Amifostine (WR-2721) As A Cytoprotective Agent
MAZUR L
Jagiellonian University, Department of Experimental Hematology, Cracow, Poland
Background: Chemotherapy and radiation therapy are the basic approaches in cancer treatment. The current therapies are associated with significant cytotoxicity, as chemo- and radio-therapy do not discriminate between normal and pathological cells. The attempt to increase the therapeutic ratio in an affort to improve survival or quality of life is the goal of modern cancer therapy. The use of cytoprotective agents is one approach to minimizing the toxicity caused by the therapy to normal cells. Aims: 1) to review the vast literature published on amifostine, the aminothiol formerly known as WR-2721, 2) to demonstrate the results of the preclinical experiments and clinical experience with amifostine, 3) to summarize the knowledge on chemo- and radio-protective effects of WR-2721 on normal cells, 4) to show the effects of the aminothiol on programmed cell death, 5) to determine the mechanisms of cytoprotection induced by amifostine, and 6) to provide the insight into future experimental and clinical directions.
Methods: A review of the data bases on a collection of the original papers published and the abstracts of relevant articles searched in the SCOPUS and MEDLINE dabatase.
Results: Amifostine was developed to selectively protect various normal tissues against the hemato-, nephro-, neuro-, and cardio-toxicity, mucositis and xerostomia caused by ionizing radiation and/or chemotherapeutic drugs, e.g. platinum agents, oxazaphosphorines, anthracyclines, taxanes. Amifostine provides a broad-spectrum of cytoprotection against the radio- and chemo-toxicity observed in patients with breast, bladder, cervix, head and neck, non-small cell lung, ovarian, and rectal cancers, melanoma and lymphomas, without attenuating anti-cancer response. Amifostine has potential applications in many oncologic settings, but the precise mechanisms whereby WR-2721 exerts the cytoprotective action on normal cells are not entirely clear. A better understanding of the mechanisms responsible for the cytoprotective effects of Amifostine can considerably broaden its clinical application.
Conclusions: 1) After several decades of preclinical and clinical research, amifostine is widely used in clinical practice as the best known cytoprotector against the adverse effects of chemo- and radio-therapy, 2) As a chemo- and radio-protector of normal cells, amifostine is accepted to be a powerful adjuvant to the current therapies.
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The Use of DNA-based Therapies to Restore Clinical Efficacy of Antibiotics
McARTHUR M, MOORE J, BIBB MJ
Department of Molecular Microbiology, John Innes Centre, Norwich, NR4 7UH, UK
Background: We are developing DNA-based therapies (transcription factor decoys; TFDs) to treat infectious diseases. TFDs prevent expression of targeted genes within pathogenic bacteria by interfering with the interaction of transcription factors with transcriptional promoters and so preventing expression. We have identified TFDs capable of preventing induction of antibiotic resistance genes and used them to mediate antibiotic resistance in pathogenic bacteria. This technology has the potential to tackle the phenomenon of multiple-drug resistant (MDR) hospital infections- a problem for which there is no ready solution.
Methods: TFDs are designed rationally by examination of sequence literature and data mining of microarray studies where regulators of virulence and antibiotic resistance have been determined in pathogenic bacteria. TFDs incorporate such binding sites and are derivatized with lipids and peptides to aid transfection into bacteria. There effect on growth and viability is monitored in 96 well plate assays and uptake and stability of the TFD measured by microscopy and quantitative PCR.
Results: TFDs have been transfected into examples of both Gram-negative and –positive bacteria to control genetic induction and modify patterns of cell growth, particularly in response to antibiotic stress.
Conclusions: TFDs have the advantages that they mobilize genetic information directly into the clinics (decreasing development timeline) and the generic logic of the approach means it can be applied to many targets. Hence, it has the potential to supply a new class of therapeutics that can be quickly designed, cheaply produced and capable of preventing induction of many drug resistance phenotypes. As TFDs work by targeting DNA-protein interactions controlling an essential genetic switch it becomes more difficult for the pathogen to acquire resistance as either both the genomic binding site and its cognate transcription factor would have to change or the pathogen would need require a genetically distinct antibiotic resistance pathway.
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The Hyperglycaemic Effect Of S-Nitrosoglutathione And S-Nitroso-N-
Acetylpenincillamine – Possible Mechanism Of Action
McGROWDER D, BROWN P, RAGOOBIRSINGH D
University of the West Indies, Kingston, Jamaica
Background: Nitric oxide (NO) is an important bioactive signaling molecule that mediates a variety of normal physiological functions, which, if altered, could contribute to the genesis of many pathological conditions, including diabetes. The study investigated the effects of NO released from S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione on blood glucose levels. Any possible dibetogenic effects of SNAP and GSNO was done by examining the binding of insulin to its receptor on the cell membranes of mononuclear leucocytes from dogs. In addition, the role of NO released from GSNO and SNAP on glucose uptake in skeletal muscle of normoglyceamic and type 2 diabetic rats were examined.
Results: The oral glucose tolerance test revealed an impaired glucose tolerance in GSNO- and SNAP-treated dogs. Mononuclear leucocytes from SNAP-treated dogs had decreased ability to bind insulin (16.30 +/- 1.24%) when compared with those from captopril-treated controls (20.30 +/- 1.93%). Scatchard analysis demonstrated that this decrease in insulin binding was accounted for by a decrease in insulin receptor sites per cell, with mononuclear leucocytes of SNAP-treated dogs having 55 % less insulin receptor sites per cell compared with those of captopril-treated controls (P < 0.05). The abnormality in glucose metabolism on administration of GSNO was attributed to decreased binding of insulin to its receptor on the cell membrane of mononuclear leucocytes, 11.60 +/- 0.60% in GSNO-treated dogs compared with 18.10 +/- 1.90% in captopril-treated control (p < 0.05). The decreased insulin binding was attributed to decreased insulin receptor sites per cell, 21.43 +/- 2.51 x 104 in GSNO-treated dogs compared with 26.60 +/- 1.57 x 104 in captopril-treated controls (p < 0.05). In rats, 10 mM & 20 mM of GSNO and SNAP significantly decreased basal and insulin-stimulated glucose uptake in skeletal muscle strips of normoglycaemic and type 2 diabetic rats in a concentration-dependent manner (P<0.05). The inhibition of insulin-stimulated glucose uptake was greater in the diabetic rats using both NO donors compared with normoglycaemic rats (P<0.05).
Conclusion: These findings suggest the first evidence of the novel role of NO as a modulator of insulin binding and glucose uptake, and the involvement of NO in the etiology of diabetes mellitus.
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Paul Ehrlich And The Search For Magic Bullets
McKENZIE MW
College of Pharmacy, University of Florida, Gainesville, FL USA
The College of Pharmacy offers an Honors Program course to attract students to pursue careers as professional practitioners and/or as pharmaceutical/medical scientists. The course is designed to focus on the continuing search for magic bullets (MBs) as first described by Paul Ehrlich.
The Honors Seminar is a three-credit semester course that incorporates historical, social, and scientific perspectives about the development of medications that attempt to meet the ideal characteristics of a MB. A historical review of Paul Ehrlich’s life is presented with an emphasis on his research and development of a MB for the treatment of syphilis. Ehrlich’s concept of the MB is the context for presentations on pharmaceutical research. Students are consistently asked to evaluate whether a new medication is truly a MB as envisioned by Ehrlich.
The objectives of the course are: describe the benefits of drug research; discuss the concept of pharmaceutical care; explain the concept of a MB in terms of definition and limitations; state the FDA approval process; state adverse consequences of inappropriate drug use; describe the scientific process for drug discovery; state selected mechanisms of action of drugs; describe research projects by pharmacy faculty.
The topics include: Ehrlich and the Magic Bullet: Ethical Considerations in Drug Research, Bringing a MB to Market; Are Herbal Products MBs?; Historical Perspectives on Drug Tragedies; Pharmaceutical Care: Aiming a MB; Animal Research to Develop MB; MBs to Treat Cancer; MBs to Prevent and Dissolve Clots; MBs for Migraine Headaches; MBs for Alzheimer’s Disease; Growth Hormone as a MB; MBs with Food. Does it Matter?; MBs for Asthma; Antibiotics as MBs; MBs for HIV/AIDS; MBs for Acute Otitis Media; MBs for Epilepsy; Are Vaccines the Ultimate MB?; A Debate: Is Marijuana a MB?; MBs for Obesity?; Pharmacogenomics and Drug Response.
Both pharmaceutical and clinical scientists constitute the faculty. This combination of faculty expertise mirrors the scientist-clinician role of Ehrlich, which imparts significant perspectives about research and the use of medications.
Many of the students who have taken this course have continued their education in pharmacy or medicine or pursued graduate studies in the pharmaceutical and medical sciences. Perhaps one or more will emulate Paul Ehrlich’s contributions to science and healthcare.
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Effect Of Commonly Prescribed Nsaids, Proton Pump Inhibitor And Newer Anti-Malarial Compound On Pharmacokinetics Of Different Antiepileptics
MEDHI B, PRAKASH A, PRASADBYRAV DS
Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Background: The aim of the study was to determine the effect of newer NSAIDs, Proton Pump Inhibitor, artemisinin compound on the pharmacokinetics of phenytoin and carbamazepine in rabbits.
Methods: In a parallel design study, phenytoin (30 mg/kg/day) and carbamazepine (40 mg/kg/day orally) were given daily for 7 days in 12 rabbits. On day 7 and 14th day, blood samples were taken at various time intervals between 0 and 24 h. Animals were treated with etoricoxib, acceclofenac, esomeprazole, rabeprazole, artemisinin, artemether, and arteether from 7 day onwards to 14th day. Plasma phenytoin and carbamazepine levels were assayed by HPLC, and pharmacokinetic parameters were calculated.
Results: Treatment with etoricoxib and aceclofenac, there was a decrease in t(1/2)a and t(1/2)el significantly as compared to phenytoin and carbamazepine group alone. Significant changes were observed in the pharmacokinetic parameters in etoricoxib and acceclofenac treated group. With esomeprazole and rabeprazole, there was a decrease in the AUC0-24 when carbamazepine and phenytoin was co-administered with esomeprazole. The decrease in AUC0-24 (22.78±4.71 to 10.46±2.29), Cmax (2.76± 0.77 to 1.412±1.08), Tmax (2.83±0.17 to 3±0.40) was statistically significant (p<0.05). In the artemether group, t(1/2) el decreased compared to that of controls. In the arteether group, no significant change was observed in the pharmacokinetic parameters, when carbamazepine was co-administered with artemisinin, artemether or arteether. The increase in AUC(0-infinity) (22.78 +/- 4.71 to 63.10 +/- 12.29), Cmax (2.76 +/- 0.77 to 7.02 +/- 1.08), Tmax (2.83 +/- 0.17 to 4.16 +/- 0.40) was statistically significant when artemether was given along with carbamazepine (p < 0.05).
Conclusion(s): These results suggest that newer NSAIDs, Proton Pump Inhibitor, and artemisinin compounds alter the pharmacokinetics of phenytoin and carbamazepine. Confirmation of these results in human studies will warrant changes in phenytoin and carbamazepine dose or frequency, when either of these drug is co-administered with it.
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Direct Lentiviral Injection Induces Potent Anti-CEA Immunity In CEA Transgenic Mice
LOISEL-MEYER S1, FOLEY JE2, KAMMERER R3,4, MIZUE N1, KEEFE R5, MCCART JA6,8, ZIMMERMANN W3, DROPULIC B5, FOWLER DH2, MEDIN JA1,6,7,8
1Ontario Cancer Institute, UHN, Toronto, Canada; 2ETIB, NCI, NIH, Bethesda, USA; 3Tumor Immunology Laboratory, LIFE-Center, Klinikum Grosshadern, Ludwig-Maximilians-University Munich, Germany; 4Institute fur Immunologie, Friedrich-Loeffler-Institut, Tubingen, Germany; 5Lentigen Corp., Baltimore, USA; 6TGRI, UHN, Toronto, Canada; 7Department of MBP and the 8Institute of Medical Sciences, Univ. of Toronto, Canada.
Background: Immunotherapy would be dramatically broadened to more recipients if direct ‘off-the-shelf’ products could be engineered to engender functionally potent immune responses against true ‘self’ tumor antigens. The carcinoembryonic antigen (CEA) is upregulated in colon cancers, non-small cell lung cancers, and breast cancers. CEA is an excellent and important target for cancer immunotherapy.
Methods: The human CEA cDNA was used to construct the lentiviral vector (LV-huCEA). huCEA Tg mice were used for anti-tumor immunity studies. A murine gastric carcinoma cell line expressing huCEA was used to establish subcutaneous tumors. Mice were grafted at day 0 with 0.8106 mGC4CEA tumor cells in the flank and subsequently immunized in the footpad on days 14 and 21 with PBS or 0.15106 transducing units (TU) of LV-enGFP or LV-huCEA. Antibody was measured and splenocytes were used unstimulated in cytokine analyses. Tetramer staining was performed against the EAQNTTYL immunogenic peptide. Tumor sections were stained for immunofluorescence.
Results: We show stabilization (mostly reductions) of 14-day established subcutaneous mGC4CEA tumors in human CEA-transgenic mice following two direct low-dose injections of LV-huCEA and not LV-enGFP. This stabilization result was reproducible and detailed analyses including antibody assays, multiplex cytokine analyses on unstimulated splenocytes, tetramer staining, and immunofluorescence staining of tumor sections demonstrated that this outcome correlated with both a cellular and humoral immune response.
Conclusions: We observed that we can safely break tolerance to huCEA and engineer an efficient anti-tumor response along with anti-huCEA antibody and CTL responses. These data support the use of direct injections of low doses of LV-huCEA for enhancement of tumor immunotherapy directed against CEA.
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Bromocriptine Effect In Cardiorenal Damage In Patients With Type 2 Diabetes Mellitus
MEJÍA-RODRÍGUEZ O1, 3, PANIAGUA-SIERRA R2, HERRERA-ABARCA J3, CEBALLOS-REYES G3
1Unidad de Medicina Familiar N° 80 Instituto Mexicano del Seguro Social (IMSS), Morelia, Michoacán, México. 2Unidad de Investigación en Enfermedades Nefrológicas, Centro Medico Nacional Siglo XXI, IMSS. México DF. 3Instituto Politécnico Nacional. México DF. México. México
Background: Left ventricular hypertrophy (LVH) predicts cardiovascular morbidity in patients with diabetic nephropathy and chronic kidney disease (CKD). Its prevalence increases as the renal function declines. Bromocriptine a DA2 receptor agonist inhibits norepinephrine release, aldosterone secretion, the expression of type-1 angiotensin II receptors. The aim of this study was to analyze the effect of BEC on LVH and its influence in residual renal function in patients with LVH, diabetic nephropathy and stage IV of CKD.
Methods: A 6-month double blind randomized controlled clinical trial was conducted in 28 diabetic patients. Fourteen patients received bromocriptine (BEC) (2.5 mg tablet trice a day), 14 received placebo (PLO) (1 tablet trice a day), Changes in left ventricular hypertrophy (assessed by two dimensionally guided M-mode echocardiography). Blood pressure (24h ambulatory blood pressure monitoring), 24h creatinine clearance, cystatin pro brain natriuretic peptide (pBNP), prolactin and other biochemical determinations were assessed at baseline, three and six months of follow-up. The repeated measures analysis was done.
Results: Bromocriptine significantly reduced from baseline: left ventricular mass (-46±8.35g), left ventricular mass index (-28.28 g/m2), interventricular septum (-1.14 mm), left ventricular diastolic diameter (-1.8 mm) and left ventricular posterior wall thickness (-1.71±0.46); BNP (-1.51±1.1 pg/ml) p < .001. Mean blood pressure (-4.23±0.68 mmHg). 24h creatinine clearance and cystatin levels didn’t change in the BEC group. No differences from baseline were observed in echocardiography parameters in the PLO group. However, these patients had reduction in 24h creatinine clearance and increased cystatin levels. Normalization of cholesterol and glucose levels was reached earlier in patients receiving BEC than those in the PLO group.
Conclusions: 1. - BEC treatment reduced: left ventricular mass, blood pressure, pBNP and plasma prolactin levels. 2. - It prevented the decline of residual renal function. 3.-It improved the metabolic control.
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Are The Substituted Phenethylamines Magic Bullets? Benefits And Harms Of Amphetamines And Related Compounds
MENDELSON J, GALLOWAY G, BAGGOTT M
Addiction Pharmacology Research Laboratory, St Luke’s Hospital, California Pacific Medical Center Research Institute, San Francisco, CA, USA
The substituted phenethylamines (including amphetamine, methamphetamine and methylenedioxymethamphetamine; MDMA) are potent therapeutics and major drugs of abuse. Amphetamine was first synthesized in 1897 in Berlin and is one of medicines oldest synthetic therapeutics. Substituted phenethylamines have demonstrated efficacy in treating conditions as diverse as nasal congestion and attention deficit disorder. When used for defined indications and under medical supervision substituted phenethylamine compounds are among the safest and most effective medications ever developed – magic bullets by Ehrlich’s definition. However, magic bullets can harm if not used appropriately. Over the last 50 years the substituted phenethylamines methamphetamine and MDMA have become major drugs of abuse; methamphetamine is the most widely abused synthetic drug in the world with high rates of addiction in all developed countries. In this presentation the pharmacology of the substituted phenethylamines will be reviewed. Therapeutic indications, non-medical military and athletic uses, abuse and addiction will be discussed and pharmacologic mechanisms described. We have conducted several studies defining the human pharmacology of MDMA and methamphetamine. Our work suggests that the pro-social effects of MDMA are mediated by increases in oxytocin release and MDMA alter recognition of emotional stimuli. Phenethylamine has a chiral center and there are substantial differences in the pharmacologic effects of the substituted phenethylamine stereoisomers – data describing these differences will be presented. Due to widespread abuse of phenethylamine compounds there has been little interest in developing new phenethylamine therapeutics. In this presentation we will advance the hypothesis that many undiscovered magic bullets exist within this class of compounds and that more investigation and interest is warranted.
Authors’ disclosure statement: Supported by NIH P50 DA018179, DA016776 and DA017716
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