1. Ventura, C; Maioli, M; Asara, Y; Santoni, D; Scarlata, I; Cantoni, S; Perbellini, A. Butyric and retinoic mixed ester of hyaluronan. A novel differentiating glycoconjugate affording a high throughput of cardiogenesis in embryonic stem cells. J. Biol. Chem., 2004, 279, 23574-23579. 2. Ventura, C; Cantoni, S; Bianchi, F; Lionetti, V; Cavallini, C; Scarlata, I; Foroni, L; Maioli, M; Bonsi, L; Alviano, F; Fossati, V; Bagnara, GP; Pasquinelli, G; Recchia, FA; Perbellini, A. Hyaluronan mixed esters of butyric and retinoic Acid drive cardiac and endothelial fate in term placenta human mesenchymal stem cells and enhance cardiac repair in infarcted rat hearts. J. Biol. Chem., 2007, 282, 14243-14252. 3. Nakamura, T; Nishizawa, T; Hagiya, M; Seki, T; Shimonishi, M; Sugimura, A; Tashiro, K; Shimizu, S. Molecular cloning and expression of human hepatocyte growth factor. Nature, 1989, 342, 440-443. 4. Nakamura, T; Mizuno, S; Matsumoto, K; Sawa, Y; Matsuda, H; Nakamura, T. Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. J. Clin. Invest., 2000, 106, 1511-1519. 5. Scheubel, RJ; Zorn. H; Silber, RE; Kuss, O; Morawietz, H; Holtz, J; Simm, A. Age-dependent depression in circulating endothelial progenitor cells in patients undergoing coronary artery bypass grafting. J. Am. Coll. Cardiol., 2003, 42, 2073–2080. 6. Bailo, M; Soncini, M; Vertua, E; Signoroni, PB; Sanzone, S; Lombardi, G; Arienti, D; Calamani, F; Zatti, D; Paul, P; Albertini, A; Zorzi, F; Cavagnini, A; Candotti, F; Wengler, GS; Parolini, O. Engraftment potential of human amnion and chorion cells derived from term placenta. Transplantation, 2004, 78, 1439-1448.
Newer antifungal drugs in kidney transplant recipients
VEROUX M, CORONA D
Department of Surgery, Transplantation and Advanced Technologies, Organ Transplant Unit, University Hospital of Catania, Italy
Background: Infection is a common cause of morbidity and the second cause of death after cardiovascular disease in renal transplant recipients . Although renal transplant recipients have been thought to be at low risk for fungal infections compared with other transplant recipients, the rate of hospitalization for fungal infections is much higher than the general population. Aspergillosis in renal transplant patients is the commonest cause of systemic fungal disease with an incidence ranging from 0.4 % to 2.4 % with a high mortality of 56-100%. Fluconazole is the treatment of choice for fungal infections; however invasive candidiasis and aspergillosis are relatively less susceptible to fluconazole. For many years, amphotericin B has served as the mainstay for the treatment of invasive fungal infections. However, infusion related toxicity, nephrotoxicity and electrolyte disturbances have limited its use; moreover, the efficacy of amphotericin B is relatively limited with a mortality rate in treated patient that exceed 80%. Newer antifungal drugs, such as caposfungin and voriconazole, have been introduced recently in the treatment of invasive fungal infections and aspergillosis: these drugs have demonstrated to be as effective as amphotericin B in the treatment of invasive fungal infections with less drug-related side effects.
Methods: From January 2002 to December 2007, 247 kidney transplants have been performed at Organ Transplant Unit of University Hospital of Catania. Among these, 17 recipients developed an invasive fungal infection (13 an oesophageal infection and 4 an urinary tract infection), while 4 patients developed an invasive aspergillosis. The patients with invasive fungal infection have been treated with caspofungin, administered once-daily at a loading dose of 70 mg followed by 50 mg/die for a median time of 12 days. We observed a complete relief of symptoms in all patients. Caspofungin was well tolerated, with no signs of drug related nephrotoxicity or hepatotoxicity. Four patients with invasive aspergillosis were treated with voriconazole, starting with a dose of 200 mg b.i.d. and was administered for a period of 60 days. All patients experienced a complete relief of symptoms, without recurrence of aspergillosis.
Conclusion: Newer antifungal drugs, such as voriconazole and caspofungin are potent and well-tolerated antifungal therapies that are extremely efficacious in the treatment of invasive aspergillosis and invasive fungal infections in kidney transplant recipients. A careful monitoring of immunosuppressive drugs should be considered to avoid nephrotoxicity.
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Cardiac Hormones: Magic Bullets for the Treatment of Congestive Heart Failure, Renal Failure and Cancer
VESELY DL
University of South Florida Health Sciences Center, Tampa, FL, USA; J. A. Haley Veterans Hospital, Tampa, FL, USA
Background: William Harvey in 1628 discovered that the heart was a pump. It was another 350 years before it was discovered that the heart was a sophisticated endocrine organ making a family of peptide hormones. One gene in the heart i.e. the atrial natriuretic peptide gene synthesizes four peptide hormones, i.e. long acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide and atrial natriuretic peptide (ANP). These hormones are important in controlling blood pressure and maintaining blood volume by enhancing excretion of sodium and water.
Methods: These investigations of cardiac hormones involved in vitro study of cancer cells for their mechanism of action and in vivo studies of human cancers in athymic mice (n=30, for each cancer) where the cardiac hormones were infused for 28 days at a concentration of 3 nM/kg body weight/min.
Results: One of these cardiac hormones, i.e. vessel dilator causes a 5-fold excretion of sodium and water while at the same time enhancing cardiac output in persons with congestive heart failure. This same “magic bullet” decreases elevated creatinine (eight average) to normal after six days of acute ischemic renal failure in animals and regenerates the nuclei in the tubules. These peptide hormones eliminate up to 97% (p<0.001) of human pancreatic, breast, colon, ovarian, kidney and prostate adenocarcinomas, glioblastomas of the brain, as well as small-cell and squamous cell lung carcinoma cells in vitro. When infused subcutaneously they eliminate up to 80% of the human pancreatic adenocarcinomas. The treated animals lived a normal lifespan. Similarly, these peptide hormones eliminate two-thirds of human breast adenocarcinomas and up to 86% of human small-cell lung carcinomas growing in athymic mice without surgery. These cardiac hormones mechanism(s) of action in cancer cells includes a 97% inhibition of the phosphorylation of extracellular-signal regulated kinases (ERK) 1/2 and of the upstream mitogen-activated protein kinases MEK 1/2 (p<0.001) ANOVA. These inhibitions are mediated by the intracellular mediator cyclic GMP.
Conclusion: These “magic bullets” synthesized by the heart are truly “magic” as they have beneficial effects in several diseases that cause a large portion of the morbidity and mortality in mankind, i.e. congestive heart failure, renal failure, and cancer(s).
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What happens with the large DNA when it meets intercalating drugs?
VIGLASKY V1, BAUER L
Safarik Univ., Inst. Chemistry, Kosice , Slovakia
Background: DNA intercalating drugs locally distort a regular DNA conformation. Usually any local changes of helical parameters cause some biological impact e.g. steric hindrance and change of binding affinities for DNA associated enzymes. In case we know the molecular target, we are able to estimate optimal but efficient dosage of drug to eliminate many side effects. DNA is a huge macromolecule containig many potencial places for intercalator binding. The sum of local changes causes a great global change in chromosomal DNA structure. DNA intercalation might be a reason for chromosome rearagement and reassembling, causing inappropriate gene switching on and off.
Methods: Principal method is the temperature-gradient gel electrophoresis. The complemetary methods AFM, UV-VIS spectroscopies and for cell cytotoxicity MTT test have been used. Data obtained on the plasmid system were extrapolated to chromosomal DNA.
Results: The table summarizes results obtained for selected intercalators, the reversibility of intercalator (ability to dissociate from DNA), where Cex represents the concentration of drug measured by TGGE in 50 mM Tris–HCl (pH 7.8) extrapolated to chromosomal DNA and 5mM MgCl2. IC50, concentration required to reduce the number of living cells to 50% as determined by dose–response curves using the MTT assay. The ratio in the last column gives information about the possibility to achieve toxic concentration inside the cell.
Drug
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Reversibility
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Cex (M)
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IC50 (M)
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Ratio Cext/ IC50
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Actinomycin D
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-
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1.0 ± 0.2
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0.001 – 2.0
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0.5 - 1000
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Daunorubicin
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+
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1.3 ± 1.0
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0.02 - 3.0
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0.33 - 65
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Ellipticine
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+
|
2.5 ± 1.2
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0.3 - 4.0
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0.3– 8.3
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Quinacrine
|
+
|
2.7 ± 1.8
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1.6 - 2.2
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1,2– 1.7
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Quinine
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+
|
225 ± 180
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~40
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~5.5
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Quercetin
|
-
|
230 ± 150
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20 - 50
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4.6 – 11
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Chloroquine
|
-
|
20 ± 22
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17 - 33
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0.6– 1.2
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Conclusions: For drugs where Cex are ranked at 20–230 is not considered to be a standard cytotoxic drug, most likely because the probability that the intercalator will attain cytotoxic concentrations, eliminating any non-B structure from the DNA inside the cell. Therefore, only the cases where r<1.3 and and Cex <10 mM could play a significant biological role in forming alternative non-B structures. When the ratios are lower, cytotoxicity must be mediated by other processes such as the direct inhibition of certain metabolic pathways.
Authors’ disclosure statement: If the cytotoxic concentration is lower than Cex, then the effect of intercalator to DNA and on the formation on alternative non-B conformation is not caused by this drug.
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Desipramine and Panic: Complex Approaches to Understand Complex Interactions in Psychopharmacology
Vigliecca NS 1, Molina SC 2, Peñalva MC 2
1 Consejo Nacional de Investigaciones Científicas y Técnicas de la Argentina (CONICET) y Servicio de Neurología y Neurocirugía del Hospital Córdoba
1, 2 Centro de Investigaciones de la Facultad de Filosofía y Humanidades (CIFFyH)
Córdoba. Argentina
Background: Clinical studies have shown that some antidepressants may be more efficient than benzodiazepines to alleviate anxiety associated with panic disorder. Nevertheless, operant and open-field behavioral procedures developed in rats so far do not seem particularly able to model human anxiety sensitive to antidepressant treatments. Researchers do not usually statistically subtract the effect of confounding factors from the variables of interest.
Methods: Undernourished rats, which showed a generalized activation of noradrenergic system, were selected due to their neurobiological resemblance to human patients suffering from panic disorder. The Geller- Seifter paradigm (under a cross over design) and the open field drink test (under an all-inclusive behavioral design) represented, respectively, the learned and ethological conflictive conditions in adult life. Desipramine (10 mg/kg/day) or saline were administered IP during 7 days to approximately ten rats per experimental group. Both studies were contemplated under a multifactor and multivaried perspective.
Results: In the Geller-Seifter paradigm, the repeated measure Anova with Diet as the independent variable and Drug performances (Saline and Desipramine) as the dependent ones indicated non-significant effects of Diet or Drug. However, a significant Diet x Drug interaction was observed in the complex dependent variable, which represented the level of “suppression/ suppression release”. I.e., deprived rats showed a statistically demonstrated suppression release compared to control rats in the complex operant performance. The Diet x Drug interaction was independent of the effects of treatments on milk consumption, reactivity to the electric foot shock, unpunished responding, weight and decision-making. In the Open Field Drink Test, the four dependent variables selected by factor analysis indicated also a significant Diet x Drug interaction in the two- way Manova. This interaction was independent of the effects of treatments on weight or intake and was expressed, on deprived rats, as a decrease in all the selected open field-behaviors except for the time of drinking with respect to the control rats, which displayed, in general, a decrease in all the behaviors except for the frequency of grooming.
Conclusion: The Diet x Drug interaction was interpreted as a selective anticonflict effect of desipramine on subjects predisposed to develop panic-like expressions. Complex approaches allow more complete inferences than those which contemplate only one target behavior
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Study of Tenoxicam on Various Drug Delivery Systems
VIJAYA RAGHAVAN C1, JUDITH JUSTIN2
1PSG College of Pharmacy, Coimbatore, India; 2Avinashilingam University, Coimbatore, India.
Background: Tenoxicam is an antiinflammatory and analgesic agent which absorbs completely from the G.I. tract by oral route. It undergoes first pass metabolism and causes ulceration. Hence through the buccal and colon specific delivery system the drug circumvents the G.I tract and avoids the first pass metabolism and also the side effects frequently associated with oral administration like ulceration. Aims: (1) To evaluate the natural flax seed polymer by the buccal and colon specific delivery for tenoxicam.(2)To study the effect of the polymer for the bioavailability of the drug.
Method: The drug tenoxicam in the form of tablets containing various concentration of flax seed polymer (20,30 and 40mg) were evaluated using invitro and invivo methods. The mucoadhesion of the tablets were evaluated using porcine buccal mucosa. The tablets had been subjected to invitro drug release studies at a pH 6.8 phosphate buffer. The Invivo study had been performed with 16 healthy human volunteers. In colonic delivery tablets of tenoxicam were prepared by compression coating with 400, 450 and 500 mg flax seed polymer. The formulated tablets were subjected to invitro drug release studies in simulated colonic fluids (4% w/v of rat cecal contents). The Invivo study had been performed in 6 healthy human volunteers.
Results:. The cumulative percentage release of tenoxicam at pH 6.8 phosphate buffer were found to be 98.200.08, 91.010.09, 84.390.72, 78.450.08. The bioavailability (AUC0-t*) of buccal and oral tablets was found to be 2226228, 3251409, 3379269 and 173296. The invitro studies of colon specific tablets at pH 6.8 phosphate buffer containing 4% w/v rat cecal contents showed that the cumulative percentage release after 26 h were 52.160.06, 64.100.08 and 98.000.19. The Invivo studies conducted in six healthy voltmeters revealed that the drug release was initiated only after 5h (ie) transit time of small intestine and the bioavailability of the drug (AUC0-t*) was found to be 2014210, 2890220 and 2920215.
Conclusion:(1) Buccal formulation of tenoxicam containing 40 mg flax seed polymer gives high bioavailability and also had significant mucoadhesive property for clinical application. (2)The colon specific formulation containing 400 mg flax seed polymer proved to have potential carrier for drug delivery into the colon for tenoxicam.
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Applications of Pharmacometrics to Immunosuppressive Therapy in Transplant Patients: Can we do better?
VINKS AA
College of Medicine and Pharmacy, Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
There exists an unmet clinical need and widespread research interest to better understand the dose-concentration-response and adverse events relationships of immunosuppressive medications in transplant patients. The transplant community is missing a significant opportunity to optimize outcomes by focusing predominantly on trough concentrations and the area under the curve (AUC) of the blood concentrations as the most important parameters to correlate with empirical evidence of rejection. This presentation will provide a brief overview of transplant pharmacology and a contemporary view of current and potential use of biomarkers as part of a pharmacokinetically guided therapeutic drug management process. Participants will learn how an improved understanding of the use of biomarker information linked to determinations of blood drug concentrations by PK/PD modeling can lead to individualization and optimization of immunosuppressive therapy in transplant patients.
Learning Objectives:
After attending this session, participants will be able to:
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Appreciate the importance of PK/PD optimization of immunosuppressive therapy
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Describe examples of the application of population PK/PD models as part of the therapeutic drug monitoring (TDM) process to improve individualized pharmacotherapy.
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Anticancer Effects of Statins
VÍTEK L
Institute of Clinical Biochemistry and Laboratory Diagnostics and 4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University in Prague, Czech Republic
Background: Despite supporting theoretical reasons as well as experimental evidence, there is still clinical controversy whether statins (inhibitors of HMG-CoA reductase) can prevent from cancer diseases. These contradictory views are based on large epidemiological studies and their meta-analyses. Available data, however, have been focused primarily on cardiovascular outcomes; and secondly, the possible anticancer action of statins have been studied as a group effect. Nevertheless, statins represent a heterogenous group of compounds, which differ in their physical-chemical properties, as well as different pharmacokinetic and pharmacodynamic properties.
Methods: Both experimental and clinical data available from Pubmed, as well as own results on the effect of statins on experimental pancreatic cancer, have been used for analysis of the chemopreventive effects of individual statins.
Results: Large differences in antiproliferative effects among statins used for clinical purposes have been described in available literature. In our experimental study on pancreatic cancer the least efficient statins were pravastatin and atorvastatin, whereas rosuvastatin (despite its low lipophilicity) and cerivastatin were the most effective. These data may account for inconclusiveness of cancer prevalence/incidence among statin users in cardiovascular trials. Provided that pravastatin might be the least efficient statin, recent meta-analytic studies might have been confounded by pravastatin trials. This, indeed, is the case for meta-analysis of 7 trials by Hebert et al. [JAMA 1997], where 3 out of 7 studies involved were pravastatin trials. The same is true for a study by Bjerre et al. [Am J Med 2001] (3 of 5 studies involved), CTT Collaborator´s study [Lancet 2005] (5 of 14 studies involved), as well as meta-analysis by Dale et al. [JAMA 2006] (10 of 20 studies). It also should be noted that data are lacking on cancer incidence in subjects treated with rosuvastatin, which has been introduced to the market only recently and which seems to have higher chemopreventive potential.
Conclusion: It is apparent that only further large and well-designed epidemiological studies may determine possible chemopreventive role of individual statins.
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Design and Synthesis of Folate Targeted Chemotherapeutics
VLAHOV IR, WANG Y, KLEINDL PJ, and LEAMON CP
Endocyte Inc., 3000 Kent Ave, Suite A1-100, West Lafayette, IN 47906, USA
Background: Receptor-specific targeting is an attractive concept to control at molecular level the selective delivery of a drug to pathologic cells. One of the many targeting strategies for cell specific drug delivery exploits the folate receptor (FR), a glycosylphosphatidylinositol anchored cell-surface glycoprotein that is over expressed in some epithelial malignancies. The vitamin folic acid (FA) is the ligand that binds FR with high affinity and is transported into the cancer cell via FR-mediated endocytosis. Consequently, attaching biologically active molecules to FA through releasable self-immolative linkers generates a new class of “magic bullet” that utilize FR for targeted delivery.
Tubulysins are members of a new class of natural products isolated from a Myxobacteria species. While possessing exceptionally potent cytotoxicity exceeding epothilones, paclitaxel, and vinblastine, the natural tubulysins alone are not considered suitable for drug development due to their lack of therapeutic window. In contrast, these compounds are ideal war heads for folate-targeted therapy.
Methods: Here we report a simple general approach for producing naturally occurring tubulysins and novel analogs. Thus, treatment of a fermentation mixture of tubulysins with trifluoroacetic acid (TFA) and consecutive addition of the corresponding carboxylic acid produced a single natural tubulysin (A, B, C, G or I) in excellent yield. Next, the efficient synthesis of folate conjugates of tubulysins was designed. In these water soluble “magic bullets” FA and the war head are connected in regioselective manner via a hydrophilic peptide spacer and a reducible disulfide linker.
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