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Flavone acetic acid (FAA) is a semi-synthetic flavonoid characterised by potent immune-modulatory and antivascular activity on mice but not in humans. Previously, the synthesis and cytotoxic activity on a human adenocarcinoma cell line of coumarin-, flavanon- and flavonol-derivatives of FAA were described. These analogues were able to induce the reduction of lysosomal neutral red uptake at 5 x 10(-5) M concentration and some of them were more effective than FAA. Some of these derivatives were selected to investigate their ability to exert immune-modulation on a human model, by using the most potent analogue that has emerged thus far, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), as a reference compound. We investigated the cytotoxicity of the selected derivatives on two human ovarian adenocarcinoma cell lines and their ability to activate the immune system by inducing lytic properties, TNF-alpha and nitric oxide in human monocytes. The immune-modulating activity was assessed by treating a cell line of human monocytes (Mono Mac 6, MM6) with FAA-derivatives alone or in association with lipopolysaccharide (LPS). None of the tested molecules showed any significant ability to directly affect tumor cell proliferation, whereas they were able to induce the lytic properties of MM6 cells. In particular, two coumarin derivatives, a and d, and the flavonol acetic acid, l, showed comparable results to DMXAA. The combination with LPS did not lead to synergistic interactions in the induction of the lytic properties of MM6, but it significantly increased the release of TNF-alpha, especially after 4 h of treatment. Instead, the maximum release of nitric oxide (NO) was detected after 24 h of treatment and after exposure to the FAA derivatives alone. Derivative a combined with LPS and analogue d alone were able to induce a higher TNF-alpha and NO release, respectively, whereas flavonol acetic acid was characterised by a strictly similar activity to DMXAA.

Aminosalicylates, corticosteroids and immunosuppressants are currently the therapeutic choices in inflammatory bowel diseases (IBD), however, with limited remission and often serious side effects. Meanwhile complementary and alternative medicine (CAM) use is increasing, particularly herbal medicine. Boswellia serrata is a traditional Ayurvedic remedy with anti-inflammatory properties, of interest for its usefulness in IBDs. The mechanism of this pharmacological potential of Boswellia serrata was investigated in colonic epithelial cell monolayers exposed to H2O2 or INF-γ+TNF-α, chosen as in vitro experimental model of intestinal inflammation. The barrier function was evaluated by the transepithelial electrical resistance (TEER) and paracellular permeability assay, and by the tight junction proteins (zonula occludens-1, ZO-1 and occludin) immunofluorescence. The expression of phosphorylated NF-κB and reactive oxygen species (ROS) generation were determined by immunoblot and cytofluorimetric assay, respectively. Boswellia serrata oleo-gum extract (BSE) and its pure derivative acetyl-11-keto-β-boswellic acid (AKBA), were tested at 0.1-10 μg/ml and 0.027 μg/ml, respectively. BSE and AKBA safety was demonstrated by no alteration of intestinal cell viability and barrier function and integrity biomarkers. H2O2 or INF-γ+TNF-α treatment of Caco-2 cell monolayers significantly reduced TEER, increased paracellular permeability and caused the disassembly of tight junction proteins occludin and ZO-1. BSE and AKBA pretreatment significantly prevented functional and morphological alterations and also the NF-κB phosphorylation induced by the inflammatory stimuli. At the same concentrations BSE and AKBA counteracted the increase of ROS caused by H2O2 exposure. Data showed the positive correlation of the antioxidant activity with the mechanism involved in the physiologic maintenance of the integrity and function of the intestinal epithelium. This study elucidates the pharmacological mechanisms mediated by BSE, in protecting intestinal epithelial barrier from inflammatory damage and supports its use as safe adjuvant in patients affected by IBD.

New derivatives of xanthenone-4-acetic acid, bearing an alkoxy chain of variable length and a basic moiety, were synthesised in order to test the influence of this additional function on antitumour activity. The introduction of bulky substituents carrying a basic nitrogen seems to be somewhat tolerated, since for some of the compounds the enhancement of lytic potential of human monocytes was comparable to that of the reference molecule DMXAA. The induction of the release of TNF-α and nitric oxide by human monocytes, as well as the hypothesis of a potentiation of the activity of lipopolysaccharide in the induction of those cytotoxic factors, was also evaluated. In this respect, the most interesting compound ( 6a ) exhibited the same spectrum of biological activity shown by DMXAA and seems therefore to be endowed with the same mechanism of action of the reference compound.

Background: The prevalence of diagnosed asthma and wheezing in young subjects is increasing; among environmental risk factors, occupational exposure can play a relevant role. Study objectives: The purpose of the study was to evaluate the effects of occupational exposure to a large variety of irritants and/or sensitizers on the incidence of respiratory symptoms and pulmonary function impairment in a group of young apprentices during the first year of work exposure, and to determine the prevalence of asthma-like symptoms and the role of different risk factors (gender, smoking habit, atopy and occupational exposure) in this young population. Design and methods: We studied 448 young apprentices at the first pre-employment evaluation with a standardized questionnaire, spirometry and skin prick tests; in 244 of them clinical and functional evaluation was repeated after 1 year exposure to respiratory irritants or sensitizers. Results: At the first examination, males had higher prevalence of attacks of shortness of breath with wheeze, diagnosis of asthma, smoking habit and atopy than females. At the second examination there was no significant increase in the prevalence of respiratory symptoms. However, incident cases for cough, phlegm, wheezing, shortness of breath with wheeze (SOBWHZ) and asthma were all higher than remittent cases. Incidence of respiratory symptoms was associated with atopy and smoking habit. Conclusions: Respiratory symptoms slightly increase over 1 year occupational exposure to sensitizers or irritants. The loss at the follow-up of subjects with higher smoking habit suggests a small “health worker effect” and could underestimate the effect of occupational exposure in apprentices.

New analogues of flavone-8-acetic acid were synthesized, bearing an alkoxy group in position 3 and different substituents on the benzene ring in position 2 of the flavone nucleus. The compounds were tested for direct cytotoxicity against four human tumor cell lines and for indirect antitumor effects by measuring their ability to enhance lytic properties of murine macrophages and human monocytes. Though direct toxicity was very low, the compounds were able to induce significant indirect toxicity. Notably, most of them (4c, 4d, 4e, 4f, 4h, 4i, 4m,4n, and 4o) showed important activity on human monocytes and could be regarded as the first flavone derivatives endowed with such activity. Particularly interesting seem to be compounds 4m and 4n, which showed IC(50) values up to 7 times higher than DMXAA, which has now completed phase I clinical trials.

Xanthen-9-one-4-acetic acid (XAA) analogues in which the substituents in positions 5 and 6 are included in cyclic structures are described. Direct in vitro toxicity of the synthesized compounds against four tumor cell lines was evaluated, and their ability to stimulate mouse peritoneal macrophages and human monocytes in culture to become tumoricidal (indirect toxicity) was also studied. Despite low direct toxicity, almost all the compounds proved to be able to significantly enhance the lytic properties of both murine macrophages and human monocytes as well as the parent compound XAA and its most active derivative DMXAA taken as reference. In particular, compounds 4a, 5a, 7a, 13a,b, and 16a,b showed higher activity than the lead compound on human monocytes, compound 7a being 2.5 times more active than DMXAA, which is the most potent compound synthesized so far. Moreover, compounds 4a, 5a, 7a, 13a, 16a, and 16b proved to be able to induce TNF production in human immune cells.

Cough associated with acute and chronic respiratory conditions is common in patients of all ages. Levocloperastine is a novel antitussive with a pharmacological profile distinct from that of the racemic DL-cloperastine. Levocloperastine with its dual mechanism of action acts on both the central bulbar cough centre and on peripheral receptors in the tracheobronchial tree. In preclinical studies, levocloperastine demonstrated antitussive effects similar to those observed with codeine. In acute and repeated-dose toxicity studies, levocloperastine was well tolerated in rodents and dogs, with no clinically significant cardiovascular or gastrointestinal adverse events. The pharmacokinetic behaviour of levocloperastine, best described by a two-compartmental model with absorption phase, is similar to that of the racemic compound DL-cloperastine. In clinical trials, levocloperastine had a faster onset of action and produced greater reductions in the intensity and frequency of cough compared with DL-cloperastine, codeine and levodropropizine. The antitussive effects (reduction in intensity and frequency of cough) of levocloperastine were observed after the first day of treatment in patients of all ages. In children, levocloperastine reduced night-time awakenings and irritability; in adults, it was also effective in treating ACE-inhibitor cough. Levocloperastine was generally well tolerated. There was no evidence of clinically significant central adverse events, whereas drowsiness, dry mouth and nausea were reported with comparator agents (levodropropizine, codeine, DL-cloperastine). Levocloperastine represents an effective alternative to currently used antitussive agents with the added advantage of faster onset of action and improved tolerability in all patient groups.

Some rigid analogues of flavone-8-acetic acid are described. Direct in vitro toxicity of the synthesised compounds was evaluated towards four tumoral cell lines and the ability of these compounds to stimulate mouse peritoneal macrophages in culture to become tumoricidal (indirect toxicity) was also studied. All compounds were able to induce direct cytotoxicity only at very high concentrations but showed a remarkable indirect activity. In particular compound 4d was able to significantly increase macrophage lytic properties and has been selected for further investigations.

This study was designed to compare the activity of two MDR modulators, verapamil and dipyridamole, on the in vitro growth of a human colon carcinoma cell line. The aims were: a) to investigate the different sensitivity of the parental cell line (LoVo S) and the doxorubicin-resistant one (LoVo R) towards the treatment with several antiblastics and their associations with verapamil or dipyridamole; b) to evaluate if the combined use of these drugs with verapamil or dipyridamole increases their cytotoxicity; c) to understand whether the mechanism of action of each modulator is the same. Idarubicin and vinblastine were the most active drugs on both cell lines. LoVo R cells showed cross-resistance to vinblastine, teniposide and mitoxantrone, while chemosensitivity towards cisplatin and cyclophosphamide was almost the same in both cell lines. The inhibitory effect on cell growth was enhanced when the drugs were associated with verapamil, but no difference was detected with cisplatin and cyclophosphamide. Verapamil is thus an effective MDR modulator when used with drugs actively pumped out of tumour cells by P-glycoprotein, while it is ineffective with drugs that induce resistance by different mechanisms. When combined with dipyridamole, a significant result was observed in the case of cisplatin, where a marked increase of cytotoxicity was detected.

In order to proliferate, solid tumours require the development and continuous expansion of an organised host-derived vascular network. The anti-vascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) emerged as derivative of the flavone-8-acetic acid (FAA) and xanthenone-4-acetic acid (XAA). Its anti-vascular activity is not based on direct cytotoxic effects, but is characterized by an immune-mediated component, through the activation of NF-kappaB pathway, and a direct anti-vascular action, involving the induction of endothelial cell apoptosis and changes in tumour vessel permeability. Despite promising pre-clinical results, DMXAA showed moderate anti-tumour activity in clinical trials. In this study, we compared to DMXAA the in vitro immune-modulating and the anti-vascular properties of two XAA analogues, AP/1649 and AP/1897. Their immune-stimulating activities were evaluated on a human monocyte cell line and their anti-vascular activities were studied by measuring the induction of HUVECs apoptosis and using DCE-MRI to determine tumour perfusion following drug treatment. Although the two molecules exerted an immune stimulation comparable to that produced by DMXAA, they showed reduced (AP/1649) or minimal (AP/1897) anti-vascular activity in vitro, and no anti-vascular effects in vivo. These results endorse the current theories concerning two independent actions exerted by DMXAA.

The preparation and the pharmacological profile of a selected number of homologues at C2 (homoflavones) of dimefline-type analeptics are described. The structural modifications introduced in I seems to cause a remarkable alteration of the CNS stimulating pattern so that the new compounds are to be considered as minor analeptics.

Phytochemical investigation of the aerial parts of Aconitum naviculare, a medicinal plant used in traditional Nepalese medicine, led to the isolation and characterization of two new diterpenoid alkaloids, navirine B (1), and navirine C (2), along with (+) chellespontine (3), kaempferol-7-O-β-D-glucopyranosyl(1→3)α-L-rhamnopyranoside (4), kaempferol-7-O α-L-rhamnopyranoside,3-O-β-D-glucopyranoside (5), p-coumaric-4-O-β-D-glucopyranoside acid (6), and ferulic-4-O-β-D-glucopyranoside acid (7). The structures of the isolated compounds were elucidated on the basis of extensive analyses of 1D and 2D NMR spectra (HMQC, HMBC, COSY, ROESY) and HR-MS data. The antiproliferative activity of alkaloids 1–3 against human tumor cell lines (LoVo and 2008) was also evaluated.

The effects of glycine on morphine-induced antinociception were investigated in mice, using a cutaneous thermal test (hot-plate), a visceral chemical test (acetylcholine writhing test), and a locomotor activity test. When glycine (200 mg/kg p.o.) and morphine (5 mg/kg s.c.) were given together during the first 30 min, glycine first antagonized the morphine-induced antinociception then this was followed by a synergistic effect. The two-phase influence of glycine on morphine-induced antinociception may be due to the interaction of glycine with different receptors.

The acetylcholine writhing test and the hot plate test were used in mice to evaluate peripheral and central analgesia after porcine, salmon and human calcitonin administrations. ICV and IV injection of calcitonins caused a peripheral analgesia that persisted for at least 2 hr. SC injection of calcitonins did not produce peripheral analgesia. However, when administered by IP route, an increasing peripheral analgesia was observed. Although it had a slow onset, it was as powerful as after ICV or IV administration. Employing the hot plate test to determine the entity of a central analgesic response, the IP administration of calcitonin surprisingly revealed a hyperalgesic effect. It started soon after the injection, reaching its maximum after about 2 hr. At this point the hyperalgesic effects were fully antagonized by EDTA·2 Na ICV, or by Ca − ICV. Moreover only the latter produced a strong and long acting analgesia. Applying a central or peripheral test, calcium seems to play different roles on the algesia variations induced by calcitonins.

Synthesis and pharmacological properties of N-disubstituted (aminomethyl)benzoylazepines are described. The new compounds show interesting neuroleptic properties comparable to those of droperidol. Basische 5-Benzoyl-10,11-dihydro-5H-dibenz[b,f]azepin-derivate Synthesen und pharmakologische Wirkungen einiger N-disubstituierter Aminomethylbenzoyl-azepine werden beschrieben. Die neuen Verbindungen zeigen interessante, mit jenen von Droperidol vergleichbare, neuroleptische Eigenschaften.

New Pt-dithiocarbamate adducts were prepared and characterized in order to study the interaction cisplatin/dithiocarbamates, in relation to the lipophilic/hydrophilic character of the Pt-adducts. The effects of the dithiocarbamates on B16-F10 cell growth are reported. Changes in surface morphology were observed by scanning electron microscopy (SEM).

It had previously been shown that D-phenylalanine and hydrocinnamic acid, two in vitro inhibitors of carboxy-peptidase A, possess an analgesic action when injected i.p. in mice. We have studied the in vivo effects of indole-3-acetic acid, another carboxypeptidase A inhibitor, and of the following analogs of D-phenylalanine substituted in position 4: D-tyrosine, p-fluoro-D-phenylalanine and trifluoroacetyl-p-fluoro-D-phenylalanine. Whereas indole-3-acetic acid caused a higher and shorter analgesia in comparison with D-phenylalanine, p-fluoro-D-phenylalanine and its N-trifluoroacetyl derivative yielded both a greater and a much longer lasting analgesic effect. Since the latter compound showed only slight inhibitory activity on carboxypeptidase A in vitro, we suggest that inhibition of this enzyme and analgesia might not be directly correlated.

The synthesis and the pharmacological properties of some new prazosin analogues are described. Einige neue Prazosin-Analoge Einige Prazosin-ahnliche Derivative und ihre pharmakologischen Eigenschaften werden beschrieben.

Three isomeric cyclovinylogues of guanethidine are described in which a benzene ring is interposed between the methylene groups of the basic chain. The pharmacological properties of the products were investigated. Guanethidin-Cyclovinyloge Es wird uber die Darstellung und die pharmakologischen Eigenschaften von drei Guanethidin-Cyclovinylogen berichtet, die einen Benzolring zwischen den Methylengruppen der basischen Kette aufweisen.

As a part of a research program on the structure-activity relationships of geiparvarin (Fig.1, 1), a naturally occurring coumarin with promising antineoplastic properties (Padmawinata 1973; Smith and Jerris 1980; Jerris and Smith 1981), this contribution reports some new simple benzene analogues (Fig. 1,2a-1). In fact, after examining some of the bioisosters of 1 (Montanari et al. 1986) as well as the 3, 4, 5, 6, and 8 regional isomers (unpublished data), it seemed appropriate to complete the analysis of the hetero-arenoxy part of such molecules by retaining from the parent compound the benzene ring only. The new structure would allow a number of modifications, in particular the introduction of selected substituents in order to evaluate the contribution of hydrophobic, steric, and electronic parameters to the activity. With this aim, ten new derivatives of the structure shown in Fig. 1 were prepared according to the method of Jackson and Raphael (1984) for geiparvarin.

The search for inert solvent mixtures to assay lipophilic molecules in cell cultures has been carried out in order to test aquamimetic compounds such as dimethyl sulfoxide (DMSO) or nonionic surfactants such as sorbitan derivatives and macrogol esters in the absence or in the presence of ethanol or glycols. However, some cytotoxic effects have been reported for these solvent mixtures which are largely employed for pharmaceutical purposes. Polyoxyethyleneglycerol triricinoleate (Cremophor EL) holds an important role among the solubilizers best tolerated in vivo. For instance, it emulsifies fat soluble vitamins and cyclosporin A in aqueous-alcoholic solution, without producing any apparent cell injury. On the other hand, anaphylactoid reactions (Dye and Watkins 1980), transient hematological and biochemical disturbances (Padfield and Watkins 1977), and unusual hyper-lipidemias (Forrest et al. 1977) have been reported when Cremophor EL was used as aqueous solution for intravenous injection of anesthetic drugs, e.g., Althesin (alphaxalone and alphadolone; Forrest et al. 1977) and propanidid (Watkins 1979).

The muscarin-specific radioligand 1-quinuclidinyl-[phenyl-4-3H]-benzilate was used to determine the development of muscarinic receptors in particulate membranes of rat lung. Postnatal development is associated with a decrease in the number of binding sites (Bmax). Bmax was 65.61 +/- 11.33 fmol/mg protein in 21-day-old rat fetuses and it decreased to 36.64 +/- 10.18 at postnatal day 1, 32.37 +/- 4.99 at day 7 and 16.15 +/- 4.13 fmol/mg protein at 2 months. Bmax at 2 months was significantly different from all the others (Dunnett's test). The dissociation constant Kd was 0.25 nM in 2-month-old animals and it did not undergo significant changes during development.

Three isomeric cyclovinylogues of guanethidine are described in which a benzene ring is interposed between the methylene groups of the basic chain. The pharmacological properties of the products were investigated. Guanethidin-Cyclovinyloge Es wird uber die Darstellung und die pharmakologischen Eigenschaften von drei Guanethidin-Cyclovinylogen berichtet, die einen Benzolring zwischen den Methylengruppen der basischen Kette aufweisen.

Synthesis and pharmacological properties of N-disubstituted (aminomethyl)benzoylazepines are described. The new compounds show interesting neuroleptic properties comparable to those of droperidol. Basische 5-Benzoyl-10,11-dihydro-5H-dibenz[b,f]azepin-derivate Synthesen und pharmakologische Wirkungen einiger N-disubstituierter Aminomethylbenzoyl-azepine werden beschrieben. Die neuen Verbindungen zeigen interessante, mit jenen von Droperidol vergleichbare, neuroleptische Eigenschaften.

Fucus vesiculosus and Ascophyllum nodosum have been traditionally used for the treatment of obesity and several gastrointestinal diseases. We have recently demonstrated that the phytocomplex obtained from these algae (Gdue™) controls postprandial glucose levels in a mouse model of steatohepatitis, a condition often associated with obesity and type 2 diabetes mellitus. We analyzed the effect of Gdue™ on HOMA index, waist circumference, fasting blood glucose and insulin levels in overweight or obese subjects. Waist circumference decreased significantly after 6 months of treatment (112 ± 17 at t0 vs 105 ± 13 cm after 6 months of treatment; p™ (110 ± 15 at t0 vs 98 ± 15 mg/dL after 6 months for glucose; p0 vs 4.419 ± 2.382 after 6 months; p