Evalution of anti-ulcer activity of Polyalthia longifolia (Sonn.) Thwaites in experimental animals

Objective:

To evaluate the anti-ulcer activity of ethanol extract of leaves of Polyalthia longifolia (Sonn.) Thwaites.

Materials and Methods:

The ethanol extract of Polyalthia longifolia was investigated for its anti-ulcer activity against aspirin plus pylorous ligation induced gastric ulcer in rats, HCl -Ethanol induced ulcer in mice and water immersion stress induced ulcer in rats at 300 mg/kg body weight.p.o.

Results:

A significant (P < 0.01, P < 0.001) anti ulcer activity was observed in all the models. Pylorous ligation showed significant (P< 0.01) reduction in gastric volume, free acidity and ulcer index as compared to control. It also showed 89.71% ulcer inhibition in HCl- Ethanol induced ulcer and 95.3% ulcer protection index in stress induced ulcer.

Conclusion:

This present study indicates that P. longifolia leaves extract have potential anti ulcer activity in the three models tested.     

Six-Month Emergency Department Use among Older Adults Following Jail Incarceration

Although the number of older adults who are arrested and subject to incarceration in jail is rising dramatically, little is known about their emergency department (ED) use or the factors associated with that use. This lack of knowledge impairs the ability to design evidence-based approaches to care that would meet the needs of this population. This 6-month longitudinal study aimed to determine the frequency of 6-month ED use among 101 adults aged 55 or older enrolled while in jail and to identify factors associated with that use. The primary outcome was self-reported emergency department use within 6 months from baseline. Additional measures included baseline socio-demographics, physical and mental health conditions, geriatric factors (e.g., recent falls, incontinence, functional impairment, concern about post-release safety), symptoms (pain and other symptoms), and behavioral and social health risk factors (e.g., substance use disorders, recent homelessness). Chi-square tests were used to identify baseline factors associated with ED use over 6 months. Participants (average age 60) reported high rates of multimorbidity (61%), functional impairment (57%), pain (52%), serious mental illness (44%), recent homelessness (54%), and/or substance use disorders (69%). At 6 months, 46% had visited the ED at least once; 21% visited multiple times. Factors associated with ED use included multimorbidity (p = 0.01), functional impairment (p = 0.02), hepatitis C infection (p = 0.01), a recent fall (p = 0.03), pain (p < 0.001), loneliness (p = 0.04), and safety concerns (p = 0.01). In this population of older adults in a county jail, geriatric conditions and distressing symptoms were common and associated with 6-month community ED use. Jail is an important setting to develop geriatric care paradigms aimed at addressing comorbid medical, functional, and behavioral health needs and symptomatology in an effort to improve care and decrease ED use in the growing population of criminal justice-involved older adults.     

Evaluation of Polycyclic Aromatic Hydrocarbons Using Analytical Methods,Toxicology, and Risk Assessment Research: Seafood Safety after a Petroleum Spill as an Example

Background: Polycyclic aromatic hydrocarbons (PAHs) are abundant and widespread environmental chemicals. They are produced naturally and through man-made processes, and they are common in organic media, including petroleum. Several PAHs are toxic, and a subset exhibit carcinogenic activity. PAHs represent a range of chemical structures based on two or more benzene rings and, depending on their source, can exhibit a variety of side modifications resulting from oxygenation, nitrogenation, and alkylation.Objectives: Here we discuss the increasing ability of contemporary analytical methods to distinguish not only different chemical structures among PAHs but also their concentrations in environmental media. Using seafood contamination following the Deepwater Horizon accident as an example, we identify issues that are emerging in the PAH risk assessment process because of increasing analytical sensitivity for individual PAHs, and we describe the paucity of toxicological literature for many of these compounds.Discussion: PAHs, including the large variety of chemically modified or substituted PAHs, are naturally occurring and may constitute health risks if human populations are exposed to hazardous levels. However, toxicity evaluations have not kept pace with modern analytic methods and their increased ability to detect substituted PAHs. Therefore, although it is possible to measure these compounds in seafood and other media, we do not have sufficient information on the potential toxicity of these compounds to incorporate them into human health risk assessments and characterizations.Conclusions: Future research efforts should strategically attempt to fill this toxicological knowledge gap so human health risk assessments of PAHs in environmental media or food can be better determined. This is especially important in the aftermath of petroleum spills.Citation: Wickliffe J, Overton E, Frickel S, Howard J, Wilson M, Simon B, Echsner S, Nguyen D, Gauthe D, Blake D, Miller C, Elferink C, Ansari S, Fernando H, Trapido E, Kane A. 2014. Evaluation of polycyclic aromatic hydrocarbons using analytical methods, toxicology, and risk assessment research: seafood safety after a petroleum spill as an example. Environ Health Perspect 122:6–9; http://dx.doi.org/10.1289/ehp.1306724     

Open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of intravenously administered CNF1010 (17-(allylamino)-17-demethoxygeldanamycin [17-AAG]) in patients with solid tumors

Background

17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin that binds to and inhibits the Hsp90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG.

Methods

Patients with advanced solid tumors and adequate organ functions received CNF1010 by 1-h intravenous (IV) infusion, twice a week, 3 out of 4 weeks. Doses were escalated sequentially in single-patient (6 and 12 mg/m²/day) and three-to-six-patient (≥25 mg/m²/day) cohorts according to a modified Fibonacci’s schema. Plasma pharmacokinetic (PK) profiles and biomarkers, including Hsp70 in PBMCs, HER-2 extracellular domain, and IGFBP2 in plasma, were performed.

Results

Thirty-five patients were treated at doses ranging from 6 to 225 mg/m². A total of 10 DLTs in nine patients (2 events of fatigue, 83 and 175 mg/m²; shock, abdominal pain, ALT increased, increased transaminases, and pain in extremity at 175 mg/m²; extremity pain, atrial fibrillation, and metabolic encephalopathy at 225 mg/m²) were noted. The PK profile of 17-AAG after the first dose appeared to be linear up to 175 mg/m², with a dose-proportional increase in C _max and AUC_0–inf. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects of CNF1010 at doses >83 mg/m².

Conclusion

The maximum tolerated dose was not formally established. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects. The CNF1010 clinical program is no longer being pursued due to the toxicity profile of the drug and the development of second-generation Hsp90 molecules.     

A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer

The mammalian target of rapamycin (mTOR) plays a critical role in promoting tumor cell growth and is frequently activated in breast cancer. In preclinical studies, the antitumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated in part by Insulin-like growth factor type 1 receptor (IGF-1R). We designed a phase I trial to determine the maximum-tolerated dose (MTD) and pharmacodynamic effects of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies. A 3 + 3 Phase I design was chosen. Temsirolimus and Cixutumumab were administered intravenously on days 1, 8, 15, and 22 of a 4-week cycle. Of the 26 patients enrolled, four did not complete cycle 1 because of disease progression (n = 3) or comorbid condition (n = 1) and were replaced. The MTD was determined from the remaining 22 patients, aged 34–72 (median 48) years. Most patients (86 %) had estrogen receptor positive cancer. The median number of prior chemotherapy regimens for metastatic disease was 3. The MTD was determined to be Cixutumumab 4 mg/kg and temsirolimus 15 mg weekly. Dose-limiting toxicities (DLTs) included mucositis, neutropenia, and thrombocytopenia. Other adverse events included grade 1/2 fatigue, anemia, and hyperglycemia. No objective responses were observed, but four patients experienced stable disease that lasted for at least 4 months. Compared with baseline, there was a significant increase in the serum levels of IGF-1 (p < 0.001) and IGFBP-3 (p = 0.019) on day 2. Compared with day 2, there were significant increases in the serum levels of IGF-1 (p < 0.001), IGF-2 (p = 0.001), and IGFBP-3 (p = 0.019) on day 8. A phase II study in women with metastatic breast cancer is ongoing.     

Curcumin protects against cigarette smoke-induced cognitive impairment and increased acetylcholinesterase activity in rats

Cigarette smoke, a widely spread habit, is associated with a decline in cognitive function and studies have demonstrated that curcumin (Cur), an Indian spice, possesses a strong neuroprotective potential. Considering the relevance of investigating dietary compounds this study aimed to investigate the effect of Cur on memory and acetylcholinesterase (AChE) activity in brain structures and blood of cigarette smoke-exposed rats. Male Wistar rats were treated with curcumin and cigarette smoke, once a day, 5 days each week, for 30 days. The experimental procedures were divided in two sets of experiments. In the first, the animals were divided into 4 groups: Vehicle (corn oil), Cur 12.5 mg/kg, Cur 25 mg/kg and Cur 50 mg/kg. In the second, the animals were divided into 5 groups: Vehicle (corn oil), Smoke, Smoke plus Cur 12.5 mg/kg, Smoke plus Cur 25 mg/kg and Smoke plus Cur 50 mg/kg. Treatment with Cur significantly prevented the decreased latency and cholinergic alterations in cigarette smoke-exposed rats. These AChE alterations could suggest a role in the memory impairment promoted by cigarette smoke-exposure and point toward the potential of Cur to modulate cholinergic neurotransmission and, consequently, improve cognition deficits induced by smoke. This study suggests that the dietary compound Cur may be involved in cholinergic system modulation and as a consequence exert an effect on learning and memory.     

A phase 2 study of temsirolimus (CCI-779) in patients with soft tissue sarcomas: a study of the Mayo phase 2 consortium (P2C)

BACKGROUND:

The primary goal of this trial was to evaluate the confirmed response rate of temsirolimus (CCI‐779), a mammalian target of rapamycin in patients with advanced soft tissue sarcomas (STS).

METHODS:

Patients ≥18 years with measurable advanced STS, no prior chemotherapy for metastatic disease (adjuvant and neoadjuvant chemotherapy allowed), adequate organ function, and performance status of ≤2 were eligible. After premedication with an antihistamine, CCI‐779 was given intravenously at 25 mg over 30 minutes on Days 1, 8, 15, and 22, repeated every 4 weeks. The primary endpoint was confirmed response rate per Response Evaluation Criteria in Solid Tumors.

RESULTS:

Between June 2004 and November 2005, a total of 41 patients were enrolled and began treatment; 40 patients are evaluable for response and adverse events. The median age was 62 years (range, 28‐72 years) with 56% women. Eighty percent had high‐grade STS, and 22% had prior adjuvant chemotherapy. There were 2 patients (5%; 95% confidence interval [CI], 1‐17) (undifferentiated fibrosarcoma and uterine leiomyosarcoma) who achieved a confirmed partial response lasting 3 and 17 months, respectively. Thirty‐nine (95%) patients have progressed, with a median time to progression of 2.0 months (95% CI, 1.8‐3.5). The median overall survival was 7.6 months (95% CI, 6.1‐15.9). Forty‐three percent experienced grade 3+ adverse events that were possibly related to therapy.

CONCLUSIONS:

Temsirolimus in this patient population of STS had limited clinical activity and had moderate toxicities. Cancer 2011. © 2011 American Cancer Society.     

Phase I study of 17-allylamino-17 demethoxygeldanamycin,gemcitabine and/or cisplatin in patients with refractory solid tumors

Purpose: To determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLT) of 17-AAG, gemcitabine and/or cisplatin. Levels of the proteins Hsp90, Hsp70 and ILK were measured in peripheral blood mononuclear cell (PMBC) lysates to assess the effects of 17-AAG. Experimental design: Phase I dose-escalating trial using a “3 + 3” design performed in patients with advanced solid tumors. Once the MTD of gemcitabine + 17-AAG + cisplatin was determined, dose escalation of 17-AAG with constant doses of gemcitabine and cisplatin was attempted. After significant hematologic toxicity occurred, the protocol was amended to evaluate three cohorts: gemcitabine and 17-AAG; 17-AAG and cisplatin; and gemcitabine, 17-AAG and cisplatin with modified dosing. Results: The 39 patients enrolled were evaluable for toxicity and response. The MTD for cohort A was 154 mg/m² of 17-AAG, 750 mg/m² of gemcitabine, and 40 mg/m² of cisplatin. In cohort A, DLTs were observed at the higher dose level and included neutropenia, hyperbilirubinemia, dehydration, GGT elevation, hyponatremia, nausea, vomiting, and thrombocytopenia. The MTD for cohort C was 154 mg/m² of 17-AAG and 750 mg/m² of gemcitabine, with one DLT observed (alkaline phosphatase elevation) observed. In cohort C, DLTs of thrombocytopenia, fever and dyspnea were seen at the higher dose level. The remaining cohorts were closed to accrual due to toxicity. Six patients experienced partial responses. Mean Hsp90 levels were decreased and levels of Hsp70 were increased compared to baseline. Conclusions: 17-AAG in combination with gemcitabine and cisplatin demonstrated antitumor activity, but significant hematologic toxicities were encountered. 17-AAG combined with gemcitabine is tolerable and has demonstrated evidence of activity at the MTD. The recommended phase II dose is defined as 154 mg/m² of 17-AAG and 750 mg/m² of gemcitabine, and is currently being investigated in phase II studies in ovarian and pancreatic cancers. There is no recommended phase II dose for the cisplatin-containing combinations.