Synthesis and structure-activity relationships of novel histamine H1 antagonists: indolylpiperidinyl benzoic acid derivatives

A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.     

Central activity of hydroalcoholic extracts from Erythrina velutina and Erythrina mulungu in mice

This work studied the central behavioural effects of hydroalcoholic extracts from the stem bark of Erythrina velutina and Erythrina mulungu on the elevated plus maze, open field, and rota rod tests in mice. These medicinal plants belong to the Fabaceae family and are popularly used in Brazil for their effects on the central nervous system. Single doses of the extracts were administered orally (200, 400 or 800 mg kg(-1)) or intraperitoneally (200 or 400 mg kg(-1)) to female mice. A reduction of the locomotor activity was observed in the open field test with both hydroalcoholic extracts after intraperitoneal treatment with all doses, but only with the highest dose after oral administration. In addition, oral and intraperitoneal administration of the extracts decreased the incidence of rearing and grooming. Decreases in the number of entries in the open (NEOA) and closed (NECA) arms of the elevated plus maze were observed after the administration of the highest dose (800 mg kg(-1), p.o.) of both hydroalcoholic extracts, and this effect may be due to the decrease in locomotor activity. These hydroalcoholic extracts failed to affect the motor coordination in the rota rod test. In conclusion, we showed that the hydroalcoholic extracts of E. velutina and E. mulungu have depressant effects on the central nervous system, which, at least partially, corroborates the popular use of these species as tranquilizers in Brazilian popular medicine.     

Analgesic, antiinflammatory and central depressor effects of the hydroalcoholic extract and fractions from Aeolanthus suaveolens

This work studied antinociceptive, antiedematogenic and central depressor effects of the hydroalcoholic extract (HAE) from Aeolanthus suaveolens and its fractions: hexane (ASHAE-H), ethyl acetate (ASHAE-A), aqueous (ASHAE-E) and precipitate (ASHAE-PPT) in experimental models in mice. The highest activity in the writhing test was presented by ASHAE-A followed by ASHAE-PPT and ASHAE-E and the lowest by ASHAE-H. In the formalin test the effect was manifested at both phases, although more intensely at the 2nd phase of the response. In this test, the most active fraction was ASHAE-PPT causing inhibitions of the order of 76 and 90% of the 2nd phase of the test at the doses of 10 and 100 mg/kg i.p., respectively. Naloxone reversed the effects of ASHAE-PPT in both phases of the test, suggesting the participation of the opioid system in the antinociceptive effect. On the other hand, the HAE effect on both phases of the formalin test was only partially reversed by naloxone, suggesting that the extract presents more than one active compound, and at least one, of a polar nature, acting through the opioid system. HAE and ASHAE-PPT presented antiinflammatory activity and were very effective in decreasing the mouse paw edema induced by carrageenan. All fractions significantly decreased locomotor activity in the open field test in mice. However, only the nonpolar fractions presented myorelaxant activity as demonstrated by the rota rod test.     

High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene

The gene encoding AIB1, an estrogen receptor coactivator, is amplified in a subset of human breast cancers. Here we show that overexpression of AIB1 in transgenic mice (AIB1-tg) leads to mammary hypertrophy, hyperplasia, abnormal postweaning involution, and the development of malignant mammary tumors. Tumors are also increased in other organs, including the pituitary and uterus. AIB1 overexpression increases mammary IGF-I mRNA and serum IGF-I protein levels. In addition, IGF-I receptor and downstream signaling molecules are activated in primary mammary epithelial cells and mammary tumor cells derived from AIB1-tg mice. Knockdown of AIB1 expression in cultured AIB1-tg mammary tumor cells leads to reduced IGF-I mRNA levels and increased apoptosis, suggesting that an autocrine IGF-I loop underlies the mechanism of AIB1-induced oncogenesis.     

CagA antibodies as a marker of virulence in chilean patients with Helicobacter pylori infection

BACKGROUND: The bacterial and host factors that influence the clinical outcomes of the Helicobacter pylori infection have not been fully identified. Cytotoxin-associated gene product (CagA), one of the virulence factors, has been associated with a more aggressive form of infection. The authors studied the relationship between CagA status and clinical outcome in Chilean children and adults with H. pylori infection. METHODS: One hundred eighty consecutive patients undergoing upper gastrointestinal endoscopic analysis were enrolled after informed consent was obtained. Rapid urease test and histologic analysis were used to detect H. pylori infection. IgA and IgG antibodies to H. pylori whole cell antigen preparation and IgG antibodies to CagA were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: H. pylori infection was detected in 42% of the patients by biopsy or urease test and in 38% and 20% of patients by IgG and IgA antibodies, respectively. The prevalence of H. pylori either by the invasive or the serologic tests was directly related to patient age. Among patients with H. pylori, there was no significant association between age and prevalence of CagA. Nearly 70% of the patients with H. pylori and peptic ulcer disease had CagA-positive strains. In contrast, only 49% of the patients with chronic gastritis alone had CagA-positive strains (P < 0.05). CONCLUSIONS: In Chile, patients infected with H. pylori have a proportion of CagA-positive strains similar to that reported in developed countries. CagA prevalence was not significantly different in adults and children infected with H. pylori, suggesting that variations in clinical outcome may be related to host immune or environmental factors.     

Co-treatment with melanotan-II,a potent melanocortin,does not protect against cisplatin ototoxicity

Cisplatin, an important chemotherapeutic agent, has severe dose-limiting side effects including peripheral neurotoxicity and ototoxicity. Peripheral neurotoxicity can be delayed or prevented by simultaneous treatment with a class of neuropeptides known as melanocortins. Examples are ORG 2766, alpha-melanocyte stimulating hormone (alpha-MSH) and melanotan-II (MT-II). In albino guinea pigs, our group has found that ORG 2766 and alpha-MSH can also reduce cisplatin-induced ototoxicity. In this study we investigated the possibly protective effects of MT-II upon cisplatin ototoxicity. Guinea pigs, equipped with a permanent round-window electrode for electrocochleography, were treated with cisplatin (1.5 mg/kg/day intraperitoneal) and simultaneously with MT-II (30 or 3 microg/kg/day subcutaneous) or saline until a 40 dB suppression of the compound action potential (CAP) threshold (3 microV criterion) at 8 kHz occurred. This -40 dB criterion was reached after 5-18 days. Thereafter, the treatment was stopped, but electrocochleography was continued for another 4 weeks. The number of days in which the -40 dB criterion was reached in the MT-II co-treated group did not differ from the period in the saline group. Ten days after the end of the treatment a spontaneous recovery of the CAP was observed in all groups and at all frequencies, although it was more pronounced at lower frequencies. Also with respect to recovery, no differences were found between the saline and the MT-II co-treated group. Thus, in contrast with the otoprotective properties of other melanocortins, MT-II has no protective properties against cisplatin-induced ototoxicity, at least not with the doses applied here.