen test for neoplastic fever may reduce suffering.

Abstract Neoplastic fever (NF) is a paraneoplastic syndrome that is encountered in a significant proportion of patients with cancer. We present the case of a 37 year old female with matastatic renal transitional cell carcinoma. She was hospitalized with fever, constitutional symptoms, and worsening performance status. There was no identifiable infection source. In the third week of hospitalization, she was started on naproxen, resulting in complete lysis of fever, control of constitutional symptoms and improvement in performance status. She was discharged the next day and died of advanced disease within two months. Workup of NF can lead to unnecessary and prolonged hospitalization in patients near the end of their life, resulting in significant suffering. While it is important to rule out infection, an early trial of naproxen is inexpensive and, in patients who can tolerate NSAIDs, may provide good control for NF.

Opioid needs of patients with advanced cancer and the morphine dose-limiting law in Egypt.

BACKGROUND: Morphine is the drug of choice for moderate to severe cancer pain management. The Egyptian Narcotics Control Law limits the amount of morphine prescribed in a single prescription to a maximum of 420 mg for tablets and 60 mg for ampoules. The usual practice in Egypt is to provide that limited amount of morphine on a weekly basis. The aim of this study is to estimate the extent to which Egyptian patients may be undertreated because of this law. METHODS: We reviewed the medical records of advanced cancer patients referred to the first palliative care unit in Egypt over a seven-month period. Cancer pain was managed following the WHO guidelines. After modifying the internal institutional policy, patients received adequate amounts of the available opioids without any violations of the law. RESULTS: From 117 eligible advanced cancer patients, 58 (50%) patients required strong opioids, 32 (27%) required weak opioids, and 27 (23%) required no regular opioids. The mean last prescribed opioid dose for those who required strong opioids was 194 mg of oral morphine equivalent/24 h (± 180). For this group of patients, a single weekly prescription would supply enough oral morphine for only 26% of them. In the case of parenteral morphine, none of these patients would receive an adequate supply. CONCLUSIONS: In view of the current morphine dose-limiting law and practices in Egypt, the majority of patients suffering severe cancer pain would not have access to adequate morphine doses. That dose-limiting law and other restrictive regulations represent an obstacle to cancer pain control in Egypt and should be revised urgently.

Where do Egyptian palliative care patients with cancer die?

This report describes the death place of patients with advanced cancer referred to an Egyptian palliative care program over 1 year. Of 79 patients included, 73% died at home and 27% in hospital or ambulance. Patients who were visited by a palliative care physician at home were significantly more likely to die at home compared to those who did not (92% vs 64%, P = .008). The palliative care survival of those who died at home was significantly longer than those who died in hospital or ambulance (63 vs 39 days, P = .04). These results demonstrate the need for the integration of effective home care model in evolving Egyptian palliative care programs and suggest that physician home visits and earlier referral to palliative care help patients die at home.

Randomized double-blind phase II trial comparing gemcitabine plus LY293111 versus gemcitabine plus placebo in advanced adenocarcinoma of the pancreas.

BACKGROUND: LY293111 (LY) is a novel oral anticancer agent with leukotriene B4 receptor antagonist and peroxisome proliferator-activated receptor gamma agonist properties, producing promising results alone and in combination with gemcitabine in pancreatic cancer xenograft models. A phase I study proved that the combination (gemcitabine plus LY) is safe and well tolerated. PATIENTS AND METHODS: Chemotherapy-naive patients with histologically confirmed locally advanced or metastatic adenocarcinoma of the pancreas were randomly assigned to gemcitabine 1000 mg/m on days 1, 8, and 15 of a 28-day cycle and continuously administered LY 600 mg twice daily or gemcitabine 1000 mg/m on days 1, 8, and 15 of a 28-day cycle and daily oral placebo. Arms were balanced for Eastern Cooperative Oncology Group performance status and disease stage. The primary end point was 6-month survival; secondary objectives include response rate (RR), progression-free survival, and overall survival. RESULTS: Six-month survival was not different between groups (P>0.2, 1-sided); progression-free survival and RR were not different (P>0.05, 2-sided). RR was also not impacted. LY did not increase grades 3-4 hematologic toxicities, but was associated with a trend toward more, grades 3-4 diarrhea. CONCLUSIONS: These results do not demonstrate any benefit to adding LY to gemcitabine in unpretreated patients with advanced pancreatic carcinoma.

Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients.

BACKGROUND: This randomized, double-blind, phase II study assessed two doses of the selective estrogen receptor modulator arzoxifene in women with advanced breast cancer. The primary end point was to choose the best of two doses of arzoxifene based on the response rate or the clinical benefit rate (CBR). Pharmacokinetics and toxicities were also assessed. PATIENTS AND METHODS: Ninety-two patients with advanced breast cancer received arzoxifene 20 or 50 mg/day. Tumor response was assessed using World Health Organization criteria. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) system. Pharmacokinetic data were analyzed using the NONMEM software program (GloboMax, Hanover, MD, USA). RESULTS: Response rates in the 20 mg arm were numerically higher than the 50-mg arm according to the investigator (40.5% versus 36.4%) and the independent review panel (42.9% versus 27.3%). CBR was higher in the 20 mg arm according to the investigator (64.3% versus 61.4%) and the independent review panel (59.5% versus 47.7%). Arzoxifene was well tolerated. There were no study drug-related deaths. Mean observed steady-state plasma concentrations of arzoxifene were 3.62 and 7.48 ng/ml for the 20 and 50 mg doses, respectively. CONCLUSIONS: There were no significant differences in efficacy or safety between 20 and 50 mg of arzoxifene. Accordingly, arzoxifene 20 mg/day was selected for further study in patients with breast cancer.

Phase I study of a third-generation selective estrogen receptor modulator, LY353381.HCL, in metastatic breast cancer.

PURPOSE: We conducted this phase I trial to determine the safety and toxicity profile of LY353381.HCl-a novel, potent, third-generation selective estrogen receptor modulator (SERM)-because this benzothiophene derivative demonstrated an SERM profile in preclinical studies. PATIENTS AND METHODS: We studied 32 patients with recurrent or metastatic breast cancer. Patients were treated in four cohorts with oral daily doses of 10, 20, 50, and 100 mg. Pharmacokinetic sampling was performed during the first 72 hours following the first dose on day 1 and during the 24 hours after the day 57 dose. Eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 to 2; no significant major organ dysfunction; and at least 3 weeks elapsed since most recent hormonal therapy, chemotherapy, and estrogen replacement therapy. RESULTS: The median patient age was 56 years (range, 30 years to 76 years). The median number of prior chemotherapies for metastatic disease was one (range, zero to four), while the median number of prior hormone regimens for metastatic disease was two (range, zero to five). Receptor status was estrogen receptor (ER) positive and progesterone receptor (PR) positive, 19 patients; ER positive and PR negative, eight patients; ER positive and PR unknown, two patients; and ER and PR unknown, three patients. Dose-limiting toxicity was not observed. Treatment was well tolerated with mild to moderate hot flashes in 18 of 32 patients (56%) at all dose levels. Transvaginal ultrasound performed at baseline and after 12 weeks of treatment showed no endometrial thickening. Of the 32 patients evaluable for response, six patients had stable disease for at least 6 months with a median duration of 7.7 months (range, 6.2 months to 33.8 months). The pharmacokinetics of LY353381.HCl were generally linear with respect to time and studied dose range. CONCLUSION: As predicted in preclinical testing, daily oral LY353381.HCl is safe, is well tolerated at all tested dose levels, and may be clinically beneficial in patients with extensively pretreated metastatic breast cancer. Further studies with LY353381 to evaluate the efficacy in patients with or without prior exposure to tamoxifen and fewer overall prior regimens are under way.