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Preclinical Data (preclinical + data)
Selected AbstractsTreatment of Acute Stroke with Recombinant Tissue Plasminogen Activator and AbciximabACADEMIC EMERGENCY MEDICINE, Issue 12 2003Daniel C. Morris MD Objectives: Preclinical data suggest that treatment of acute ischemic stroke (AIS) with the combination of recombinant tissue plasminogen activator (rt-PA) and abciximab may increase efficacy and decrease the rate of symptomatic intracranial hemorrhage (sICH). The authors report pilot data of five AIS patients with half-dose rt-PA and abciximab as part of an ongoing phase I safety trial with sICH as the primary outcome. Methods: Five patients with AIS were treated with the combination of half-dose rt-PA (0.45 mg/kg) and abciximab (0.25 mg/kg bolus followed by a 0.125 ,g/kg/min infusion over 12 hours). Head computed tomographic scan was obtained after 24 hours of treatment onset. Results: Four patients received the combination of half-dose abciximab and rt-PA without major complications. One patient experienced a parenchymal hematoma type-1 ICH without significant decline of his neurological status. The average National Institutes of Health Stroke Scale change at discharge in comparison with pretreatment was ,5.4 ± 7.0, and the median change was 6 points with a range of 4 points (worsening) to ,13 points (improvement) (p = 0.07) based on a one-sided t-test. Conclusions: Administration of rt-PA and abciximab to AIS patients was completed without difficulty. No sICH were observed; however, 20% (1 out of 5) experienced an asymptomatic ICH. Based on our observation of five patients, there was a trend of treatment efficacy; however, these results need to be confirmed in a larger-scale placebo-controlled clinical trial. [source] Clinical Pharmacokinetics of FrovatriptanHEADACHE, Issue 2002P. Buchan PhD Objective.,To review available data on the clinical pharmacokinetics of frovatriptan. Background.,Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from that of the currently available triptans. Methods.,Studies of healthy volunteers, subjects with renal or hepatic impairment, elderly subjects, and patients with migraine during and between attacks were reviewed. Results.,Oral bioavailability of frovatriptan is 22% to 30%, and although the time to maximum concentration is typically 2 to 3 hours, approximately 60% to 70% of plasma maximum concentration is achieved within 1 hour of dosing. Frovatriptan distributes into erythrocytes, with binding reversible and time dependent. The relatively long terminal elimination half-life (about 26 hours) confers good systemic exposure and may produce a long duration of therapeutic action, thus reducing migraine recurrence and the need for redosing. Systemic exposure to frovatriptan generally correlates with dose between 1 and 100 mg. Blood and plasma frovatriptan concentrations are consistently higher in females, but there is no need to adjust dose according to gender. Pharmacokinetics are essentially unaffected by food and were predictable after repeat dosing; steady state is approached in about 4 to 5 days. Pharmacokinetics were changed only slightly in subjects with renal impairment or mild-to-moderate hepatic impairment, elderly individuals, and during migraine attacks. Frovatriptan is principally metabolized by the CYP1A2 isoenzyme of cytochrome P-450 and is cleared by the kidney and liver, each having sufficient capacity to compensate for impairment of the other. Conclusions.,Frovatriptan can be taken without regard for food intake, and because of the large therapeutic margin and shallow dose-response curve, there is no need for dosage adjustment in the elderly, in women taking a combined oral contraceptive, in patients with mild-to-severe renal impairment, mild-to-moderate hepatic impairment, or according to gender. The long duration of exposure may reduce the likelihood of early migraine recurrence. [source] Inhibition of myostatin with emphasis on follistatin as a therapy for muscle diseaseMUSCLE AND NERVE, Issue 3 2009Louise R. Rodino-Klapac PhD Abstract In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic,pituitary,gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease. Muscle Nerve 39: 283,296, 2009 [source] An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma,,AMERICAN JOURNAL OF HEMATOLOGY, Issue 10 2009Ravi Vij RANKL is a key mediator of osteoclast differentiation, activation, and survival. Preclinical data suggest that aberrant production and activation of osteoclasts may influence proliferation of multiple myeloma (MM) cells in the bone marrow. Reports have also shown that inhibiting RANKL may have a direct effect on RANK-expressing myeloma cells and a therapeutic role in treating the disease. In mouse myeloma models, inhibition of RANKL led to reduced serum paraprotein levels and tumor burden. Based on this hypothesis, this proof-of-concept, single-arm study investigated whether RANKL inhibition with denosumab could reduce serum M-protein levels in relapsed or plateau-phase myeloma subjects. All subjects received denosumab monthly, with loading doses on days 8 and 15 of month one, until disease progression or subject discontinuation. Results of this ongoing study demonstrated that no subjects in either cohort met the protocol-defined objective response criteria of complete response (CR) or partial response (PR), but that denosumab effectively inhibited the RANKL pathway regardless of previous exposure to bisphosphonates, as evidenced by suppressed levels of the bone turnover marker, serum C-terminal telopeptide of type 1 collagen (sCTx). Eleven (21%) subjects who relapsed within 3 months before study entry maintained stable disease for up to 16.5 months. Nineteen (46%) subjects with plateau-phase myeloma maintained stable disease for up to 18.3 months. The adverse event (AE) profile for denosumab and its dosing schedule in these populations was consistent with that for advanced cancer patients receiving systemic therapy. Additional controlled clinical studies of denosumab in subjects with both relapsed and plateau-phase MM are warranted. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic functionAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2006R. M. Eglen Summary 1 Muscarinic M1,M5 receptors mediate the metabotropic actions of acetylcholine in the nervous system. A growing body of data indicate they also mediate autocrine functions of the molecule. The availability of novel and selective muscarinic agonists and antagonists, as well as in vivo gene disruption techniques, has clarified the roles of muscarinic receptors in mediating both functions of acetylcholine. 2 Selective M1 agonists or mixed M1 agonists/M2 antagonists may provide an approach to the treatment of cognitive disorders, while M3 antagonism, or mixed M2/M3 antagonists, are approved for the treatment of contractility disorders including overactive bladder and chronic obstructive pulmonary disease. Preclinical data suggest that selective agonism of the M4 receptor will provide novel anti-nociceptive agents, while therapeutics-based upon agonism or antagonism of the muscarinic M5 receptor have yet to be reported. 3 The autocrine functions of muscarinic receptors broadly fall into two areas , control of cell growth or proliferation and mediation of the release of chemical mediators from epithelial cells, ultimately causing muscle relaxation. The former particularly are involved in embryological development, oncogenesis, keratinocyte function and immune responsiveness. The latter regulate contractility of smooth muscle in the vasculature, airways and urinary bladder. 4 Most attention has focused on muscarinic M1 or M3 receptors which mediate lymphocyte immunoresponsiveness, cell migration and release of smooth muscle relaxant factors. Muscarinic M4 receptors are implicated in the regulation of keratinocyte adhesion and M2 receptors in stem cell proliferation and development. Little data are available concerning the M5 receptor, partly due to the difficulties in defining the subtype pharmacologically. 5 The autocrine functions of acetylcholine, like those in the nervous system, involve activation of several muscarinic receptor subtypes. Consequently, the role of these subtypes in autocrine, as well neuronal cholinergic systems, significantly expands their importance in physiology and pathophysiology. [source] Emerging strategies for exploiting cannabinoid receptor agonists as medicinesBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2009Roger G Pertwee Mandarin translation of abstract Medicines that activate cannabinoid CB1 and CB2 receptor are already in the clinic. These are Cesamet® (nabilone), Marinol® (dronabinol; ,9 -tetrahydrocannabinol) and Sativex® (,9 -tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol® can also be prescribed to stimulate appetite, while Sativex® is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB2 receptors; or (v) ,multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. Mandarin translation of abstract [source] Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumorsCANCER, Issue 6 2010Faye M. Johnson MD Abstract BACKGROUND: The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen. METHODS: The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography. RESULTS: Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed. CONCLUSIONS: The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided. Cancer 2010. © 2010 American Cancer Society. [source] Pre-clinical studies of pramipexole: clinical relevanceEUROPEAN JOURNAL OF NEUROLOGY, Issue 2000J. P. Hubble This paper reviews the preclinical study of the novel dopamine agonist pramipexole and its use in early Parkinson's disease (PD). Emphasis will be given to those properties distinguishing this drug from other dopamine agonists, the relevance of the preclinical data to clinical trial results in early PD, and the putative neuroprotective properties of the compound. The conventional dopamine agonists are ergot-derived compounds that are most widely used as adjunctive therapies in advancing Parkinson's disease (PD). Examples of conventional agonists are bromocriptine and pergolide. Pramipexole is an aminobenzothiazole compound, recently introduced for the treatment of both early and advanced PD. Its nonergot structure may reduce the risk of side-effects, considered unique to ergot drugs, such as membranous fibrosis. Pramipexole is a full dopamine agonist with high selectivity for the D2 dopamine receptor family. This family includes the D2, D3 and D4 receptor subtypes. Pramipexole has a 5- to 7-fold greater affinity for the D3 receptor subtype with lower affinities for the D2 and D4 receptor subtypes. The drug has only minimal ,2 -adrenoceptor activity and virtually no other receptor agonism or antagonism. The optimal dopamine receptor activation for the safe and effective treatment of PD is not known. Findings in animal models and clinical studies indicate that activation of the postsynaptic D2 receptor subtype provides the most robust symptomatic improvement in PD. Given its pharmacological profile, it is not surprising that pramipexole was found to be effective in ameliorating parkinsonian signs in animal models. This therapeutic effect has been confirmed in clinical trials in both early and advanced PD. In early disease, it provides a clear reduction in the chief motor manifestations of PD and improved activities of daily living. Perhaps most striking is the large number of clinical trial patients who have remained on pramipexole monotherapy for many months. The majority of these subjects have been maintained on pramipexole for an excess of 24 months without requiring additional symptomatic treatment with levodopa. This is in contrast to the general clinical experience with older conventional agonists. Pramipexole also has a favourable pharmacokinetic profile. It is rapidly absorbed with peak levels appearing in the bloodstream within 2 h of oral dosing. It has a high absolute bioavailability of > 90% and can be administered without regard to meals. It has no significant effects on other antiparkinson drugs such as levodopa or selegiline. Its excretion is primarily renal and, thus, has little or no impact on hepatic cytochrome P450 enzymes or other related metabolic pathways. Pramipexole has also been theorized to have ,neuroprotectant' properties. Oxyradical generation is posited as a cause or accelerant of brain nigral cell death in PD. Pramipexole stimulates brain dopamine autoreceptors and reduces dopamine synthesis and turnover which may minimize oxidative stress due to dopamine metabolism. Furthermore, the compound has a low oxidation potential that may serve as an oxyradical scavenger in the PD brain. In summary, pramipexole is a new antiparkinson medication found to have unique dopamine agonist characteristics and putative neuroprotective properties. [source] Antiadult T-cell leukemia effects of brown algae fucoxanthin and its deacetylated product, fucoxanthinolINTERNATIONAL JOURNAL OF CANCER, Issue 11 2008Chie Ishikawa Abstract Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by human T-cell leukemia virus type 1 (HTLV-1) infection and remains incurable. Carotenoids are a family of natural pigments and have several biological functions. Among carotenoids, fucoxanthin is known to have antitumorigenic activity, but the precise mechanism of action is not elucidated. We evaluated the anti-ATL effects of fucoxanthin and its metabolite, fucoxanthinol. Both carotenoids inhibited cell viability of HTLV-1-infected T-cell lines and ATL cells, and fucoxanthinol was approximately twice more potent than fucoxanthin. In contrast, other carotenoids, ,-carotene and astaxanthin, had mild inhibitory effects on HTLV-1-infected T-cell lines. Importantly, uninfected cell lines and normal peripheral blood mononuclear cells were resistant to fucoxanthin and fucoxanthinol. Both carotenoids induced cell cycle arrest during G1 phase by reducing the expression of cyclin D1, cyclin D2, CDK4 and CDK6, and inducing the expression of GADD45,, and induced apoptosis by reducing the expression of Bcl-2, XIAP, cIAP2 and survivin. The induced apoptosis was associated with activation of caspase-3, -8 and -9. Fucoxanthin and fucoxanthinol also suppressed I,B, phosphorylation and JunD expression, resulting in inactivation of nuclear factor-,B and activator protein-1. Mice with severe combined immunodeficiency harboring tumors induced by inoculation of HTLV-1-infected T cells responded to treatment with fucoxanthinol with suppression of tumor growth, showed extensive tissue distribution of fucoxanthinol, and the presence of therapeutically effective serum concentrations of fucoxanthinol. Our preclinical data suggest that fucoxanthin and fucoxanthinol could be potentially useful therapeutic agents for patients with ATL. © 2008 Wiley-Liss, Inc. [source] Treatment of type 2 diabetes with glucagon-like peptide-1 receptor agonistsINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 8 2009K. B. Hansen Summary The incretin system is an area of great interest for the development of new therapies for the management of type 2 diabetes. Existing antidiabetic drugs are often insufficient at getting patients to glycaemic goals. Furthermore, current treatment modalities are not able to prevent the continued ongoing decline in pancreatic beta-cell function and, lastly, they have a number of side effects including hypoglycaemia and weight gain. Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of pharmacological agents, which improve glucose homeostasis in a multifaceted way. Their effects include potentiation of glucose-stimulated insulin secretion, glucose-dependent inhibition of glucagon secretion and reduction in gastric emptying, appetite, food intake and body weight. Additionally, preclinical data suggest that they may preserve beta-cell mass and function. The incidence of hypoglycaemia with GLP-1 receptor agonists is low, the compounds have clinically relevant effects on body weight, and data are suggesting beneficial effects on cardiovascular risk factors. Exenatide was released in 2005 for the treatment of type 2 diabetes and liraglutide is expected to be approved by the Food and Drug Administration in US and the European Medical Agency in Europe for use in 2009. In this review, the available data on the two drugs are presented and discussed. [source] Pharmacokinetic/pharmacodynamic studies in drug product developmentJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2002Bernd Meibohm Abstract In the quest of ways for rationalizing and accelerating drug product development, integrated pharmacokinetic/pharmacodynamic (PK/PD) concepts provide a highly promising tool. PK/PD modeling concepts can be applied in all stages of preclinical and clinical drug development, and their benefits are multifold. At the preclinical stage, potential applications might comprise the evaluation of in vivo potency and intrinsic activity, the identification of bio-/surrogate markers, as well as dosage form and regimen selection and optimization. At the clinical stage, analytical PK/PD applications include characterization of the dose,concentration,effect/toxicity relationship, evaluation of food, age and gender effects, drug/drug and drug/disease interactions, tolerance development, and inter- and intraindividual variability in response. Predictive PK/PD applications can also involve extrapolation from preclinical data, simulation of drug responses, as well as clinical trial forecasting. Rigorous implementation of the PK/PD concepts in drug product development provides a rationale, scientifically based framework for efficient decision making regarding the selection of potential drug candidates, for maximum information gain from the performed experiments and studies, and for conducting fewer, more focused clinical trials with improved efficiency and cost effectiveness. Thus, PK/PD concepts are believed to play a pivotal role in streamlining the drug development process of the future. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:18,31, 2002 [source] Selected Line Difference in the Effects of Ethanol Dependence and Withdrawal on Allopregnanolone Levels and 5,-Reductase Enzyme Activity and ExpressionALCOHOLISM, Issue 12 2009Michelle A. Tanchuck Background:, Allopregnanolone (ALLO) is a progesterone derivative that rapidly potentiates ,-aminobutyric acidA (GABAA) receptor-mediated inhibition and modulates symptoms of ethanol withdrawal. Because clinical and preclinical data indicate that ALLO levels are inversely related to symptoms of withdrawal, the present studies determined whether ethanol dependence and withdrawal differentially altered plasma and cortical ALLO levels in mice selectively bred for differences in ethanol withdrawal severity and determined whether the alterations in ALLO levels corresponded to a concomitant change in activity and expression of the biosynthetic enzyme 5,-reductase. Methods:, Male Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mice were exposed to 72 hours ethanol vapor or air and euthanized at select times following removal from the inhalation chambers. Blood was collected for analysis of ALLO and corticosterone levels by radioimmunoassay. Dissected amygdala, hippocampus, midbrain, and cortex as well as adrenals were examined for 5,-reductase enzyme activity and expression levels. Results:, Plasma ALLO was decreased significantly only in WSP mice, and this corresponded to a decrease in adrenal 5,-reductase expression. Cortical ALLO was decreased up to 54% in WSP mice and up to 46% in WSR mice, with a similar decrease in cortical 5,-reductase activity during withdrawal in the lines. While cortical gene expression was significantly decreased during withdrawal in WSP mice, there was a 4-fold increase in expression in the WSR line during withdrawal. Hippocampal 5,-reductase activity and gene expression was decreased only in dependent WSP mice. Conclusions:, These results suggest that there are line and brain regional differences in the regulation of the neurosteroid biosynthetic enzyme 5,-reductase during ethanol dependence and withdrawal. In conjunction with the finding that WSP mice exhibit reduced sensitivity to ALLO during withdrawal, the present results are consistent with the hypothesis that genetic differences in ethanol withdrawal severity are due, in part, to modulatory effects of GABAergic neurosteroids such as ALLO. [source] Alcohol Abuse Enhances Pulmonary Edema in Acute Respiratory Distress SyndromeALCOHOLISM, Issue 10 2009David M. Berkowitz Background:, Pulmonary edema is a cardinal feature of the life-threatening condition known as acute respiratory distress syndrome (ARDS). Patients with chronic alcohol abuse are known to be at increased risk of developing and dying from ARDS. Based upon preclinical data, we hypothesized that a history of chronic alcohol abuse in ARDS patients is associated with greater quantities and slower resolution of pulmonary edema compared with ARDS patients without a history of alcohol abuse. Methods:, A PiCCOÔ transpulmonary thermodilution catheter was inserted into 35 patients within 72 hours of meeting American European Consensus Criteria definition of ARDS. Pulmonary edema was quantified as extravascular lung water (EVLW) and measured for up to 7 days in 13 patients with a history of chronic alcohol abuse and 22 patients without a history of chronic alcohol abuse. Results:, Mean EVLW was higher in patients with a history of chronic alcohol abuse (16.6 vs. 10.5 ml/kg, p < 0.0001). Patients with alcohol abuse had significantly greater EVLW over the duration of the study (RM-ANOVA p = 0.003). There was a trend towards slower resolution of EVLW in patients with a history of alcohol abuse (a decrease of 0.5 ml/kg vs. 2.4 ml/kg, p = 0.17) over the study period. A history of alcohol abuse conferred a greater than 3-fold increased risk of elevated EVLW [OR 3.16, (1.26 to 7.93)] using multivariate logistic regression analysis. Conclusions:, In patients who develop ARDS, alcohol abuse is associated with greater levels EVLW and a trend towards slower resolution of EVLW. Combined with mechanistic and preclinical evidence linking chronic alcohol consumption and ARDS, targeted therapies should be developed for these patients. [source] Noninvasive blood flow imaging for real-time feedback during laser therapy of port wine stain birthmarksLASERS IN SURGERY AND MEDICINE, Issue 3 2008Yu-Chih Huang MS Abstract Background and Objectives During laser therapy of port wine stain (PWS) birthmarks, regions of persistent perfusion may exist. Immediate retreatment of such regions may improve PWS laser therapeutic outcome. To address this need, we propose use of laser speckle imaging (LSI) to provide real-time, quantitative feedback during laser surgery. Herein, we present in vitro and in vivo data collected with a clinic-based LSI instrument. Study Design/Materials and Methods Prior to clinical implementation, we first investigated three aspects of LSI deemed important for clinical imaging: (1) instrument depth of field (DOF); (2) effects of laser irradiance on speckle flow index (SFI) values; and (3) measurement repeatability. Clinical measurements were acquired from the lesions of PWS patients immediately prior to and after laser therapy at the Beckman Laser Institute. Results Our preclinical data suggest the following: (1) instrument DOF was ,1 cm; (2) quantitative flow characterization with LSI was practically unaffected at normalized irradiance values between 0.06 and 0.5; and (3) our LSI instrument was capable of highly reproducible SFI values. From our clinical measurements, we found that the relative difference between blood perfusion in PWS lesions and adjacent normal skin was highly variable. Based on SFI images, the perfusion of PWS skin is sometimes indistinguishable from that of adjacent normal skin. With laser therapy, we measured a global decrease in blood perfusion, and we frequently observed distinct regions of persistent perfusion. Conclusions Our results demonstrate the potential role of image-guided laser therapy of PWS birthmarks. LSI is a promising tool for noninvasive blood flow characterization during laser therapy due to its relative simplicity and low cost. Laser Surg. Med. 40:167,173, 2008. © 2008 Wiley-Liss, Inc. [source] Fundamentals of neuronal apoptosis relevant to pediatric anesthesiaPEDIATRIC ANESTHESIA, Issue 5 2010MORGAN BLAYLOCK PhD Summary The programmed cell death or apoptosis is a complex biochemical process that has risen to prominence in pediatric anesthesia. Preclinical studies report a dose-dependant neuronal apoptosis during synaptogenesis following exposure to intravenous and volatile anesthetic agents. Although emerging clinical data do not universally indicate an increased neurodegenerative risk of general anesthesia in early human life, a great deal of uncertainty was created within the pediatric anesthesia community. This was at least partially caused by the demand of understanding of basic science concepts and knowledge of apoptosis frequently out of reach to the clinician. It is, however, important for the pediatric anesthesiologist to be familiar with the basic science concepts of neuronal apoptosis to be able to critically evaluate current and future preclinical data in this area and future clinical studies. This current review describes the extrinsic and intrinsic pathways involved in the cell death process and discusses techniques commonly employed to determine apoptosis. In addition, potential mechanisms of anesthesia-induced neuronal apoptosis are illustrated in this review. [source] Biases affecting the proportional reporting ratio (PRR) in spontaneous reports pharmacovigilance databases: the example of sertindolePHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 4 2003Nicholas Moore Abstract Background Automated measures of reporting disproportionality in databases of spontaneous reports of adverse drug reactions are an emerging tool to identify drug-related alerts. Sertindole, a new atypical neuroleptic known to prolong the QT interval, was suspended in November 1998 because the proportion of reports of fatal reactions suggesting arrhythmia among all reports with sertindole was almost ten times higher than that for other atypical neuroleptics in the UK. This excess risk was not predicted in preclinical data and had not been found in premarketing trials. Method Reporting patterns over time were analysed. Prescription Event Monitoring (PEM) studies and a large retrospective cohort allowed for the comparison of actual death rates with atypical neuroleptics, and to assess which proportion of the deaths that occurred were reported. Results There were indications of possible skewing of reporting related to notoriety, surveillance and market size effects. Death rates in PEM studies were essentially similar between sertindole and other neuroleptics. Cardiac deaths had been two to three times more often reported than other causes of death. Conclusion Proportional reporting ratios indicate differential reporting of possible reactions, not necessarily differential occurrence. There was no indication of an actual increase of risk of all causes or cardiac deaths during sertindole treatment, but only an increased risk of its being reported. The suspension of sertindole was rescinded by Committee on Proprietary Medicinal Products (CPMP) in October 2001. Copyright © 2003 John Wiley & Sons, Ltd. [source] 5-Aminolevulinic Acid Derivatives in Photomedicine: Characteristics, Application and PerspectivesPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2006Nicolas Fotinos ABSTRACT The introduction of lipophilic derivatives of the naturally occurring heme precursor 5-aminolevulinic acid (5-ALA) into photomedicine has led to a true revival of this research area. 5-ALA-mediated photodynamic therapy (PDT) and fluorescence photodetection (FD) of neoplastic disease is probably one of the most selective cancer treatments currently known in oncology. To date, this method has been assessed experimentally for the treatment of various medical indications. However, the limited local bioavailability of 5-ALA has widely prevented its use in daily clinical practice. Although researchers were already aware of this drawback early during the development of 5-ALA-mediated PDT, only recently have well-established concepts in pharmaceutical science been adapted to investigate ways to overcome this drawback. Recently, two derivatives of 5-ALA, methylaminolevulinate (MAL) and hexylaminolevulinate (HAL), gained marketing authorization from the regulatory offices in Europe and Australia. MAL is marketed under the trade name Metvix for the treatment of actinic keratosis and difficult-to-treat basal cell carcinoma. HAL has recently been launched under the trade name Hexvix to improve the detection of superficial bladder cancer in Europe. This review will first present the fundamental concepts underlying the use of 5-ALA derivatives in PDT and FD from a chemical, biochemical and pharmaceutical point of view. Experimental evidences from preclinical data on the improvements and limits observed with 5-ALA derivatives will then be introduced. The state-of-the-art from clinical studies with 5-ALA esters will be discussed, with special emphasis placed on the process that led to the development of MAL in dermatology and to HAL in urology. Finally, we will discuss promising medical fields in which use of 5-ALA derivatives might potentially lead to further use of this methodology in photomedicine. [source] The prediction of human response to ONO-4641, a sphingosine 1-phosphate receptor modulator, from preclinical data based on pharmacokinetic,pharmacodynamic modelingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2010Tomoya Ohno Abstract The pharmacokinetic (PK) and pharmacodynamic (PD) parameters of ONO-4641 in humans were estimated using preclinical data in order to provide essential information to better design future clinical studies. The characterization of PK/PD was measured in terms of decreased lymphocyte counts in blood after administration of ONO-4641, a sphingosine 1-phosphate receptor modulator. Using a two-compartment model, human PK parameters were estimated from preclinical PK data of cynomolgus monkey and in vitro human metabolism data. To estimate human PD parameters, the relationship between lymphocyte counts and plasma concentrations of ONO-4641 in cynomolgus monkeys was determined. The relationship between lymphocyte counts and plasma concentrations of ONO-4641 was described by an indirect-response model. The indirect-response model had an Imax value of 0.828 and an IC50 value of 1.29,ng/ml based on the cynomolgus monkey data. These parameters were used to represent human PD parameters for the simulation of lymphocyte counts. Other human PD parameters such as input and output rate constants for lymphocytes were obtained from the literature. Based on these estimated human PK and PD parameters, human lymphocyte counts after administration of ONO-4641 were simulated. In conclusion, the simulation of human lymphocyte counts based on preclinical data led to the acquisition of useful information for designing future clinical studies. Copyright © 2010 John Wiley & Sons, Ltd. [source] Improving the efficacy of trastuzumab in breast cancerCANCER SCIENCE, Issue 6 2007Eiji Suzuki Although overexpression of human epidermal growth factor receptor 2 (HER2) protein, amplification of the gene or both are associated with poor prognosis in breast cancer, trastuzumab has clearly provided clinical benefits in metastatic breast cancer, adjuvant treatment settings and primary systemic therapy. However, even in those HER2 overexpressors, the majority of patients who achieve an initial response generally acquire resistance within 1 year. Therefore, it is critical to elucidate the mechanism of resistance and to search for better combination treatments with chemotherapeutic agents or other novel modalities. Here, we discuss both clinical and preclinical data regarding these issues. (Cancer Sci 2007; 98: 767,771) [source] Molecular targets of lithium actionACTA NEUROPSYCHIATRICA, Issue 6 2003B Corbella Lithium is an effective drug for both the treatment and prophylaxis of bipolar disorder. However, the precise mechanism of lithium action is not yet well understood. Extensive research aiming to elucidate the molecular mechanisms underlying the therapeutic effects of lithium has revealed several possible targets. The behavioral and physiological manifestations of the illness are complex and are mediated by a network of interconnected neurotransmitter pathways. Thus, lithium's ability to modulate the release of serotonin at presynaptic sites and modulate receptor-mediated supersensitivity in the brain remains a relevant line of investigation. However, it is at the molecular level that some of the most exciting advances in the understanding of the long-term therapeutic action of lithium will continue in the coming years. The lithium cation possesses the selective ability, at clinically relevant concentrations, to alter the PI second-messenger system, potentially altering the activity and dynamic regulation of receptors that are coupled to this intracellular response. Subtypes of muscarinic receptors in the limbic system may represent particularly sensitive targets in this regard. Likewise, preclinical data have shown that lithium regulates arachidonic acid and the protein kinase C signaling cascades. It also indirectly regulates a number of factors involved in cell survival pathways, including cAMP response element binding protein, brain-derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases, and may thus bring about delayed long-term beneficial effects via under-appreciated neurotrophic effects. Identification of the molecular targets for lithium in the brain could lead to the elucidation of the pathophysiology of bipolar disorder and the discovery of a new generation of mood stabilizers, which in turn may lead to improvements in the long-term outcome of this devastating illness (1). [source] | |||||||||||||||||||||||||