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1.
Eur Rev Med Pharmacol Sci ; 20(1): 146-9, 2016.
Article in English | MEDLINE | ID: mdl-26813467

ABSTRACT

OBJECTIVE: Prodigest® is the standardized combination of artichoke and ginger extracts. This combination was safe and effective in the treatment of functional dyspepsia. However, further evidence could be useful to shed new lights on the effect of Prodigest® on gastric motility. This pilot randomized study on healthy volunteers investigates the prokinetic activity of Prodigest®. SUBJECTS AND METHODS: This was a randomized, cross-over study in healthy volunteers comparing Prodigest® versus placebo. Eleven healthy volunteers were enrolled. Each participant underwent two evaluations, at a 7-day interval. Ten minutes before the main meal, the baseline area of gastric volume was determined by ultrasonography. The subject was then given one Prodigest® or placebo capsule and, then consumed a standardized meal. One hour after the meal, the gastric volume was measured again. Two weeks after the second evaluation, three subjects repeated the above-mentioned procedures taking two capsules of Prodigest®. RESULTS: The mean gastric area at baseline was 3.2 ± 0.5 cm(2); after the meal, this figure was 8.4 ± 0.7 cm(2) with Prodigest® and 11.0 ± 1.5 cm2 with placebo (p<0.001). The after-meal gastric area was significantly smaller, with a -24% difference, following the combination of extracts, as compared with placebo (p<0.001). The effect of two capsules of Prodigest® seems to be more evident but due to the very small number of the patients sample further clinical data are necessary before confirming the dose-related effects. CONCLUSIONS: This pilot study shows that Prodigest®, a standardized extract of ginger and artichoke, significantly promotes gastric emptying in healthy volunteers without being associated with notable adverse effects.


Subject(s)
Cynara , Gastric Emptying/drug effects , Plant Extracts/pharmacology , Zingiber officinale , Adult , Cross-Over Studies , Dietary Supplements , Female , Healthy Volunteers , Humans , Male , Middle Aged , Pilot Projects , Stomach/drug effects
2.
Eur Rev Med Pharmacol Sci ; 19(7): 1291-6, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25912592

ABSTRACT

Ginger (Zingiber officinale) is a spice traditionally used to treat indigestion, nausea and vomiting. Ginger extracts accelerate gastric emptying and stimulate gastric antral contractions. These effects are mainly due to the presence of gingerols and shogaols and their activity on cholinergic M receptors and serotonergic 5-HT and 5-HT receptors. Various researches on this subject have led to controversial results, due to the chemical instability of ginger extracts and particularly of gingerols, which are readily-oxidizable substances. A systematic review of double-blind, placebo-controlled, randomized studies highlighted the potential efficacy of ginger on the prevention and treatment of nausea and vomiting of various origins, even though additional controlled studies are needed. This review focuses on pregnancy-induced nausea and vomiting and on chemotherapy induced nausea, and hypothesizes a therapeutic role for ginger extracts in case of side effects, as an alternative to traditional prokinetic drugs such as domperidone, levosulpiride or metoclopramide.


Subject(s)
Antiemetics/therapeutic use , Nausea/drug therapy , Plant Extracts/therapeutic use , Pregnancy Complications/drug therapy , Vomiting/drug therapy , Zingiber officinale , Animals , Antiemetics/isolation & purification , Antiemetics/pharmacology , Antineoplastic Agents/adverse effects , Catechols/isolation & purification , Catechols/pharmacology , Catechols/therapeutic use , Fatty Alcohols/isolation & purification , Fatty Alcohols/pharmacology , Fatty Alcohols/therapeutic use , Female , Gastric Emptying/drug effects , Humans , Nausea/chemically induced , Nausea/diagnosis , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Pregnancy , Pregnancy Complications/diagnosis , Vomiting/chemically induced , Vomiting/diagnosis
3.
Support Care Cancer ; 21(3): 827-34, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22945882

ABSTRACT

PURPOSE: This randomised, placebo-controlled single-blind trial investigated the safety and efficacy of SAMITAL®, a formulation of highly standardised botanical extracts, in the treatment of chemo/radiotherapy-induced oral mucositis (OM) in patients with head and neck cancer. METHODS: Patients received SAMITAL® or placebo four times daily for up to 50 days during scheduled chemo/radiotherapy. Severity of OM was monitored according to a modified WHO severity scale, and pain and quality-of-life assessments were based on the effect of symptoms of OM on relevant daily activities, according to a visual analogue scale. RESULTS: Mean scores for the severity of OM were significantly (p < 0.05 versus baseline) reduced from day 31 until the end of treatment in patients treated with SAMITAL® (n = 20). No significant improvement was observed in the placebo group (n = 10). Pain reduction was significant from day 4 till end of treatment with SAMITAL® and from days 7 to 21 in placebo patients. SAMITAL® also significantly improved quality of life, as shown by improvements in scores for relevant daily activities including eating, drinking and sleeping. All SAMITAL® patients completed the treatment period, but no placebo recipients completed treatment. No severe adverse events were observed with SAMITAL®, and systemic absorption of relevant active ingredients was undetectable. CONCLUSIONS: SAMITAL® significantly decreased the severity of chemo/radiotherapy-induced OM in patients with head and neck cancer, with no treatment-related adverse events. Pain relief lasted through the treatment period, and improvements in quality of life were reflected by the significant benefits of SAMITAL® on activities like drinking, eating and speaking.


Subject(s)
Chemoradiotherapy/adverse effects , Head and Neck Neoplasms/therapy , Plant Extracts/therapeutic use , Stomatitis/drug therapy , Adult , Aged , Chemoradiotherapy/methods , Female , Humans , Male , Middle Aged , Pain/drug therapy , Pain/etiology , Plant Extracts/adverse effects , Quality of Life , Severity of Illness Index , Single-Blind Method , Stomatitis/etiology , Stomatitis/pathology , Treatment Outcome
4.
Bioorg Med Chem ; 20(2): 920-6, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22182580

ABSTRACT

Use of herbal plant remedies to treat infectious diseases is a common practice in many countries in traditional and alternative medicine. However to date there are only few antimicrobial agents derived from botanics. Based on microbiological screening tests of crude plant extracts we identified four compounds derived from Krameria, Aesculus hippocastanum and Chelidonium majus that showed a potentially interesting antimicrobial activity. In this work we present an in depth characterization of the inhibition activity of these pure compounds on the formation of biofilm of Staphylococcus aureus as well as of Staphylococcus epidermidis strains. We show that two of these compounds possess interesting potential to become active principles of new drugs.


Subject(s)
Anti-Bacterial Agents/chemistry , Biofilms/drug effects , Biological Products/chemistry , Plant Extracts/pharmacology , Plants/chemistry , Staphylococcus aureus/physiology , Staphylococcus epidermidis/physiology , Aesculus/chemistry , Anti-Bacterial Agents/pharmacology , Biological Products/pharmacology , Chelidonium/chemistry , Krameriaceae/chemistry , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/metabolism , Microbial Sensitivity Tests , Plant Extracts/chemistry
5.
Phytother Res ; 26(2): 265-72, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21674629

ABSTRACT

This study compared the efficacy and tolerability of an optimized botanical combination containing policosanol, tomato extract, orally bioavailable grape procyanidins and Oenothera biennis oil against placebo in the management of patients with primary hypercholesterolemia and mixed dyslipidemia. Such a combination is endowed with biological properties targeted to cholesterol control and vasoprotection. This randomized, double-blind, parallel-group trial consisted of a 6 week treatment period following 4 week baseline period, and a 2 week post-treatment follow-up. At baseline, both the groups were comparable to each other. Both the active treatment and the placebo group included 30 patients (active treatment: mean age 46.80 ± 7.43 years, nine males; placebo: mean age 45.50 ± 6.76 years, eight males). Significant reductions in the LDL-cholesterol (LDL-C; -17.33% from baseline, p < 0.001) and total cholesterol (TC; -13.38% from baseline, p < 0.0001) values over the treatment period were observed with the tested product. The treatment also resulted in reductions in C-reactive protein (CRP), malondialdehyde (MDA) and superoxide dismutase (SOD) values, which are indices of oxidative stress. This rational combination of different compounds is effective and safe in lowering the elevated LDL-C and TC values. It is also effective in the modulation of the oxidation indices values; however, a further long term study in a larger population would be needed in order to confirm these preliminary findings.


Subject(s)
Anticholesteremic Agents/therapeutic use , Dyslipidemias/drug therapy , Hypercholesterolemia/drug therapy , Phytotherapy , Plant Preparations/therapeutic use , Adult , C-Reactive Protein/analysis , Cholesterol/blood , Double-Blind Method , Female , Humans , Male , Malondialdehyde/analysis , Middle Aged , Oxidative Stress/drug effects , Prospective Studies , Superoxide Dismutase/analysis
6.
Curr Alzheimer Res ; 7(2): 126-33, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19939230

ABSTRACT

The use of natural compounds is an interesting stratagem in the search of drugs with therapeutic potential for the treatment of Alzheimer's disease (AD). We report here the effect of the hyperforin derivative (IDN5706, tetrahydrohyperforin), a semi-synthetic derivative of the St. John's Wort, on the brain neuropathology, learning and memory in a double transgenic (APPswe, PS-1dE9) mouse model of AD. Results indicate that, IDN5706 alleviates memory decline induced by amyloid-beta (Abeta) deposits as indicated by the Morris water maze paradigm. Moreover, the analysis of Abeta deposits by immunodetection and thioflavin-S staining of brain sections, only reveals a decrease in the frequency of the larger-size Abeta deposits, suggesting that IDN5706 affected the turnover of amyloid plaques. Immunohistochemical analysis, using GFAP and n-Tyrosine indicated that the hyperforin derivative prevents the inflammatory astrocytic reaction and the oxidative damage triggered by high Abeta deposit levels. We conclude that the hyperforin derivative, IDN5706, has therapeutic potential for prevention and treatment of AD.


Subject(s)
Alzheimer Disease/drug therapy , Brain/drug effects , Memory Disorders/drug therapy , Phloroglucinol/analogs & derivatives , Terpenes/pharmacology , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/drug effects , Amyloid beta-Peptides/metabolism , Animals , Astrocytes/drug effects , Astrocytes/pathology , Brain/metabolism , Brain/physiopathology , Bridged Bicyclo Compounds/pharmacology , Bridged Bicyclo Compounds/therapeutic use , Disease Models, Animal , Encephalitis/drug therapy , Encephalitis/physiopathology , Encephalitis/prevention & control , Glial Fibrillary Acidic Protein/analysis , Glial Fibrillary Acidic Protein/metabolism , Gliosis/drug therapy , Gliosis/physiopathology , Gliosis/prevention & control , Humans , Maze Learning/drug effects , Maze Learning/physiology , Memory Disorders/metabolism , Memory Disorders/physiopathology , Mice , Mice, Transgenic , Oxidative Stress/drug effects , Oxidative Stress/physiology , Phloroglucinol/pharmacology , Phloroglucinol/therapeutic use , Terpenes/therapeutic use , Tyrosine/analysis , Tyrosine/metabolism
7.
Ann N Y Acad Sci ; 1028: 294-312, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15650255

ABSTRACT

Cancer of the prostate is still controlled or cured by surgery, radiotherapy, and hormone therapy. The present criteria of complication and prediction are criticized more and more for not being sufficiently reliable, due to the high heterogeneity of prostatic cells. The continuing discoveries of intra- and extracellular mechanisms of the molecular informational network, which allow the continuity or discontinuity of the cell's life, are also related to prostate cancer. The role of androgen receptors is now under close scrutiny, in the light of the knowledge of regulatory genes and their molecular expression. In the near future, a complete study of prostate cancer's DNA is certainly envisaged. Looking forward to the extraordinary applications of molecular biology in this field, this article is aimed at establishing a clear link between the conventional ways of interpreting the clinical expression of prostate cancer and the oncoming applications of genomics and proteomics.


Subject(s)
Gene Expression Regulation, Neoplastic , Neoplasm Staging/methods , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Carcinoma/epidemiology , Carcinoma/genetics , Carcinoma/pathology , Hormones/therapeutic use , Humans , In Situ Hybridization, Fluorescence , Male , Models, Biological , Models, Genetic , Prostatic Neoplasms/epidemiology , Receptors, Androgen/metabolism , Signal Transduction
8.
Eur J Cancer ; 39(16): 2403-10, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14556934

ABSTRACT

This study aimed to assess, in an in vivo experimental model, the growth inhibitory effects of IdB 1016 (Silipide, a complex of silybin/phosphatidylcholine) when used as a single agent against human ovarian cancer. We also wanted to investigate the mechanism of the antiangiogenic action by assessing Vascular Endothelial Growth Factor (VEGF) levels and by using macroarray technology to evaluate the regulation of a panel of genes involved in angiogenesis. We also aimed to establish the plasma and tumour bioavailability of silybin after repeated administration of IdB 1016. Female nude mice bearing human ovarian cancer xenografts (A2780) received 450 mg/kg/day IdB 1016 daily by oral gavage until the end of the study. At sacrifice, blood and tumour specimens were collected and subsequently processed for the determination of silybin levels, VEGF levels or a gene expression profile. IdB 1016 was significantly active in inhibiting ovarian tumour growth. Treatment with 450 mg/kg/day for a total of 20 administrations produced a tumour weight inhibition (TWI%) of 78% and a Log10 Cell Kill (LCK) of 1.1. Free silybin levels were found to be 7.0+/-5.3 microg/ml and 183.5+/-85.9 ng/g tissue (mean+/-standard deviation (S.D.)) in the plasma and tumour samples, respectively. No significant differences were found in the concentration of human VEGF in xenografts from control and IdB 1016-treated mice. The array analysis suggested the downregulation of the VEGR receptor 3 and the upregulation of angiopoietin-2 as potential mechanisms for the antiangiogenic activity. In conclusion, these findings suggest IdB 1016 is a good candidate, with a relevant clinical potential, for use in the management of recurrent ovarian cancer. A phase II, non-randomised clinical study is now ongoing in our Institute aimed at evaluating the efficacy of daily administrations of IdB 1016 in the serological recurrence of ovarian cancer.


Subject(s)
Antineoplastic Agents/therapeutic use , Ovarian Neoplasms/drug therapy , Phosphatidylcholines/therapeutic use , Silymarin/therapeutic use , Animals , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , DNA, Complementary/metabolism , Drug Evaluation , Drug Screening Assays, Antitumor , Female , Humans , Mice , Mice, Nude , Neovascularization, Pathologic/genetics , Ovarian Neoplasms/blood supply , Phosphatidylcholines/pharmacokinetics , Silymarin/pharmacokinetics , Vascular Endothelial Growth Factor A/metabolism
9.
Br J Cancer ; 88(6): 965-72, 2003 Mar 24.
Article in English | MEDLINE | ID: mdl-12644838

ABSTRACT

The recognition of the antiangiogenic properties of taxanes provides a basis for novel therapeutic approaches. A prolonged exposure to low drug concentrations has been proposed to be the most suitable approach to exploit the antiangiogenic potential of cytotoxic agents. Such schedule is required to target preferentially slowly dividing endothelial cells. The protracted use of taxanes could benefit from the availability of a taxane endowed with a favourable tolerability profile. Among compounds of a novel series of C-seco taxanes, IDN 5390 was originally selected on the basis of its potent antimotility activity and poor cytotoxicity on endothelial cells. The aim of the study was to investigate the preclinical pharmacologic profile of IDN 5390 in a variety of human tumour xenografts, including ovarian and colon carcinoma and a glioblastoma. IDN 5390, delivered by s.c. injection, daily for 5 days per week, exhibited a high activity against all tumours investigated (tumour growth inhibition was always >85%) in the range of well-tolerated doses. The maximum tolerated dose/injection (MTD), with no signs of systemic or local vesicant toxicity, was 120 mg kg(-1). In contrast, paclitaxel, delivered according to the same schedule, exhibited a variable antitumour efficacy associated with a substantial local toxicity (MTD=10 mg kg(-1)). Considering the remarkable efficacy of IDN 5390 delivered s.c. by protracted treatment schedule, the oral route of administration was further investigated, as the most suitable for daily treatment. Indeed, a good bioavailability of oral IDN 5390 was found. Oral IDN 5390 maintained a substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency with respect to s.c. administration. In conclusion, the therapeutic advantages of IDN 5390, over paclitaxel, in protracted daily treatment schedules are represented by the oral efficacy and the high tolerability, which are favourable features to exploit the antiangiogenic potential and to design combinations with other effective agents.


Subject(s)
Brain Neoplasms/drug therapy , Bridged-Ring Compounds/administration & dosage , Bridged-Ring Compounds/pharmacology , Carcinoma/drug therapy , Colonic Neoplasms/drug therapy , Glioblastoma/drug therapy , Ovarian Neoplasms/drug therapy , Paclitaxel/analogs & derivatives , Paclitaxel/administration & dosage , Paclitaxel/pharmacology , Administration, Oral , Animals , Drug Administration Schedule , Female , Humans , Injections, Subcutaneous , Mice , Mice, Nude , Neoplasms, Experimental , Taxoids , Transplantation, Heterologous
10.
Article in English | MEDLINE | ID: mdl-12383484

ABSTRACT

A HPLC assay was developed to determine IDN 5390, a new paclitaxel analogue, in mouse plasma. The method involves solid-phase extraction from cyano cartridges (recovery >80%), HPLC separation on Symmetry C(18) (4.6 x 150 mm), on isocratic mobile phase of water-acetonitrile-acetic acid (49:50:1) and detection at 227 nm. Retention times of IDN 5390 and IDN 5517 (internal standard, I.S.) were 9.1 and 10.5 min, respectively. The assay was linear from 0.05 to 5 micro g/ml (r(2)>or=0.995), showed intra- and inter-day precision within 1.0 and 6.2%, and accuracy of 94.7-106.8%. LOQ was 0.050 micro g/ml. Using this method IDN 5390 pharmacokinetics was determined in mice.


Subject(s)
Bridged-Ring Compounds/blood , Chromatography, High Pressure Liquid/methods , Paclitaxel/analogs & derivatives , Paclitaxel/blood , Animals , Bridged-Ring Compounds/pharmacokinetics , Female , Mice , Paclitaxel/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Spectrophotometry, Ultraviolet , Taxoids
11.
Cancer ; 92(12): 3085-92, 2001 Dec 15.
Article in English | MEDLINE | ID: mdl-11753988

ABSTRACT

BACKGROUND: The development of effective chemotherapy for central nervous system tumors is hampered by the blood-brain barrier and by limited drug diffusion in the brain tissue. BAY 59-8862 is a new taxane analog that was selected and developed for its activity against tumors with a P-glycoprotein-mediated, multidrug-resistant phenotype. Because P-glycoprotein is implicated in limiting the access of drugs to central nervous system tumor targets, the objective of this study was to evaluate the ability of intravenously administered BAY 59-8862 to affect the growth of central nervous system tumors. METHODS: The U-87 MG human glioma cell line was xenografted orthotopically (intracranially) in nude mice. Paclitaxel or BAY 59-8862 was delivered intravenously four times every fourth day, and antitumor efficacy was assessed by examining the effects on mouse survival time and by histologic examination of mouse brain. Drug levels in plasma and brain were determined according to a high-performance liquid chromatography method. RESULTS: The analog was as potent as paclitaxel in inhibiting the proliferation of three human glioma cell lines (U-87 MG, SW1783, and GBM) and was as effective as paclitaxel in inhibiting the heterotopic (subcutaneous) tumor growth in nude mice of U-87 MG cells (tumor weight inhibition, approximately 60%). In contrast, BAY 59-8862 was more active than paclitaxel (P < 0.05 in two of three experiments) in increasing the survival time of mice that were injected orthotopically with U-87 MG cells. The results were supported by the pharmacokinetic data, which indicated a much higher (about 15-fold) brain:plasma level ratio in BAY 59-8862-treated animals compared with paclitaxel-treated animals. CONCLUSIONS: The study provides evidence of an additional pharmacologic advantage of BAY 59-8862, i.e., the ability to affect the growth of intracranial tumors, probably due to the lack of recognition by the P-glycoprotein-mediated transport systems. The favorable behavior of BAY 59-8862 supports the potential interest in the analog for clinical studies in patients with brain tumors or metastases.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/pharmacokinetics , Blood-Brain Barrier , Brain Neoplasms/drug therapy , Bridged-Ring Compounds/pharmacology , Bridged-Ring Compounds/pharmacokinetics , Glioma/drug therapy , Paclitaxel/pharmacology , Paclitaxel/pharmacokinetics , Taxoids , ATP Binding Cassette Transporter, Subfamily B, Member 1/pharmacokinetics , Animals , Brain Neoplasms/pathology , Glioma/pathology , Humans , Indoles , Infusions, Intravenous , Mice , Mice, Nude , Paclitaxel/analogs & derivatives , Transplantation, Heterologous
12.
Planta Med ; 67(5): 475-7, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11488468

ABSTRACT

In the search of a convenient synthesis for isocordoin (1), a potential anticancer natural product, 2',4'-dihydroxychalcone was inoculated in cell suspension cultures of Morus nigra, which were expected to contain an active prenyltransferase. After 24 hours the target compound was easily isolated from the metabolite extract. Optimization of the biotransformation resulted in a 85% yield of the prenyl derivative.


Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Catechols/chemical synthesis , Chalcone/analogs & derivatives , Rosales/chemistry , Acetophenones/chemistry , Benzaldehydes/chemistry , Biotransformation , Cell Line , Chalcone/chemistry , Chalcone/metabolism , Chalcones , Culture Techniques , Dimethylallyltranstransferase/metabolism , Resorcinols/chemistry
13.
Rapid Commun Mass Spectrom ; 15(12): 929-34, 2001.
Article in English | MEDLINE | ID: mdl-11400198

ABSTRACT

Liquid chromatography/atmospheric pressure chemical ionization mass spectrometry (LC/APCI-ITMS) was applied to evaluate the levels of ginkgolides A and B and bilobalide in plasma of volunteers after administration of Ginkgo biloba extracts in free (Ginkgoselect) or phospholipid complex (Ginkgoselect Phytosome) forms, providing 9.6 mg of total terpene lactones. The maximum plasma concentrations, C(max), of total ginkgolides A, B and bilobalide were 85.0 and 181.8 microg/mL for Ginkgoselect and Ginkgoselect Phytosome, respectively. The C(max) values were reached at 120 min for the free form and at 180--240 min for the phospholipid complex form. In both cases, the mean elimination half-life of each terpene lactone was in the range 120--180 min. Due to its sensitivity (about 1 ng/mL) and specificity, LC/APCI-ITMS proved to be a very powerful tool for pharmacokinetic studies of these phytochemicals.


Subject(s)
Chromatography, Liquid/methods , Cyclopentanes/blood , Diterpenes , Furans/blood , Ginkgo biloba , Lactones/blood , Mass Spectrometry/methods , Plant Extracts/pharmacokinetics , Plants, Medicinal , Adult , Area Under Curve , Food Deprivation , Ginkgolides , Half-Life , Humans , Male
14.
J Med Chem ; 44(10): 1576-87, 2001 May 10.
Article in English | MEDLINE | ID: mdl-11334567

ABSTRACT

Analogues of Taxol (paclitaxel) with the side chain conformationally restricted by insertion of a carbon linker between the 2'-carbon and the ortho-position of the 3'-phenyl ring were synthesized. Biological evaluation of these new taxoids showed that activity was dependent on the length of the linker and the configuration at C2' and C3'. Two analogues in the homo series, 9a and 24a, showed tubulin binding and cytotoxicity comparable to that of Taxol. NAMFIS (NMR analysis of molecular flexibility in solution) deconvolution of the averaged 2-D NMR spectra for 9a yields seven conformations. Within the latter set, the hydrophobically collapsed "nonpolar" and "polar" classes are represented by one conformation each with predicted populations of 12-15%. The five remaining conformers, however, are extended, two of which correspond to the T-conformation (47% of the total population). The latter superimpose well with the recently proposed T-Taxol binding conformer in beta-tubulin. The results provide evidence for the existence of two previously unrecognized structural features that support Taxol-like activity: (1) a reduced torsion angle between C2' and C3' and (2) an orthogonal arrangement of the mean plane through C1', C2' and the 2'-hydroxyl and the 3'-phenyl plane, the latter ring bisected by the former plane. By contrast, epimerization at 2',3' and homologation of the tether to CH2-CH2 were both detrimental for activity. The decreased activity of these analogues is apparently due to configurational and steric factors, respectively.


Subject(s)
Antineoplastic Agents/chemical synthesis , Paclitaxel/analogs & derivatives , Paclitaxel/chemical synthesis , Taxoids , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Humans , Magnetic Resonance Spectroscopy , Molecular Conformation , Paclitaxel/chemistry , Paclitaxel/pharmacology , Tubulin/chemistry , Tumor Cells, Cultured
15.
Breast Cancer Res Treat ; 69(2): 153-64, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11759821

ABSTRACT

This study was designed to assess the potential chemopreventive effect of the administration of a standardized soy extract, SOYSELECT, on 7,12-Dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in rats. Three groups, 24 females each, were used. Animals were fed either a phytoestrogen-free diet alone (control) or the same diet supplemented with 0.35% or 0.7% of soy extract. Treatment started at weaning and continued to the end of the study (24 weeks after DMBA administration). At day 50 of age all animals received via oral gavage 80 mg/kg DMBA. Only tumors subsequently classified as adenocarcinomas were considered for data evaluation. In rats on the soy diet, mammary tumors took a longer period of time to develop as compared to control rats. However, at the end of the study, no relevant difference in tumor incidence and multiplicity was observed among the groups. The most significant changes were seen between control and soy-treated groups when tumor dimension and results from histopathologic examination were considered. The latter, in fact, showed a dose-dependent reduction in the percentage of poorly differentiated tumors in treated animals. This change was statistically significant in animals receiving 0.7% soy. In addition, assessment of estrogen and progesterone receptor (ERalpha, PR) levels, revealed a significant reduction in the percentage of ERalpha and PR positive tumors in animals receiving 0.7% dietary soy, when compared to controls. Interestingly, genistein and daidzein plasma levels determined at the end of the study were within the range of those detected in people consuming large amounts of soyfoods.


Subject(s)
Adenocarcinoma/prevention & control , Chemoprevention , Mammary Neoplasms, Animal/prevention & control , Soybean Proteins/pharmacology , 9,10-Dimethyl-1,2-benzanthracene/adverse effects , Adenocarcinoma/etiology , Adenocarcinoma/veterinary , Administration, Oral , Animals , Carcinogens/adverse effects , Diet , Female , Mammary Neoplasms, Animal/etiology , Neoplasms, Experimental , Rats , Rats, Sprague-Dawley , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis
16.
Br J Cancer ; 83(12): 1762-8, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11104578

ABSTRACT

Taxanes antitumour agents such as paclitaxel and docetaxel represent a successful family of chemotherapeutic drugs. Unfortunately, acquired and innate resistance represents a clinical problem for these drugs. We investigated, on a panel of 7 human cancer cell lines, the growth inhibition effect of 3 newly developed taxanes (SB-T-1213, SB-T-1250 and SB-T-101187) with modification at the C10 and C3' positions of the taxane framework. These positions have been previously characterized as critical to make taxanes highly active against cells overexpressing the efflux pump P-glycoprotein (P-gp). Paclitaxel and docetaxel were used as reference compounds. Results unambiguously indicate the exceptional activity of the novel taxanes toward P-gp positive cells (up to >400 fold higher potency than that of paclitaxel). SB-T-1213 and SB-T-1250 are also substantially more active than the reference compounds against P-gp negative cells. To better understand the mechanisms underlying the enhanced activity of the newly developed taxanes, we performed cell cycle and apoptosis analysis. This study demonstrates that the striking growth inhibition effect exhibited by the novel taxanes is ascribed to their increased ability in inducing apoptosis and G(2)/M cell cycle block. SB-T-1213 and SB-T-1250 are also more active than reference compounds in inducing intracellular accumulation of the beta-tubulin subunits. Finally, it is revealed that these novel taxanes have ability to inhibit the function of the P-gp efflux pump on the basis of the Rhodamine 123 assay. These findings strongly suggest that SB-T-1213, SB-T-1250 and SB-T-101187 represent a new tool to overcome innate or acquired P-gp mediated taxane-resistance.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Bridged-Ring Compounds/pharmacology , Cell Division/drug effects , Paclitaxel/analogs & derivatives , Taxoids , ATP Binding Cassette Transporter, Subfamily B/metabolism , Apoptosis/drug effects , Bridged-Ring Compounds/chemistry , DNA Fragmentation/drug effects , Dose-Response Relationship, Drug , G2 Phase/drug effects , Humans , Mitosis/drug effects , Paclitaxel/pharmacology , Tubulin/biosynthesis , Tubulin/drug effects , Tumor Cells, Cultured
17.
Life Sci ; 67(15): 1799-814, 2000 Sep 01.
Article in English | MEDLINE | ID: mdl-11043603

ABSTRACT

Besides erythema and sunburn reactions, UVB stress can promote erythrocyte extravasation from skin capillaries and hemolysis, and photosensitized hemoglobin can in turn lead to an overload of free radicals in dermis which exacerbates photodamage. The objective of this study was to investigate in rat erythrocytes (RBC) the pattern of events leading to membrane peroxidation and hemolysis following UVB insult (1.5-8.5 J/cm2), and the protective action of grape seed procyanidins. UVB causes a dramatic dose-dependent decrease of intracellular glutathione (paralleled by the formation of pro-oxidant ferryl-hemoglobin), of intramembrane vitamin E and of membrane fluidity, then a rise of conjugated dienes (CD), and thiobarbituric acid-reactive substances (TBARS) and finally a strong hemolytic effect. Procyanidins prevent membrane peroxidation (but not intracellular GSH depletion nor ferryl-hemoglobin formation), with a minimal effective concentration of 0.1 microM (IC50 for TBARS and CD after 120 min UVB exposure: 0.71 microM and 0.56 microM) and dose-dependently delay the onset of hemolysis, by 30 min at 0.1 mciroM, by 90 and 120 min at 0.5 and 1.0 microM. Epigallocatechin-3-O-gallate (EGCG) and catechin, typical constituents of the fraction, were significantly less potent. This since procyanidins (1 microM) inhibit the formation of phospholipid hydroperoxides of the inner (phosphatidylserine, phosphatidylethanolamine) and outer (phosphatidylcholine) layers of the RBC membrane (HPLC analysis), suppress the decrease in membrane fluidity due to lipid and protein thiol oxidation and spare vitamin E from consumption in a dose-dependent manner (0.1-1 microM). Hence procyanidins, preserving membrane phospholipids, since their strong antilipoperoxidant activity, may maintain in vivo the integrity of RBC in sub-epidermal capillaries and effectively counteract in dermis the onset/exacerbation of the UVB-induced skin photodamage.


Subject(s)
Antioxidants/pharmacology , Biflavonoids , Catechin/analogs & derivatives , Catechin/pharmacology , Erythrocytes/radiation effects , Hemolysis/drug effects , Proanthocyanidins , Ultraviolet Rays/adverse effects , Animals , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Erythrocyte Membrane/drug effects , Erythrocyte Membrane/metabolism , Erythrocyte Membrane/radiation effects , Erythrocytes/drug effects , Erythrocytes/metabolism , Glutathione/metabolism , Hemoglobins/drug effects , Hemoglobins/metabolism , Hemoglobins/radiation effects , Hemolysis/radiation effects , Lipid Peroxidation/drug effects , Lipid Peroxidation/radiation effects , Male , Membrane Fluidity/drug effects , Membrane Fluidity/radiation effects , Oxidants/pharmacology , Oxidation-Reduction , Phospholipids/metabolism , Phospholipids/radiation effects , Rats , Rats, Wistar , Rosales/chemistry , Thiobarbituric Acid Reactive Substances/metabolism , Vitamin E/metabolism
18.
Cancer Chemother Pharmacol ; 46(4): 305-12, 2000.
Article in English | MEDLINE | ID: mdl-11052628

ABSTRACT

PURPOSE: Among flavonoids, chalcones have been identified as interesting compounds having chemopreventive and antitumor properties. We studied a panel of newly developed chalcone analogues (S1-S10) using MDA-MB 231 and MCF-7 ADRr breast cancer cells and the T-leukemic Jurkat cell line. Quercetin was used as the reference compound. METHODS: Antiproliferative activity was evaluated by cell counts performed after 72 h of exposure to the drugs. DNA analysis and redox activity were evaluated using flow cytometry. Apoptosis was assessed by morphological analysis, using YOYO-1 as DNA dye; p-glycoprotein function was ascertained by quantitating the efflux of rhodamine 123. RESULTS: All cells were sensitive to chalcone analogues yielding IC50 in micromolar concentrations with the following order regardless of the multidrug resistance (MDR) status: S1 > S2 > quercetin. S1 and S2, the most active compounds, were selected to evaluate their effect on the cell cycle, apoptosis, redox activity, and modulation of the p-glycoprotein function. No significant perturbation in cell cycle was seen with concentration up to 1 microM after 24 h. After 72 h a slight increase in G2/M block and DNA fragmentation occurred at 10 microM. Morphological analysis of apoptosis showed that chalcone analogues induced apoptosis to a higher extent than quercetin. Redox analysis demonstrated that all substances were able to increase intracellular thiol levels, which returned to baseline value after 24 h for all drugs except quercetin. Production of reactive oxygen species was essentially unaffected by all compounds. Finally, in MDR-positive MCF-7 ADRr cells chalcone analogues were unable to modulate p-glycoprotein function while quercetin was able to. CONCLUSIONS: Newly developed S1 and S2 chalcones have a different but higher antitumor activity than quercetin and could be considered as potential new anticancer drugs.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Chalcone/analogs & derivatives , Chalcone/pharmacology , ATP Binding Cassette Transporter, Subfamily B/biosynthesis , Apoptosis/drug effects , Breast Neoplasms/pathology , Cell Cycle/drug effects , Cell Survival/drug effects , DNA, Neoplasm/drug effects , DNA, Neoplasm/genetics , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Fabaceae/chemistry , Genes, MDR/genetics , Humans , Jurkat Cells/drug effects , Plants, Medicinal , Reactive Oxygen Species/metabolism , Rhodamine 123 , Tumor Cells, Cultured
19.
Fitoterapia ; 71 Suppl 1: S21-8, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10930709

ABSTRACT

The prostate, after the age of 45 years, may undergo benign hyperplasia (BPH). Its etiology has not yet been completely explained, but different factors play a major role in its occurrence, among them, the sexual hormones (with a fundamental role of 5 alpha reductase). The 5-alpha reductase activity and inflammatory aspects in the prostate tissue can be effectively controlled with the use of highly standardized plant extracts (Pygeum africanum, Serenoa repens, etc.), which yield excellent results in the prophylaxis and treatment of the symptoms linked to prostate hypertrophy. The prostate tissue is not affected only by benign diseases but may also be subject to neoplastic transformation. From an epidemiological point of view, a vegetable derivative, lycopene, was linked with a lower occurrence of prostate carcinoma. A recent clinical study demonstrated that lycopene might not only prevent prostate cancer but also have therapeutic effects.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Phytotherapy , Plant Extracts/therapeutic use , Prostatic Hyperplasia/drug therapy , Prunus africana , Serenoa , Animals , Carotenoids/therapeutic use , Humans , Lycopene , Male , Rats
20.
Fitoterapia ; 71 Suppl 1: S38-42, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10930711

ABSTRACT

The present paper briefly reviews the most relevant experimental data on the reducing effect of some medicinal herbs on voluntary alcohol intake in animal models of alcoholism. Pueraria lobata, Tabernanthe iboga, Panax ginseng, Salvia miltiorrhiza and Hypericum perforatum proved to be effective in decreasing alcohol consumption. Reduction of alcohol absorption from the gastrointestinal system appears to be a common feature among most of the above plants. These data suggest that medicinal plants may constitute novel and effective pharmacotherapies for alcoholism.


Subject(s)
Alcoholism/drug therapy , Antidepressive Agents/therapeutic use , Phytotherapy , Plant Extracts/therapeutic use , Plants, Medicinal , Animals , Disease Models, Animal , Humans , Hypericum , Panax , Plant Roots , Pueraria , Rats , Salvia , Tabernaemontana
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