Synthesis and in vitro pharmacological evaluation of novel 2-hydroxypropyl-4-arylpiperazine derivatives as serotoninergic ligands.

This paper reports the synthesis of new norbornene and exo-N-hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide derivatives and their binding to the 5-HT1A , 5-HT2A , and 5-HT2C receptors, in order to identify selective ligands for these 5-hydroxytryptamine (5-HT, serotonine) receptor subtypes. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4-substituted piperazine) known to be critical for affinity to 5-HT1A receptors and the proper selection of substituents led to compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected and further evaluated for their binding affinities to D1 , D2 dopaminergic and α1 , α2 adrenergic receptors. 4-[3-[4-(2-Furoyl)piperazin-1-yl]propoxy-2-ol]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione 3e with Ki = 5.04 ± 0.227 nM was the most active and selective derivative for the 5-HT2C receptor with respect to other serotonin receptors, and the most selective derivative versus dopaminergic and adrenergic receptors.

Severe hypoglycemia associated with levofloxacin in Type 2 diabetic patients receiving polytherapy: two case reports.

OBJECTIVE: Although hypoglycemia is known to be associated with levofloxacin, patients are continually being hospitalized because of this adverse event. Here we have reported two further cases of severe hypoglycemia and discussed the possibility that the hypoglycemia is the result of interactions between levofloxacin and certain drugs, in order to alert physicians to be aware that geriatric patients, particularly those with Type 2 diabetes and in polytherapy, are at risk of showing this adverse reaction. CASES SUMMARY: A 91-year-old woman with Type 2 diabetes on metformin and glibenclamide, also under treatment with oral antihypertensive drugs, platelet antiaggregant, low-molecular- weight heparin and buprenorphine, was prescribed levofloxacin for a bacterial infection. Liver function and renal function parameters were within normal limits. After repeated administration of levofloxacin, her serum glycemic levels had decreased to 47 mg/dl and the patient was in a coma. After stopping levofloxacin her glycemia level returned to the normal value. A 61 year-old male, affected by tonsillar squamous cell carcinoma, with Type 2 diabetes on metformin and glibenclamide, under treatment with low-molecular-weight heparin for deep venous thrombosis, hydromorphone and undergoing nutritional support, was treated with levofloxacin for a bacterial infection. After 72 h the patient was unresponsive and his blood glucose levels were 38 mg/dl. After discontinuation of levofloxacin administration the patient was treated with glucose infusion and his glycemic values gradually returned to the normal range. DISCUSSION: The causality relationship between the levofloxacin and the hypoglycemia was established using Naranjo's ADR probability scale. These case reports confirm the literature data that serious hypoglycemia may develop due to the use of levofloxacin and appears to occur most frequently in elderly patients with Type 2 diabetes who are receiving oral hypoglycemic agents. We described the possible pharmacokinetic and pharmacodinamic mechanisms of the interaction between levofloxacin and the other drugs. CONCLUSIONS: We hypothesized that the concomitant use of several drugs and particularly levofloxacin in association with oral antidiabetic drugs, opioid analgesics and low-molecular-weight heparin could concur to cause this side effect. The safety and tolerability of this anti-infective agent should be revised urgently.

In vitro antioxidant activity of aged extracts of some Italian Allium species.

Antioxidant activity of fresh Allium sativum L. (garlic) is well known and is mainly due to unstable and irritating organosulphur compounds. Fresh garlic extracted over a prolonged period (up to 20 months) produces odourless aged garlic extract (AGE) containing stable and water soluble organosulphur compounds that prevent oxidative damage by scavenging free radicals. The aim of this study was to investigate the in vitro antioxidant activity of aged (up to 20 months) 15% hydroethanolic extracts of different parts (bulbs, bulblets, flower bulblets, flowers, and leaves) of three Allium spontaneous species which are endemic for Italian flora: Allium neapolitanum Cyr., Allium subhirsutum L., Allium roseum L. and to compare it with the in vitro antioxidant activity of aged 15% hydroethanolic extracts of bulbs and leaves of garlic. The antioxidant potential of aged extracts of all species has been evaluated using two different spectrophotometric assays: 2,2-diphenylpicrylhydrazyl (DPPH) test and the ferric reducing/antioxidant power (FRAP) assay. Furthermore the polyphenol content was determined. The aged extracts obtained from the leaves showed the best antioxidant activity, followed by flowers and then by bulbs in both used tests, while flower bulblets and bulblets exhibited lower results or no activity. The polyphenol content was generally directly correlated with antioxidant/antiradical activity. This study confirms the data obtained in previous researches, the wild-type species of Allium and in particular organs other than bulbs are more active and efficacious than garlic bulb. Surely leaves of these Allium spp. deserve special attention.

New 5-HT(1A) receptor ligands containing a N'-cyanoisonicotinamidine nucleus: synthesis and in vitro pharmacological evaluation.

N'-cyanoisonicotinamidine derivatives, linked to an arylpiperazine moiety, were prepared to identify highly selective and potent 5-HT(1A) ligands as potential pharmacological tools in studies of wide spread psychiatric disorders. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to be critical in order to have affinity on 5-HT(1A) receptor and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed affinity in nanomolar and subnanomolar range at 5-HT(1A) and moderate to no affinity for other relevant receptors (5-HT(2A), 5-HT(2C), D(1), D(2), alpha(1) and alpha(2)). N'-cyano-N-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isonicotinamidine (4o) with K(i)=0.038 nM, was the most active and selective derivative for the 5-HT(1A) receptor with respect to other serotoninergic, dopaminergic and adrenergic receptors.

Cardiovascular receptor binding affinity of aqueous extracts from Allium species.

INTRODUCTION: The aims of this study were to evaluate whether the antihypertensive effect of garlic could to be associated to interactions with adrenergic and dopaminergic receptors involved in regulating blood pressure and to compare these data with those obtained from wild Allium species. METHODS: The aqueous extracts of bulbs or leaves of Allium sativum L. (garlic), Allium neapolitanum Cyr., Allium subhirsutum L., and Allium roseum L. were tested for their in vitro affinity for the adrenergic (alpha(1), alpha(2), beta(1) and beta(2)) and dopaminergic (D(1) and D(2)) receptors by radioligand binding assays. RESULTS: Interesting results were shown by bulbs extracts of A. neapolitanum and A. subhirsutum with higher affinities for the beta(2) receptors and by bulbs extract of A. roseum for D(2) receptors. CONCLUSIONS: The known antihypertensive activity of Allium sativum cannot be correlated with binding to receptors involved in blood pressure regulation. However, aqueous extracts of the wild-type species of Allium show much higher affinities, warranting further explorations.

Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients.

PURPOSE: Tumor cell killing by anticancer drugs may be supported by their immuno- and pharmacologic effects. Chemotherapy is in fact able to (A) upregulate tumor-associated antigen expression, including carcinoembryonic antigen (CEA) or other target molecules such as thymidylate synthase (TS); and (B) downregulate tumor cell resistance to the death signals induced by tumor antigen-specific cytotoxic T lymphocytes. This provides the rationale for combining chemo- and immunotherapy. MATERIALS AND METHODS: We describe the results of a translational phase II trial designed to evaluate the toxicity, antitumor activity and immunologic effects of gemcitabine + FOLFOX-4 (oxaliplatin, fluorouracil, and folinic acid) polychemotherapy followed by the subcutaneous administration of granulocyte macrophage colony-stimulating factor and low-dose interleukin-2 in colorectal carcinoma patients. The study involved 29 patients (16 males and 13 females with a mean age of 69 years), 21 of whom had received a previous line of treatment, and 19 had liver involvement. RESULTS: The treatment was well tolerated and induced very high objective response (68.9%) and disease control rates (96.5%), with an average time to progression of 12.5 months. An immunologic study of peripheral blood mononuclear cells (PBMCs) taken from 20 patients showed an enhanced proliferative response to colon carcinoma antigen and a significant reduction in suppressive regulatory T lymphocytes (CD4+CD25T-reg+). A cytofluorimetric study of the PBMCs of five HLA-A(*)02.01+ patients who achieved an objective response showed an increased frequency of cytolytic T lymphocyte precursors specific for known CEA- and TS-derived epitopes. CONCLUSION: The results show that our regimen has strong immunologic and antitumor activity in colorectal cancer patients and deserves to be investigated in phase III trials.

Affinity of Iresine herbstii and Brugmansia arborea extracts on different cerebral receptors.

Iresine herbstii Hook. (Amaranthaceae) and Brugmansia arborea (L.) Lagerheim (Solanaceae) are used in the northern Peruvian Andes for magic-therapeutical purposes. The traditional healers use Iresine herbstii with the ritual aim to expel bad spirits from the body. Furthermore, Iresine herbstii was used in association with other plants, such as Trichocereus pachanoi Britt. et Rose, for divination, to diagnose diseases, and to take possession of another identity. Also, species of Brugmansia have been reported to be used during ritual practices for magical and curative purposes. Given the above evidence, the aim of the present study is to evaluate if the central effects of Iresine herbstii and Brugmansia arborea could be associated with interaction with SNC receptors. Two Iresine herbstii extracts (methanolic and aqueous) and one Brugmansia arborea aqueous extract were tested for in vitro affinity on 5-HT(1A), 5-HT(2A), 5-HT(2C), D1, D2, alpha(1), and alpha(2) receptors by radioligand binding assays. The biological materials for binding assay (cerebral cortex) were taken from male Sprague-Dawley rats. The extracts affinity for receptors is definite as inhibition percentage of radioligand/receptor binding and measured as the radioactivity of remaining complex radioligand/receptor. The data obtained for Iresine extracts have shown a low affinity for the 5-HT(1A) receptor and no affinity for 5-HT(2A) receptor. Otherwise the methanolic extract showed affinity for 5-HT(2C) receptor (IC(50): 34.78 microg/ml) and for D1 receptor (IC(50): 19.63 microg/ml), instead the Iresine aqueous extract displayed a lower affinity for D1 (48.3% at the maximum concentration tested) and a higher value of affinity for D2 receptors (IC(50): 32.08 microg/ml). The Brugmansia aqueous extract displayed affinity for D1 receptors (IC(50): 17.68 microg/ml), D2 receptors (IC(50): 15.95 microg/ml) and weak affinity for the serotoninergic receptors. None of the three extracts showed relevant affinity to the alpha(1), and alpha(2) receptors. The results of our experiments indicate that Iresine herbstii methanolic extract was able to interact with the central 5-HT(2C) and D1 receptors and Iresine herbstii aqueous extract showed affinity for D2 receptors, thus confirming their ritual use. Instead Brugmansia arborea was able to interact only with the central dopamine receptors tested. Parallel studies are currently in progress for evaluating the extracts affinity and active components towards these and other receptor types (GABAergic).

Binding studies for serotoninergic, dopaminergic and noradrenergic receptors of Valeriana adscendens Trel. extracts.

Valeriana adscendens Trel. (Valerianaceae) is a psychoactive plant usually used in magical-therapeutic rituals in traditional practices of the Northern Peruvian Andes. Previous studies have been carried out on extracts of aerial parts in order to validate its traditional use. The results indicated that Valeriana adscendens exerts important effects on the central nervous system. Aim of the present study is to evaluate if the effects on the central nervous system of Valeriana adscendens extracts can be associated with interaction with some CNS receptors. In this work we examined affinity and selectivity of two Valeriana adscendens extracts (methanolic and aqueous) towards 5-HT(1A), 5-HT(2A), 5-HT(2C) serotononergic, D(1) and D(2) dopaminergic, alpha(1) and alpha(2) noradrenergic receptors by a preliminary binding screen. The results show weak affinity to 5-HT(1A) for the aqueous extract. Both extracts showed affinity for D(1) receptors, but only for the methanolic extract the IC(50) value was determinable (30.14 microg/ml). No affinity for 5-HT(2A), 5-HT(2C) serotononergic receptors, alpha(1) and alpha(2) noradrenergic receptors and D(2) receptors was recorded for the extracts.

Synthesis, in vitro and in vivo pharmacological evaluation of serotoninergic ligands containing an isonicotinic nucleus.

Isonicotinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors were evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to play critical roles in affinity for serotoninergic receptors and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1 and α2). N-(3-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)propyl)isonicotinamide (4s) with Ki = 0.130 nM, was the most active and selective derivative for the 5-HT1A receptor compared to other serotoninergic, dopaminergic and adrenergic receptors. Compound 4o, instead, showed 5-HT2A affinity values in subnamolar range. Moreover, the compounds having better affinity and selectivity binding profile towards 5-HT1A and 5-HT2A receptors were selected in order to be tested by in vitro and in vivo assays to determine their functional activity.

Endothelin-1 triggers placental oxidative stress pathways: putative role in preeclampsia.

CONTEXT: Preeclampsia (PE) is a disorder that occurs only during pregnancy. The placenta has a controlling role in this condition. Recent literature suggests that the oxidative stress is a component of PE and plays a main role in the link between decreased placental perfusion and the impaired function of maternal endothelium. OBJECTIVE: Because the human placenta expresses endothelin-1 (ET-1) and its circulating levels are high in pregnancies complicated with PE, the present study investigated the role of ET-1 on placental oxidative stress pathways. DESIGN: Human placental explants, JEG-3, and primary cytotrophoblast cells were cultured with increasing ET-1 concentrations for 6 and 24 h. SETTING: The study was conducted at tertiary clinical care centers in Siena and Padova, Italy. INTERVENTIONS: Human placental explants, JEG-3, and primary cytotrophoblast cells were used to test ET-1 effect. MAIN OUTCOME MEASURE(S): The main outcome measure was ET-1 mRNA and its receptor mRNAs, type A and B, detection by RT-PCR. The common markers of oxidative stress [malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), ascorbic acid (AA)] as well as cell proliferation and vitality were measured after stimulation periods. RESULTS: ET-1 inhibits cell proliferation and vitality and triggers oxidative stress in the human placenta by altering the balance between oxidant (increased MDA levels) and antioxidant (decreased GSH, GSSG, and AA) forces in favor of oxidation. CONCLUSIONS: Because MDA damages endothelial cells, whereas GSH, GSSG, and AA protect them, we postulate that ET-1 may be one of the key links between primary placental disorders and the systemic endothelial dysfunction of PE.

Impaired uterine artery blood flow at mid gestation and low levels of maternal plasma corticotropin-releasing factor.

OBJECTIVE: Corticotropin-releasing factor (CRF) is a placental neuropeptide that plays a role in the control of uteroplacental blood flow regulation. Because CRF has a relaxant effect on uterine vasculature in pregnant rats, we aimed to evaluate mid-gestation plasma CRF levels in women with impaired uterine artery blood flow. METHODS: Maternal plasma CRF was assayed by specific radioimmunoassay, and uterine artery resistance index (RI) was assessed by Doppler evaluation at 22-24 weeks' gestation in 55 healthy pregnant women, of whom 24 showed a unilateral or bilateral uterine artery notch, reflecting resistance. Statistical analysis was performed by the Kruskal-Wallis test followed by the post hoc Dunn's test and the Spearman rank test. RESULTS: The mean uterine artery RI was significantly (P <.001) higher in women with a notch than in healthy controls. Mean +/- standard error of the mean maternal plasma CRF levels were significantly lower in women with a unilateral (168.45 +/- 27.5 pg/mL; P <.01) or bilateral (186.07 +/- 34.5 pg/mL; P <.001) uterine artery notch than in healthy control pregnant women (375.06 +/- 21.77 pg/mL). Although no difference was found in CRF levels between patients with a unilateral or bilateral uterine artery notch, a significant inverse correlation was found between the mean RI and maternal plasma CRF levels (Spearman r = -0.6540; 95% confidence interval, -0.7865, -0.4640; P <.001). CONCLUSION: Reduced levels of circulating CRF were associated with increased uterine artery resistance, which supports the hypothesis that CRF may regulate uterine artery tone at mid gestation.

Hepatotoxicity of Teucrium chamaedrys L. decoction: role of difference in the harvesting area and preparation method.

AIM: Two recurrent cases of severe acute liver injury attributed to the use of a wild germander decoction, prepared with some variation in traditional method has been reported. The aim of the present study was to correlate the hepatotoxic effect observed in patients who consumed germander decoction with teucrin A levels. Antioxidant properties were analyzed to assess any possible differences between the decoction used traditionally by the family (without negative consequences) and the decoction taken by the patients. MATERIALS AND METHODS: Different types of germander decoctions were prepared in the laboratory by simulating the same conditions for preparing the decoction by the patients and their family members. The levels of teucrin A, the polyphenols and the antioxidant power were determined. One-way analysis of variance was used to test for differences between the groups. RESULTS AND CONCLUSIONS: The extract consumed by the patients had higher concentration of teucrin A, lower antioxidant activity and lower content of polyphenols compared with the traditional decoction, revealing an inverse relationship between teucrin A content and antioxidant capacity. These case reports emphasize that more information is needed on the safety and quality of these natural products.

New potent 5-HT(2A) receptor ligands containing an N'-cyanopicolinamidine nucleus: Synthesis and in vitro pharmacological evaluation.

N'-cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to serotonin 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors were evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to be critical for affinity to 5-HT(1A) receptors and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed affinity in nanomolar and subnanomolar range at 5-HT(2A) and moderate to no affinity for other relevant receptors (5-HT(1A), 5-HT(2C), D(1), D(2), α(1) and α(2)). N'-cyano-N-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)-picolinamidine (4l) with K(i)=0.000185nM, was the most active and selective derivative for the 5-HT(2A) receptor compared to other serotoninergic, dopaminergic and adrenergic receptors.

Synthesis of 1-naphtylpiperazine derivatives as serotoninergic ligands and their evaluation as antiproliferative agents.

Serotonin (5-hydroxytryptamine, 5-HT) is one of the most important neuromediator involved in numerous physiological and pathophysiological processes. In addition it is well established that 5-HT acts as a growth factor on several types of non-tumoral and tumoral cells, and recently it was also related to oncogenes. 5-HT1A receptor expression was identified in prostatic tumor cell lines (PC3 cells) and in human hormone refractory prostate cancer tissue. Based on these observations, development of 5-HT1A antagonists could be useful in inhibiting the growth of cancer cells. In order to investigate on potential use of 5-HT1A ligands as antiproliferative agents, we have analyzed a new set of 1-naphtylpiperazine derivatives. In binding studies, several molecules showed affinity in nanomolar and subnanomolar range at 5-HT1A and moderate to no affinity for other relevant receptors (5-HT2A, 5-HT2C, D1, D2, α1 and α2). All compounds were then evaluated in order to assess their antiproliferative activity using PC3 cells and the most active compounds (1 and 2) were fully characterized to define the mechanism responsible for the observed antiproliferative effect.

Protective effect of Allium neapolitanum Cyr. versus Allium sativum L. on acute ethanol-induced oxidative stress in rat liver.

This study investigated the protective effect of Allium neapolitanum Cyr., a spontaneous species of the Italian flora, compared with garlic (Allium sativum L.) on liver injury induced by ethanol in rats. Male albino Wistar rats were orally treated with fresh Allium homogenates (leaves or bulbs, 250 mg/kg) daily for 5 days, whereas controls received vehicle only. At the end of the experimental 5-day period, the animals received an acute ethanol dose (6 mL/kg, i.p.) 2 hours before the last Allium administration and were sacrificed 6 hours after ethanol administration. The activities of catalase (CAT), superoxide dismutase (SOD), and glutathione reductase (GR) and the levels of malondialdehyde (MDA), ascorbic acid (AA), and reduced (GSH) and oxidized glutathione in liver tissue were determined. Administration of both Allium species for 5 days (leaves or bulbs) led to no statistical variation of nonenzymatic parameters versus the control group; otherwise Allium treatment caused an increase of GSH and AA levels compared with the ethanol group and a diminution of MDA levels, showing in addition that A. neapolitanum bulb had the best protective effect. Regarding to enzymatic parameters, GR and CAT activities were enhanced significantly compared with the ethanol group, whereas SOD activity showed a trend different from other parameters estimated. However, the treatment with both Allium species followed by acute ethanol administration reestablished the nonenzymatic parameters similar to control values and enhanced the activities of the enzymes measured. These results suggest that fresh Allium homogenates (leaves or bulbs) possess antioxidant properties and provide protection against ethanol-induced liver injury.

Efficient microwave combinatorial synthesis of novel indolic arylpiperazine derivatives as serotoninergic ligands.

An easy and convenient microwave-assisted synthesis of a small library of indolic arylpiperazine derivatives is described. Parallel and mixed pool combinatorial methods are reported and compared. The described reactions are nucleophilic substitutions of several aromatic piperazines in presence of K(2)CO(3). Good yields and short reaction times are the main aspect of these procedures. Binding assays shed additional light on the influence of the LCAPs on the 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors affinity and allowed to disclose three interesting compounds as 5-HT(2C), mixed 5-HT(2A)/5-HT(2C) and 5-HT(1A)/5-HT(2C) ligands (4i, 4l and 4d, respectively), with potential antiepileptic, anxiolytic or atypical antipsychotic agent therapeutical profiles.

Evaluation of antioxidative properties of Allium species growing wild in Italy.

The genus Allium (Alliaceae) is an important dietary source of antioxidant phytochemical products. The antioxidant activity of some Allium species is well known but no information is available on the in vitro antioxidant activities of Italian Allium species growing wild. The aim of this study was to examine the in vitro antioxidant activity of aqueous extracts of different parts belonging to three Allium species growing wild, endemic to Italian flora: Allium neapolitanum Cyr., Allium subhirsutum L. and Allium roseum L., compared with the in vitro antioxidant activity of aqueous extracts of bulbs and leaves of the greatly studied garlic (Allium sativum L.). The antioxidant potential of extracts was evaluated using two different spectrophotometric assays: the DPPH test and FRAP assay. Furthermore the polyphenolic content was determined in all Allium species. The flowers of species growing wild showed the higher antioxidant power. Interesting results were shown even by the leaves, while the antioxidant capacity of the bulbs was lower. A correlation between the phenolic contents and the antioxidant activity was discovered. The differences in antioxidant capacity reflect the variability in the Allium species and the parts of the plant used and that the bulb of Allium sativum did not show higher antioxidant power.

Correlation between cardiac oxidative stress and myocardial pathology due to acute and chronic norepinephrine administration in rats.

BACKGROUND: To investigate the cardiotoxic role of reactive oxygen species (ROS) and of products derived from catecholamines auto-oxidation, we studied: (1) the response of antioxidant cardiac cellular defence systems to oxidative stress induced by norepinephrine (NE) administration, (2) the effect of NE administration on cardiac beta1-adrenergic receptors by means of receptor binding assay, (3) the cellular morphological alterations related to the biologically cross-talk between the NE administration and cytokines [tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), interleukins IL6, IL8, IL10]. METHODS AND RESULTS: A total of 195 male rats was used in the experiment. All animals underwent electrocardiogram (EKG) before being sacrificed. The results obtained show that NE administration influences the antioxidant cellular defence system significantly increasing glutathione peroxidase (GPx) activity, glutathione reductase (GR) and superoxide dismutase (SOD). The oxidized glutathione (GSH/GSSG) ratio significantly decreases and malondialdehyde (MDA) levels increase showing a state of lipoperoxidation of cardiac tissue. We describe a significant apoptotic process randomly sparse in the damaged myocardium and the effect of ROS on the NE-mediated TNF-alpha, MCP-1, and IL6, IL8, IL10 production. CONCLUSIONS: Our results support the hypothesis that catecholamines may induce oxidative damage through reactive intermediates resulting from their auto-oxidation, irrespective of their interaction with adrenergic receptors, thus representing an important factor in the pathogenesis of catecholamines-induced cardiotoxicity. The rise of the cardioinhibitory cytokines may be interpreted as the adaptive response of jeopardized myocardium with respect to the cardiac dysfunction resulting from NE injection.

In vitro antiproliferative effect of six Salvia species on human tumor cell lines.

This study was designed to examine the in vitro antiproliferative activity of the methanol crude extracts of six Salvia species: Salvia dominica L. leaves, Salvia lanigera Desf. aerial parts, Salvia menthaefolia Ten. roots, Salvia palaestina Benth. aerial parts, Salvia sclarea L. roots and Salvia spinosa L. aerial parts. Extracts were screened for their possible antitumoral activity by MTT test on nine human cancer cell lines: glioblastoma (DBTRG-05MG, T98G, U-87MG), colorectal adenocarcinoma (WiDr and HT-29), prostate adenocarcinoma (MDA Pca2b), choriocarcinoma (JEG-3), endometrium adenocarcinoma (HEC-1A) and B lymphoblast (CIR). IC(50) values were determined for only five extracts and ranged from 90 to 400 microg/mL approximately. Salvia menthaefolia extract exhibited marked antiproliferative activity against all tumor cell lines showing lower IC(50) values, while S. spinosa, S. sclarea and S. dominica extracts showed a degree cytotoxic activity dependent on the cell line type. Finally S. palaestina extract revealed a moderate antiproliferative effect only against three cell lines. Salvia lanigera extract displayed toxic activity at all concentrations tested. The results strengthen the evidence that the genus Salvia could be considered a natural resource of potential antitumor agents.

Chemo-immunotherapy of colorectal carcinoma: preclinical rationale and clinical experience.

Advanced colorectal cancer is a common disease with an high mortality rate. For four decades, pharmacological treatment of the advanced disease was based on the use of 5-fluorouracil alone or in combination with biomodulators such as folinic acid and intereferon alpha. In the last 5 years, response to therapy has been considerably ameliorated thanks to the discovery of new drugs such as oxaliplatin and CPT-11. These agents, in combination with 5-fluorouracil, according to various schedules of treatment, have reached a significant improvement of palliation, response rate and survival. Immunotherapy is an uprising modality of treatment for human cancer including colorectal carcinoma. Its rationale is based on the knowledge that tumour cells are genetically unstable and produce molecular structures which allow their recognition and destruction by the immune-surveillance system. Therefore, humoral as well as cellular compartments of the immune system can be utilized according to a "passive" strategy (e.g. monoclonal antibody administration and adoptive immunotherapy) or an "active" approach, by using different modalities of vaccine therapy. In this context, monoclonal antibodies (mAbs) and cancer vaccines are being tested for the treatment of advanced colorectal cancer. Due to their genetic instability and extraordinary adaptative potential, tumour cells may acquire resistance to the immune effectors and mAbs exactly as they do for cytotoxic drugs. To improve the results of both immunological and chemical modality of cancer treatment, an increasing number of authors is starting to combine chemo and immunotherapy in the attempt to circumvent the limitations of both strategies. This report tries to review the possible rationale of the chemo-immunotherapy combination, illustrating preliminary results of preclinical and clinical studies.