ADN-1184 a monoaminergic ligand with 5-HT6/7 receptor antagonist activity: pharmacological profile and potential therapeutic utility

Background and Purpose

Many dementia patients exhibit behavioural and psychological symptoms (BPSD) that include psychosis, aggressivity, depression and anxiety. Antipsychotic drugs are frequently prescribed but fail to significantly attenuate mood deficits, may interfere with cognitive function and are associated with motor and cardiac side effects, which are problematic in elderly patients. A need therefore exists for drugs that are better suited for the treatment of BPSD.

Experimental Approach

We used in vitro cellular and in vivo behavioural tests to characterize ADN-1184, a novel arylsulfonamide ligand with potential utility for treatment of BPSD.

Key Results

ADN-1184 exhibits substantial 5-HT₆/5-HT₇/5-HT_2A/D₂ receptor affinity and antagonist properties in vitro. In tests of antipsychotic-like activity, it reversed MK-801-induced hyperactivity and stereotypies and inhibited conditioned avoidance response (MED = 3 mg·kg⁻¹ i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg·kg⁻¹ i.p.; higher doses were not significantly active). Notably, up to 30 mg·kg⁻¹ ADN-1184 did not impair memory performance in the passive avoidance test or elicit significant catalepsy and only modestly inhibited spontaneous locomotor activity (MED = 30 mg·kg⁻¹ i.p.).

Conclusions and Implications

ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is better than that of commonly used atypical antipsychotics tested under the same conditions and suggests that it is feasible to identify drugs that improve BPSD, without exacerbating cognitive deficit or movement impairment, which are of particular concern in patients with dementia.     

An examination of self-reported chronic conditions and health status in the 2001 Medicare Health Outcomes Survey

OBJECTIVES: To estimate the prevalence of chronic conditions in managed care-enrolled Medicare seniors (age 65 years plus) and to examine the association between self-reported chronic conditions and health status, as measured by the SF-36. METHODS: Data were obtained from the 2001 Medicare Health Outcomes Survey (HOS). The HOS is conducted to assess the quality of care provided to Medicare beneficiaries enrolled in managed care. The survey questionnaire, which was administered by phone or mail, includes the SF-36 and items addressing demographic characteristics, depressive symptoms, and chronic conditions. The SF-36 produces eight multi-item scale scores and physical and mental component summary scores. For this analysis, an ordinary least squares regression model was conducted using the SF-36 scales and summary scores as dependent variables to estimate the association between each chronic condition and the scale scores after adjusting for demographic variables. RESULTS: More than three-fourths of the respondents had at least one chronic condition. Among the conditions, hypertension (56.6%) arthritis of the hip or knee (39.7%) and arthritis of the hand or wrist (33.3%) were the most commonly reported. Compared with other variables, age and arthritis were most highly associated with the SF-36 measures reflective of physical health. Depressive symptoms had the strongest association with the SF-36 measures most reflective of mental health. Among the chronic conditions, the adverse impact of having difficulty in controlling urination, a relatively neglected condition, was only second to depressive symptoms in its negative relationship with vitality, social-functioning, and mental health. CONCLUSION: Chronic conditions were commonly reported among the older adults. The unique associations found between chronic conditions and domains of health status demonstrate the importance of examining the burden of these conditions in terms of functioning and well-being. The findings of this study may help inform decision making at the patient, health plan, and societal levels.     

Gemcitabine and paclitaxel in metastatic or recurrent squamous cell carcinoma of the head and neck: a phase I-II study

The purpose of this study was to determine the maximum tolerated dose, toxicity profile and anti-tumor activity of paclitaxel in combination with gemcitabine when administered to patients with unresectable locally recurrent or metastatic squamous cell carcinoma of the head and the neck (SCCHN). Twenty-seven patients were treated in a phase I-II study with gemcitabine at a dose of 800 mg/m on days 1 and 8, escalating to a dose of 1,000 mg/m, plus escalating doses of paclitaxel (100, 135 and 175 mg/m) on day 2. Treatment consisted of 6 cycles repeated every 3 weeks. The main toxicity was myelosuppression. Other toxicities were mild and manageable. Due to grade 4 neutropenia at higher doses the recommended dose level of the gemcitabine/paclitaxel combination was 1,000/135 mg/m. Four patients achieved a partial response and no patient had a complete remission, giving an overall response rate of 14.8%. The median time of survival was 24 weeks. We conclude that the combination of paclitaxel and gemcitabine is tolerated, but shows insufficient clinical activity in patients with recurrent and/or metastatic SCCHN to warrant further testing.     

Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain

Rationale

Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates.

Objective

The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs).

Results

Tail injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes, i.e., fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception.

Conclusion

Using two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.     

水体中克雷伯菌属的分布及其在水源性急性肠道感染中的价值

俄罗斯不同气候地区不同功能水体中克雷伯菌属广泛分布。克雷伯菌属可见于遭受生物、化学污染的集中供水的地表水源,无防护的地下蓄水层,缺乏有效清洁、消毒系统的饮用水。研究表明,水体中的克雷伯菌属具有致病性和毒性,对现代药物和消毒剂(氯、紫外线)具有抗性,很容易穿透进入地下蓄水层。克雷伯菌属细菌有很强的致病性(粘附力、侵袭力、磷酸酯酶、卵磷脂酶、脱氧核糖核酸酶、溶血活性),含有致病性遗传标记cnf-1。克雷伯菌属(100 CFU/dm³)可引起急性肠道感染。在不检测总大肠菌群的情况下,检测水体尤其是饮用水中的克雷伯菌属,可以评估所用水的流行病学危险。     

Extraction of heavy metals from contaminated soil by Cinnamomum camphora

83 acres of rice paddy fields in Taoyuan county, Taiwan, were polluted by cadmium (Cd), chromium (Cr) and copper (Cu) through a nearby irrigation channel, and rice plantation was ceased in 1987. Camphor trees (Cinnamomum camphora) have been planted in 2 acre of the above fields since 1991. Heavy metal accumulation of roots, leaves, branches and heartwood of camphor trees were analyzed during 20-year afforestation. Averaged Cd contents of the roots were found larger than the ones of the branches, leaves, sapwood and heartwood of camphor trees growing in three polluted plots. Averaged diameters at breast height (DBH) of the planted camphor trees were 13–15 cm. Cd pollution did not significantly impact the growth of camphor trees, as similar DBH’s were found from both polluted and control sites. Annual growths of DBH were from 0.63 to 0.77 cm year^?1. Planting camphor trees sequestered 68.8 ton biomass per acre. During 20-year period, 0.69–1.98 ton C year^?1 ha^?1 were sequestered on three polluted plots. The above numbers exceeded IPCC LULUCF reference values 0.31–0.53 ton C year^?1 ha^?1 for activities at forest lands.     

Influenza M2 virus-like particles confer a broader range of cross protection to the strain-specific pre-existing immunity

Immunity in humans with annual vaccination does not provide effective protection against antigenically distinct strains. As an approach to improve cross-protection in the presence of pre-existing strain-specific immunity, we investigated the efficacy of heterologous and heterosubtypic protection in previously vaccinated mice at earlier times after subsequent immunization with conserved-antigenic target influenza M2 ectodomain (M2e) virus-like particle vaccine (M2e5× VLP). Immunization of mice with H1N1 split vaccine induced virus specific antibodies to homologous influenza virus but did not provide heterosubtypic hemagglutination inhibiting antibody responses and cross-protection. However, subsequent M2e5× VLP immunization induced an M2e specific antibody response as well as interferon-γ (IFN-γ) producing cells in systemic and mucosal sites. Upon lethal challenge with H3N2 or H5N1 subtype influenza viruses, subsequently immunized mice with M2e5× VLP were well protected against heterosubtypic influenza viruses. These results provide evidence that non-seasonal immunization with M2e5× VLP, an experimental candidate for universal vaccine, is a promising approach for broadening the cross-protection even in the presence of strain-specific immunity.     

Understanding HPV Vaccine Uptake Among Cambodian American Girls

Cervical cancer incidence rates vary substantially among racial/ethnic groups in the United States (US) with women of Southeast Asian descent having the highest rates. Up to 70 % of cervical cancers could be prevented by widespread use of the human papillomavirus (HPV) vaccine. However, there is a lack of information about HPV vaccine uptake among Southeast Asian girls in the US. We conducted a telephone survey of Cambodian women with daughters who were age-eligible for HPV vaccination. Survey items addressed HPV vaccination barriers, facilitators and uptake. Our study group included 86 Cambodian mothers who lived in the Seattle metropolitan area. The proportions of survey participants who reported their daughter had initiated and completed the HPV vaccine series were only 29 and 14 %, respectively. Higher levels of vaccine uptake were significantly associated with mothers having heard about the HPV vaccine from a health professional and having received a recent Pap test. Commonly cited barriers to HPV vaccination included lack of knowledge about the HPV vaccine, not having received a physician recommendation for HPV vaccination and thinking the HPV vaccine is unnecessary in the absence of health problems. Linguistically and culturally appropriate HPV educational programs should be developed and implemented in Cambodian American communities. These programs should aim to enhance understanding of disease prevention measures, increase knowledge about the HPV vaccine and empower women to ask their daughter’s doctors for HPV vaccination.     

Chemical composition of polyphenols extracted from strawberry pomace and their effect on physiological properties of diets supplemented with different types of dietary fibre in rats

Purpose

The objective of this study was to establish the composition of polyphenolic preparations obtained from industrial strawberry pomace with two methods of extraction: the water and the water-alcoholic one and then to analyse their effects in the gastrointestinal tract depending on the composition of dietary fibre—cellulose or fructooligosaccharides (FOS).

Methods

Freeze-dried water extract (PTW), containing 5.1 % of ellagic acid, 0.2 % of proanthocyanidins, and soluble carbohydrates as a major part, and water–alcohol extract (PTE), containing 17.1 % of ellagic acid and 10.9 % of proanthocyanidins, were administered, in the equivalent quantity of 0.06 % of ellagic acid, to 4- to 8-week-old rats (8 animals per group), as a component of modified AIN-93 diets containing 5 % of cellulose or FOS.

Results

The addition of strawberry pomace extracts had no effect on either the diet intake or the body weight of experimental rats. Both extracts, similarly to FOS, beneficially reduced the activity of β-glucuronidase in caecal digesta, with the PTW effect being significantly higher than that of PTE (7.59 vs. 9.20 μmol/h/g, P = 0.001). In comparison with PTE, the PTW extract significantly increased the caecal digesta mass (1.45 vs. 1.27 k/kg BW) and the total production of SCFA (86.1 vs. 71.4 μmol/100 g BW). The extract enhanced the physiological effect of FOS by inhibiting the activity of β-glucuronidase, increasing the caecal digesta mass and SCFA production. Such an effect was not recorded in the case of the PTE preparation.

Conclusions

The addition of strawberry pomace extracts affected the activity of certain enzymes of intestinal microflora and its most important products.     

Tamoxifen enhances erlotinib-induced cytotoxicity through down-regulating AKT-mediated thymidine phosphorylase expression in human non-small-cell lung cancer cells

Tamoxifen is a triphenylethylene nonsteroidal estrogen receptor (ER) antagonist used worldwide as an adjuvant hormone therapeutic agent in the treatment of breast cancer. However, the molecular mechanism of tamoxifen-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Thymidine phosphorylase (TP) is an enzyme of the pyrimidine salvage pathway which is upregulated in cancers. In this study, tamoxifen treatment inhibited cell survival in two NSCLC cells, H520 and H1975. Treatment with tamoxifen decreased TP mRNA and protein levels through AKT inactivation. Furthermore, expression of constitutively active AKT (AKT-CA) vectors significantly rescued the decreased TP protein and mRNA levels in tamoxifen-treated NSCLC cells. In contrast, combination treatment with PI3K inhibitors (LY294002 or wortmannin) and tamoxifen further decreased the TP expression and cell viability of NSCLC cells. Knocking down TP expression by transfection with small interfering RNA of TP enhanced the cytotoxicity and cell growth inhibition of tamoxifen. Erlotinib (Tarceva, OSI-774), an orally available small molecular inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is approved for clinical treatment of NSCLC. Compared to a single agent alone, tamoxifen combined with erlotinib resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells, accompanied with reduced activation of phospho-AKT and phospho-ERK1/2, and reduced TP protein levels. These findings may have implications for the rational design of future drug regimens incorporating tamoxifen and erlotinib for the treatment of NSCLC.