Tested Dose Levels Research Articles

Antifertility potential of hydroalcoholic extract of Cordia dichotoma G Forst. leaves: A folklore medicine used by Meena community in Rajasthan state in India

Abstract Objective To assess antifertility activity of hydroalcoholic extract of Cordia dichotoma G Forst. ( C. dichotoma ) leaves, which are traditionally used to produce sterility among the tribal women through its abortificient activity. Methods Acute toxicity study was carried out in adult albino rats. The antifertility activity of extract at two dose level (200 and 400 mg/kg, orally) was evaluated in two experimental animal models i.e . anti-implantation and estrogenic/antiestrogenic activity in female rats by observing number of implants, vaginal cornification, body weight, uterus weight and biochemical investigation. Results The extract was found to be safe up to dose of 2 000 mg/kg body weight when administered orally. A good anti-implantation (81.22%) activity in female rats was observed at the tested dose levels (200 and 400 mg/kg, orally). The extract further showed more significant ( P Conclusions The results suggest that hydro alcoholic extract of C. dichotoma leaves possess significant antifertility activity, which is consistent with the literature report in folk medicine of this plant in fertility regulation.

<i>In vivo</i> analgesic and antipyretic activities of N-Butanol and water fractions of <i>Ocimum sauve</i>

Ocimum suave willd is one of the plants traditionally used for the treatment of inflammation and related disorders in different parts of Ethiopia. The aim of the current study was to evaluate the analgesic and antipyretic activities of the solvent fractions (n-butanol and water) of O. suave aqueous leaves extract. Acetic acid writhing and tail flick tests were used to evaluate the analgesic activity, and yeast-induced fever in mice was used to evaluate the antipyretic activity of the solvent fractions. Both solvent fractions exhibited inhibitory effect against acetic acid induced writhing at all tested dose levels in a dose dependent manner. The water fraction inhibited writhing by 47.69% at a dose of 200 mg/kg which was comparable to that by ASA, the standard drug. In the tail flick test, 200 mg/kg dose of both solvent fractions showed significant activity (P<0.05) after 0.5h, 1h and 3hrs of their administration. Both n- butanol and water fractions produced significant reduction in yeast induced fever at all doses employed. From these findings, it can be concluded that the n-butanol and water fractions of O. suave aqueous leaves extract have potential analgesic and antipyretic activity in mice.

The Developmental Evaluation of Aspergillus Tubingensis CTM 507 Glucose Oxidase Toxicity in Wistar Rats

AbstractThe glucose oxidase (GOD) produced by the fungus Aspergillus tubingensis will be used to improve the quality of bread. The GOD preparation was assessed in a set of toxicological tests to document its safety in use. The oral administration of the GOD preparation to rats at a dose level of 0.4 mg/kg body weight/day did not cause any overt toxic effect on the survival, food intake and body weight gain throughout the 4‐week treatment period. The statistically significant changes in serum biochemical indices in treated groups like the increase in the blood glucose levels and the enzymatic activities of alpha amylase, aspartate aminotransferase and alkaline phosphatase were not concomitant with pertinent histopathological changes and were hence toxicologically inconsequential. No microscopic lesions attributable to the treatment were manifested in the experimental groups. The tested dose level has no‐observed‐adverse‐effect level for developmental toxicity in rats. This GOD can be considered as a candidate for future application especially in the food industry.Practical ApplicationsThe GOD has gained considerable importance in biotechnological applications. In fact, this enzyme is a potential candidate for both biomedical and agricultural field including the biological control of crop pest as well as food processing and formulation. It also has great benefits to biopharmaceutical field. Few studies have so far dealt with the toxicity of GOD. Indeed, studying the toxicity of GOD from A. tubingensis, a new isolate fungus, was necessary to assess its potential application in many other fields. Results showed that GOD preparation was not toxic and could be potentially used for large‐scale application. This study is of great interest as it gives us the chance to use the GOD preparation as a food additive and in bio‐pharmacy.

Piperazine Analogs of Naphthyridine‐3‐carboxamides and Indole‐2‐carboxamides: Novel 5‐HT3 Receptor Antagonists with Antidepressant‐Like Activity

Series of piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides were designed using a ligand-based approach with consideration of the pharmacophoric requirements for 5-HT3 receptor antagonists. The title carboxamides were synthesized using appropriate synthetic routes. Initially, the 5-HT3 receptor antagonistic activity of all the compounds was determined on isolated guinea pig ileum tissue against the 5-HT3 agonist, 2-methyl-5-hydroxytryptamine, which was denoted in the form of pA2 values. The structure-activity relationship regarding the influence of the aromatic part and basic moiety as features in the 5-HT3 pharmacophore was derived. Among all the compounds screened, the piperazine derivatives of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h exhibited prominent 5-HT3 receptor antagonism with pA2 values of 7.5 and 7.3, respectively. Subsequent investigation of the antidepressant activities of selected compounds in the mouse forced swim test (FST) led to the identification of the piperazine analogs of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h as the most promising compounds. Both 13i and 8h demonstrated significant reduction in the duration of immobility as compared to the control. Importantly, none of the tested compounds affected the baseline locomotion of mice at the tested dose levels.

Determination of Hematological Effects of Methanolic Leaf Extract of Vernonia lasiopus in Normal Mice

Hematologicarl disordes have attained epidemic proportions worldwide today. As a result, many people turn to medicinal plants for treatment thereby boosting and enhancing health because professional care is not immediately available, is too inconvenient, costly and time consuming. Certain medicinal plants are believed to promote positive health and maintain organic resistance against infection. The use of medicinal plants which are readily available and arguably efficacious would therefore over a better and affordable alternative for boosting and enhancing health. Assessment of hematological parameters can be used to determine the extent of deleterious effect of foreign compounds including plant extracts on the bloodconstituents of an animal. Various chemical constituents of Vernonia lasiopus are believed to possess therapeutic effects on hematological parameters. However, these effects have not been subjected to systematic studies to substantiate the therapeutic claims made regarding their clinical utility. This study was designed to investigate the hematological effects of V. lasiopus (O. Hoffman) in normal mice. The experimental groups were treated with leaf extracts at concentration of 50 mg/kg and 100 mg/kg orally once per two days for a period of fourteen days. Hematological parameters and indices were determined from unclotted blood samples using standard protocols. Presence of various types of phytochemicals was assessed using standard procedures. The leaf extract of V. lasiopus (O. Hoffman) induced changes in erythrocytes and related parameter profiles, total and differential WBC counts, platelets and their related parameters in normal mice at the two tested dose levels of 50 mg/kgbw and 100 mg/kgbw. Further, the phytochemical screening results showed that the leaf extract of V. lasiopus (O. Hoffman) have phytochemicals associated with erythropoietin promoting activity, immunostimulatory activities and thrombopoietin stimulation.

Evaluaton of hypoglycaemic and wound healing activities of Tiliacora acuminata

Natural products particularly plant origin have played a vital role in prevention and mitigation of human diseases. The present study was carried to evaluate the antihyperglycaemic and wound healing activity of the leaf Extracts of Tiliacora acuminate (Lam) on rats, the aqueous leaf extract was found to produce significant reduction of blood glucose concentration between 2-4 h of administration in alloxan induced hyperglycaemic rats at tested dose levels. However, in normoglycaemic animals, the extract at 400mg/kg produced significant reduction of blood glucose between 2-4 h of administration. In the wound healing studies, the leaf juice was found to be more active than the extract.

Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-CD19A in Relapsed or Refractory B-Lineage Non-Hodgkin Lymphoma

Background CD19, a B-cell specific marker, is expressed in the majority of patients with B-cell non-Hodgkin lymphoma (NHL). SGN-CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. Methods This ongoing phase 1, open-label, dose-escalation study investigates the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-CD19A in patients with relapsed or refractory B-cell NHL (NCT 01786135). Eligible patients are ≥12 years of age and must have a confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL), including transformed follicular histology; mantle cell lymphoma (MCL); follicular lymphoma grade 3 (FL3); Burkitt lymphoma; or B-cell lymphoblastic lymphoma. Patients must be relapsed or refractory to at least 1 prior systemic regimen. Patients with DLBCL or FL3 must have also received intensive salvage therapy with or without autologous stem cell transplant (SCT), unless they refused or were deemed ineligible. A modified continual reassessment method is used for dose allocation and maximum tolerated dose (MTD) estimation. SGN-CD19A is administered IV on Day 1 of 21-day cycles (0.5–6 mg/kg). Response is assessed with CT and PET scans according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results To date, 44 patients have been treated: 39 patients (89%) with DLBCL (including 10 with transformed DLBCL), 4 (9%) with MCL, and 1 (2%) with FL3. Median age was 65 years (range, 33–81). Patients had a median of 2 prior systemic therapies (range, 1–7), and 10 patients (23%) had autologous SCT. Twenty-six patients (59%) were refractory to their most recent prior therapy, and 18 (41%) were relapsed. Patients received a median of 3 cycles of treatment (range, 1–12) at doses from 0.5–6 mg/kg. Eleven patients (25%) remain on treatment, and 33 have discontinued treatment (18 due to progressive disease [PD], 5 for investigator decision, 5 for adverse events [AE], 4 because of patient decision/non-AE, and 1 for SCT). No dose-limiting toxicity (DLT) in Cycle 1 has been reported. Treatment-emergent AEs reported in ≥20% of patients were blurred vision (59%), dry eye (39%), fatigue (39%), constipation (32%), keratopathy (23%), and pyrexia (20%). Corneal exam findings consistent with superficial microcystic keratopathy were observed in 25 patients (57%) and were mostly Grade 1/2. Grade 3/4 corneal AEs were observed in 4 patients at the higher doses; the majority resolved or improved to Grade 1/2 at last follow-up. Corneal AEs were treated with ophthalmic steroids, and during the trial steroid eye drop prophylaxis was instituted with each dose of study drug. SGN-CD19A ADC plasma exposures were approximately dose-proportional. Accumulation was observed following multiple dose administrations, consistent with a mean terminal half-life of about 2 weeks, suggesting less frequent dosing might be possible. In the 43 efficacy-evaluable patients, the objective response rate (ORR) is 30% (95% CI [17, 46]), including 7 complete responses (CRs; 16%) and 6 partial responses (PRs; 14%). Of the 13 patients with an objective response, 8 are still on study with follow-up times of 0.1–31 weeks; 2 are no longer on study; and 3 had subsequent PD or death with response durations of 14, 19, and 31 weeks. Conclusions To date, SGN-CD19A has shown evidence of clinical activity with an ORR of 30% and CR rate of 16%. Enrollment in the trial is ongoing to further refine optimal dose and schedule. SGN-CD19A is generally well-tolerated. No DLTs have been observed in tested dose levels. Observed ocular AEs are manageable with steroid eye drops and dose modifications. The high response rate (53%) in relapsed patients and low rate of bone marrow suppression or neuropathy suggest that SGN-CD19A could be incorporated into novel combination regimens in earlier lines of therapy. Disclosures Moskowitz:Merck: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use. . Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Shah:Pharmacyclics: Speakers Bureau; SWOG: Consultancy; Celgene: Consultancy, Speakers Bureau; NCCN: Consultancy; Seattle Genetics, Inc.: Research Funding; Janssen: Speakers Bureau. Advani:Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Hamlin:Seattle Genetics, Inc.: Consultancy, Research Funding. Kim:Bayer: Consultancy; Eli Lily: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandalic:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding, Travel expenses Other.

Mitoxantrone, Etoposide, and Cytarabine (MEC) Following Epigenetic Priming with Decitabine in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS): A Phase 1 Study

Background: Most adults with AML or high-risk MDS will ultimately require salvage therapy. However, the likelihood of achieving a complete remission (CR) with standard salvage regimens is often 15-20% or less. Emerging data suggest that pre-treatment (“priming”) with a hypomethylating agent such as decitabine can sensitize AML cells to chemotherapeutics, prompting a dose-escalation study of MEC preceded by decitabine-priming in relapsed/refractory AML and high-risk MDS.Methods: This single arm study aimed to estimate the maximum tolerated dose (MTD) of decitabine-primed MEC in adults ≥18 years with relapsed/refractory high-risk MDS (>10% blasts) or AML requiring first or subsequent salvage therapy. Previous treatment with hypomethylating agents or MEC (but not the combination) was acceptable. Trial participation required a treatment-related mortality (TRM) score of <9.2, corresponding to an expected TRM of 4% with standard induction chemotherapy. Patients with post-transplant relapse were eligible if graft-versus host disease was well controlled. Excluded were patients with concomitant illness with expected survival <1 year, and active, uncontrolled infection. Cohorts of 6-12 patients were assigned to 1 of 3 total dose levels of decitabine (20mg/m2 for 5, 7, or 10 days) followed by MEC (mitoxantrone 8mg/m2/day x 5 days; etoposide 100 mg/m2/day x 5 days; cytarabine 1 g/m2/day x 5 days) after a break of 5 days. In the case of persistent leukemia, patients were eligible for re-induction provided all non-hematologic toxicities had resolved to grade <2. Patients achieving a CR or CR with incomplete platelet recovery (CRp) could receive 2 additional cycles of decitabine-MEC given at doses identical to those used during induction. Dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms, if recovery to grade ≤2 within 14 days.Results: 30 patients, median age 55 (range: 19-72) years, with primary refractory disease (n=13), first relapse (n=16), or second relapse (n=1) with median duration of prior CR of 4 (range: 1-19) months were enrolled and received a median of 1 (range: 1-3) cycles of therapy. During dose escalation, 1 DLT occurred at each the 2nd and 3rd tested dose level after cycle 1 (septic shock with multi-organ failure in both), identifying a 10-day course of decitabine together with standard dose MEC as the MTD. A total of 12 patients received therapy at the MTD level. 9/30 patients achieved a CR (30%). This CR rate compared favorably relative to a historic control population with patient matching based on duration of prior remission and number of prior salvage therapies (Blood 1996; 88:756), with an observed/expected CR ratio of 1.9. 5 additional patients achieved a CRp, and 1 achieved a CR with incomplete count recovery (CRi) for an overall response rate of 15/30 (50%). Furthermore, 4 patients achieved a morphologic leukemia-free state, 8 had refractory disease, and 3 died before a response was assessed. Of the 15 patients who achieved a remission, 3 remain on study, 9 were taken off protocol to pursue further intensive consolidation therapy including hematopoietic cell transplantation, and 3 have died after a median CR duration of 68 days. In the 15 responders, the median response duration was 68 days (range 0-437), with 6 of these responses ongoing. Overall survival of these 15 patients was longer (median of 211 [range: 59-484] days) than that for patients who failed to achieve remission but lived at least 29 days (i.e. did not experience TRM) (median of 110 [range: 30-303] days). Six patients died within 28 days of treatment initiation for a TRM rate of 20%: 4 from infection, 1 from intracranial hemorrhage, and 1 from unknown cause. Besides grade 3-4 cytopenias, cough, fatigue, nausea and infection/neutropenic fever were the most common adverse events.Conclusion: Decitabine-primed MEC is feasible, well tolerated, and has anti-leukemic activity in relapsed/refractory AML and high-risk MDS. A phase 2 study based on these findings has been initiated. DisclosuresOff Label Use: Off-label use of some of the study drugs for either AML or high-risk MDS.

&lt;i&gt;Zostera noltii&lt;/i&gt; extract lowers blood glucose and restores vascular function in diabetic rats

The antidiabetic effect of seagrass Zostera noltii extract was investigated through a crosstalk between its antioxidant and vasoprotective properties. The extract was orally administered to alloxan-diabetic rats (50, 150, 250 mg/kg body weight). Serum glucose was determined; liver and kidney functions, body weight, total leukocyte counts were measured; liver oxidative markers were assayed. Acetylcholine, phenylephrine and 5-HT responses were tested. eNOS levels and generation of ROS in aortic tissue were quantified. The extract of Z. noltii lowered blood glucose in all tested dose levels. Extract at a concentration of 50 mg/kg failed to preserve the levels of antioxidants and did not alter lipid peroxidation whereas higher doses improved liver oxidative status. Impaired acetylcholine relaxations, augmented phenylephrine and 5-HT contractions in alloxan-diabetic aortic rings were restored by Z. noltii treatment. This recovery was accompanied by increased eNOS synthesis and a reduction in ROS generation. The extract lowers blood glucose and prevents hyperglycemia-induced endothelial dysfunction in alloxan-diabetic rats.

Design, synthesis, and pharmacological evaluation of novel 2-(4-substituted piperazin-1-yl)1, 8 naphthyridine 3-carboxylic acids as 5-HT3 receptor antagonists for the management of depression.

1, 8-naphthyridine-3-carboxylic acid analogs were synthesized and found to possess potential 5-HT3 receptor antagonism as well as antidepressant-like activity. Initially, 5-HT3 receptor antagonism of all the compounds was determined in the form of pA2 value against agonist 2-methyl 5-HT in longitudinal muscle-myenteric plexus preparation from guinea-pig ileum. Among all the compounds tested, compound 7a demonstrated most promising pA2 value of 7.6. Subsequently, all the compounds were evaluated for antidepressant activity using forced swim test and tail suspension test in mice. Compounds 7a, 7d, 7f, 7h, and 7i exhibited significant (p<0.05) antidepressant-like activity as compound to vehicle-treated group. Importantly, none of the tested compound affected locomotor activity of mice at tested dose levels.

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT3 Receptor Antagonists

A series of novel 1,8-naphthyridine-3-carboxamides as 5-HT3 receptor antagonists were synthesized with an intention to explore the antidepressant activity of these compounds. The title carboxamides were designed using ligand-based approach keeping in consideration the structural requirement of the pharmacophore of 5-HT3 receptor antagonists. The compounds were synthesized using appropriate synthetic route from the starting material nicotinamide. 5-HT3 receptor antagonism of all the compounds, which was denoted in the form of pA2 value, was determined in longitudinal muscle myenteric plexus preparation from guinea-pig ileum against 5-HT3 agonist, 2-methyl-5-HT. Compound 8g (2-methoxy-1, 8-naphthyridin-3-yl) (2-methoxy phenyl piperazine-1-yl) methanone was identified as the most active compound, which expressed a pA2 value of 7.67. The antidepressant activity of all the compounds was examined in mice model of forced swim test (FST); importantly, none of the compounds was found to cause any significant changes in the locomotor activity of mice at the tested dose levels. In FST, the compounds with considerably higher pA2 value exhibited promising antidepressant-like activity, whereas compounds with lower pA2 value did not show antidepressant-like activity as compared to the control group.

Ameliorative Potential ofTamarindus indicaon High Fat Diet Induced Nonalcoholic Fatty Liver Disease in Rats

Nonalcoholic fatty liver disease (NAFLD), the prevalence of which is rising globally with current upsurge in obesity, is one of the most frequent causes of chronic liver diseases. The present study evaluated the ameliorative effect of extract of Tamarindus indica seed coat (ETS) on high fat diet (HFD) induced NAFLD, after daily administration at 45, 90, and 180 mg/kg body weight dose levels for a period of 6 weeks, in albino Wistar rats. Treatment with ETS at all tested dose levels significantly attenuated the pathological alterations associated with HFD induced NAFLD viz. hepatomegaly, elevated hepatic lipid and lipid peroxides, serum alanine aminotransferase, and free fatty acid levels as well as micro-/macrohepatic steatosis. Moreover, extract treatment markedly reduced body weight and adiposity along with an improvement in insulin resistance index. The study findings, therefore suggested the therapeutic potential of ETS against NAFLD, acting in part through antiobesity, insulin sensitizing, and antioxidant mechanisms.

Role of fumaric acid in anti-inflammatory and analgesic activities of a Fumaria indica extracts.

Aim:The aim was to test whether the ethanolic extract of Fumaria indica (FI) possesses anti-inflammatory and analgesic activities, and fumaric acid (FA) could be one of its bioactive constituent involved in such activities of the extract.Materials and Methods:For anti-inflammatory activity, carrageenan-induced edema and cotton pellet induced granuloma tests in rats and for analgesic activity rat tail flick test and hot plate and acetic acid writhing tests in mice were used. All tests were performed after seven daily oral doses of the FI extract (100, 200, and 400 mg/kg/day) and pure FA (1.25, 2.50, and 5.00 mg/kg/day).Results:Anti-inflammatory activities of FI and FA were observed in carrageenan-induced edema and cotton pallet granuloma even after their lowest tested doses. No analgesic activity of lowest tested dose of FA was observed in the acetic acid writhing test, but likewise, all tested dose levels of FI, higher tested dose levels of FA were also possess significant analgesic activity in this test. Further, significant analgesic activities of both FI and FA in hot plate and tale flick tests were observed after all their tested doses.Conclusions:These observations are in agreement with our working hypothesis on the connection of FA in mode(s) of action(s) of FI, and reaffirm the conviction that FI could be an herbal alternative against fibromyalgia and other pathologies often associate with, or caused by, inflammatory processes.

Gemtuzumab Ozogamicin In Combination With Vorinostat and Azacitidine In Older Patients With Relapsed Or Refractory Acute Myeloid Leukemia (AML): Final Results From A Phase 1/2 Study

BackgroundEpigenetic therapeutics such as the histone deacetylase (HDAC) inhibitor, vorinostat, and the DNA methyltransferase (DNMT) I inhibitor, azacitidine, sensitize AML cells in vitro to the CD33-targeting immunoconjugate, gemtuzumab ozogamicin (GO). This observation, together with the improved clinical activity when HDAC inhibitors are used with DNMT inhibitors, prompted a phase 1/2 study (NCT00895934) of GO with vorinostat and azacitidine for primary refractory AML or AML in first relapse (remission duration ≤12 months) requiring 1stsalvage therapy. MethodsPatients aged ≥50 years were eligible if they had an ECOG performance status of 0-3 and had adequate organ function. Patients with prior hematopoietic stem cell transplantation (HCT) were eligible if relapse occurred 6-12 months post-transplant. Excluded were patients with a second active malignancy, prior treatment with any of the study drugs, or central nervous system disease. Hydroxyurea was given to reduce the total white blood cell count to <25,000/μL before treatment. If there was persistent leukemia on day 15, the first cycle was repeated, and patients came off study if, after repetition, there was disease progression. In all other patients, a second cycle was begun if peripheral blood counts had recovered (blood count recovery was not required for patients with persistent leukemia) and all toxicities had resolved to ≤grade 2. Patients came off study if a partial remission was not achieved by the end of cycle 3, or if a complete remission (CR) or CR with incomplete peripheral blood count recovery (CRi) was not achieved by the end of cycle 6. During phase 1, patients were assigned to therapy according to a “3+3” study design; dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that results in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms if recovery to grade ≤2 within 14 days; and 3) prolonged myelosuppression (platelet count <20,000/μL and/or absolute neutrophil count <500/μL at day 42 after treatment in patients without evidence of persistent leukemia). During phase 2, a Simon minimax two-stage design was to monitor whether a response rate of 0.34 was reached, with type I and II errors set at 0.1 and assuming a historical CR rate of 17% in these patients. Results52 eligible patients, median age 64.8 (range, 50.2-78.9) years, with either primary refractory disease (n=29) or first relapse (n=23; median duration of first CR: 3 months) were enrolled and received a median of 2 (range, 1-4) cycles of therapy. During dose escalation, 1 DLT (death due to sepsis and respiratory failure) occurred at the 4th tested dose level after cycle 1, identifying vorinostat (400 mg/day orally from days 1-9), azacitidine (75 mg/m2/day IV or SC from days 1-7), and GO (3 mg/m2/day IV on days 4 and 8) as the maximum tolerated dose (MTD). A total of 43 patients received therapy at the MTD level. Ten of these achieved CR, while 8 achieved CRi, for a CR/CRi rate of 18/43 (41.9%; exact 95% CI: 27.0-57.9%). Thirteen of the 18 patients that achieved CR/CRi were taken off protocol to receive additional, more intensive consolidative chemotherapy, including HCT (n=12). Of these 18 patients, 5 relapsed after a median of 122 (38-146) days, while 3 died while in remission after a CR duration of 46, 97, and 130 days, and 10 are in ongoing remission after a median of 326 (68- 710) days, respectively. Median overall survival for the 18 patients achieving CR/CRi was significantly longer than for those 21 patients who failed therapy but lived at least 29 days (i.e. did not experience treatment-related mortality) after treatment initiation (224.5 [range 70-798]) vs. 95 [36-900] days, log rank P-value=0.0023). Four patients died within 28 days of treatment initiation. Besides grade 3-4 cytopenias, infectious complications were the most common grade 33 adverse events. Only 1 patient developed possible liver toxicity (abdominal pain/distention and mild ascites) after 4 cycles of therapy, although bilirubin and transaminases were only minimally elevated and doppler studies were unremarkable. ConclusionOur study indicates that GO in combination with vorinostat and azacitidine has encouraging anti-AML activity in older adults with relapsed/refractory AML. Disclosures:Walter:Amgen, Inc: Research Funding; Seattle Genetics, Inc: Consultancy, Research Funding. Off Label Use: Use of vorinostat/azacitidine/gemtuzumab ozogamicin for the treatment of relapsed/refractory AML.

IN VITRO ANTHELMINTIC ACTIVITY OF ARTEMISIA MARITIMA LINN.

Ethanolic and aqueous extracts of the flower heads of Artemisia maritima Linn. were evaluated for anthelmintic activity on Indian earthworms Pheritima posthuma, using albendazole as reference standard. The extracts caused paralysis followed by death of the worms at all tested dose levels. Ethanolic extract was found to be more potent than the reference control albendazole. The result supports the traditional claims of Artimisia maritime as a powerful anthelmintic.

Antifertility potential of the ethanolic extract of Caesalpinia pulcherrima Linn. leaves

Abstract Objective To assess the antifertility activity of ethanolic extract of Caesalpinia pulcherrima Linn ( C. pulcherrima ) leaves in albino female mice. Methods Acute toxicity study of the extract was carried out in adult albino mice. The antifertility activity of the extract at dose levels (200 and 400 mg/kg, orally) was evaluated in two experimental animal models i.e. antiimplantation and esterogenic/antiestrogenic activity in female mice by observing no. of implants, estrus cycle, vaginal cornification, uertus weight and cholesterol content. Results The extract was found to be safe up to a dose of 4 000 mg/kg body weight when administered orally. A good antiimplantation (66.66 %) activity in female mice was observed at the tested dose levels (200 and 400 mg/kg, orally). The extract further showed more significant ( P Conclusions The results suggest that ethanolic extract of C. pulcherrima leaves possess significant antifertility activity, therefore, justifying the traditional use of this plant in fertility regulation.

A first-in-human phase I study of ER-α36 modifier icaritin in patients with advanced solid tumors.

2614 Background: ER-α36 was recently identified to be expressed in varieties of cancers and may play important roles in carcinogenesis and tumor progression. Icaritin, a natural prenylflavonoid derived from the Chinese herb Epimedium, is a first of its kind ER-α36 modifier, which demonstrated potent anti-tumor effect in multiple cancer cell lines and their xenograft models. This study aims to determine its safety, tolerability, pharmacokinetics (PK), and potential antitumor activity. Methods: This phase I study comprises phase Ia and Ib. In phase Ia part, patients with advanced breast cancer (ABC) were treated with escalating doses of Icaritin orally once daily on a continuous 28-day dosing schedule. In phase Ib part, dosing was fixed to 600 or 800mg twice daily and expansion was made to other selected malignancies including hepatocellular cancer (HCC), colorectal cancer (CRC) and intrahepatic cholangiocarcinoma (ICC) to further explore PK parameters and efficacy. Results: 24 patients were enrolled to receive Icaritin at six dose levels ranging from 50mg to 1600mg per day in phase Ia. No dose limited toxicity (DLT) was found even in the highest dose defined in the protocol, thus the maximum tolerated dose (MTD) was not reached. Only grade 1 drug-related adverse events were observed including neutropenia, ALT elevation, hypercholesteremia, fatigue, anorexia, hypertriglyceridemia, proteinuria, myalgia, hot flash and rash. PK data from the fed dosing showed 3-fold increase of Cmax and AUC compared with the fast dosing. Half life was around 2-7 hours. Among 22 evaluable subjects, no complete or partial response (CR or PR) was detected, 5 patients had stable disease(SD)for 3 months or longer. For phase Ib study, 24 patients had been enrolled. One ABC, 2 CRC and 3 ICC patients progressed after 2 months of medication. Among 7 HCC patients already evaluated, 1 obtained PR and progressed after one year of treatment and 2 remained in the study, stable for 5 months. Similar drug related toxicity profile was noted in phase Ib. Conclusions: Icaritin was generally well-tolerated without DLT across tested dose levels. Evidence of promising antitumor activity was observed in ABC and HCC. Final results will be presented at the meeting. Clinical trial information: NCT01278810.

VXM01, an oral T-cell vaccine targeting the tumor vasculature: Results from a randomized, controlled, first-in-man study in pancreatic cancer patients.

3090 Background: VXM01 is an orally available, bacterially transmitted DNA vaccine targeting VEGFR-2. Pre-clinically, VXM01 showed anti-tumor activity in multiple tumor types. This first-in-human study was designed to evaluate the safety and tolerability of VXM01. Secondary endpoints included VEGFR-2 specific T-cell responses, tumor perfusion changes, and related biomarkers. Methods: A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 45 patients with advanced pancreatic cancer. VXM01 or placebo was given on days 1, 3, 5, and 7. Doses were escalated from 10(6) CFU to 10(10) CFU over 5 dose groups, each including 6 VXM01 and 3 placebo patients. VEGFR-2 specific T-cell activity was monitored by ELISpot and T(reg) specificity assays before, during and after the vaccination course. Tumor perfusion was assessed by DCE-MRI on days 0 and 38. Biomarkers included CA19-9, VEGF-A and collagen IV. Results: Patients were enrolled from 12/2011 to 10/2012. Most commonly observed AEs were leukopenia, abdominal pain, and diarrhea, which were all equally distributed between treatment and placebo group. While a mild elevation in average blood pressure was observed in the VXM01 group over the placebo group, the hypertension adverse event rate did not differ between both groups. No DLTs were observed. VEGFR-2 specific effector T-cell response was increased in 57% of evaluable VXM01 treated patients, during and after the vaccination course. In 25% of the VXM01 group, the T-cell response score post-vaccination was higher than maximum placebo levels. In contrast, VEGFR-2 specific T(reg) responses were overall reduced in vaccinated patients. DCE-MRI data indicated a &gt;33% drop in K(trans)/tumor perfusion in 35% of evaluable VXM01 treated patients vs. 10% in the placebo group. Mean changes were -4% (VXM01) and +15% (placebo). Reduced tumor perfusion correlated with VEGFR-2 specific T-cell responses and biomarker responses. Conclusions: VXM01 appeared safe and was well tolerated without DLTs across 5 tested dose levels. The data suggest further that VXM01 induces and enhances a VEGFR-2 specific T-cell response and impacts tumor perfusion. Clinical trial information: ISRCTN68809279.

Attenuating effect of Cilostazol against vincristine – Induced neuropathic pain in mice

BackgroundChemotherapy induced neuropathic pain is a very common adverse effect seen with cancer chemotherapeutic drugs. The activation of BK channels leads to reduced neuronal excitability and suggests its role in the clinical management of pain. The present study investigates the effect of non-selective BK channel activator, Cilostazol (CZ) against vincristine (VC) induced neuropathic pain in mice. MethodsNeuropathic pain was induced in the animals by a single vincristine administration (100 μg/kg, i.v) to all the group of animals. Mice were randomly divided into four groups comprising of a control, two test groups with Cilostazol (20 mg/kg & 40 mg/kg) and a standard group with Gabapentin (GBP, 100 mg/kg). Peripheral neuropathy in animals was verified by mechanical hyperalgesia and mechanical allodynia. Results and discussionControl group did not have any significant effect on mechanical hyperalgesia and mechanical allodynia. Results shows that Cilostazol at both tested dose levels of 5 days administration attenuated mechanical hyperalgesia and mechanical allodynia after the vincristine administration and were comparable with that of Gabapentin. ConclusionThe attenuating effect of Cilostazol in vincristine model suggests that pharmacological activation of BK channel may be potentially useful for managing neuropathic pain.

Anti-inflammatory and Analgesic Activities of &lt;i&gt;Amorphophallus bulbifer&lt;/i&gt; (Roxb) &lt;i&gt;Kunth&lt;/i&gt; Whole Plant

Purpose: To investigate the anti-inflammatory and analgesic activities of the Amorphophallus Bulbifer in Wistar rats and mice.Methods: The anti-inflammatory activity of the hydroalcohol extract of A. bulbifer whole plant at dose levels of 100 and 200 mg/kg p.o. in rats was determined with a plethysmograph paw volume difference of the animals pre- and post-treatment. Ibuprofen (10 mg/kg) was employed as reference standard. Analgesic activity was evaluated using tail flick and tail immersion techniques, by measuring the reaction time of the animals treated with either standard or extract. Pentazocin (30 mg/kg) was used as reference standard.Results: The extract showed significant anti-inflammatory and analgesic activities at the two test dose levels at the 4th hour (p &lt; 0.001). The extract exhibited anti inflammatory activity of 56.5 (p &lt; 0.001) and57.1 % (p &lt; 0.001) inhibition compared to the control group in the carrageenan and histamine-induced inflammation model at a dose of 200 mg/kg. For analgesic activity, the extract showed reaction times of7.33 (p &lt; 0.001) and 7.83 (p &lt; 0.001) min in the tail flick and tail immersion models, respectively, at a dose of 200 mg/kg while the normal and reference groups exhibited reaction times of 2.16, 2.66 and8.16 (p &lt; 0.001) and 8.5 (p &lt; 0.001) in the tail flick and tail immersion methods, respectively.Conclusion: Based on the findings, it can be concluded that Amorphophallus bulbifer possesses antiinflammatory and analgesic properties and this lends some support for its use in traditional medicalpractice.Keywords: Amorphophallus bulbifer, Anti-inflammatory activity, Analgesic activity