Significant Cardiovascular Side Effects Research Articles

Abstract 311: Ponatinib loaded leukocyte-based nanoparticles for osteosarcoma treatment in sarcosphere tumor model

Abstract Osteosarcoma (OS) is the most common pediatric bone tumor with a worldwide incidence of 3.4 cases per million people annually. Unfortunately, current treatments are still not sufficient to eradicate OS, due to its ability to resist the upfront standard chemotherapy. Therefore, it is essential to identify and effectively deliver novel therapeutic regimens. Multi-tyrosine kinase inhibitors have been explored as new therapeutics for different sarcomas. Among many, Ponatinib (Pon) demonstrated very potent anti-tumor activity, however, it received a black box warning from the FDA due to significant cardiovascular side effects. Recently, our lab developed novel biomimetic nanoparticles (NPs) called Leukosomes (Leuko) capable of encapsulating and effectively releasing Pon. These NPs are synthesized from activated leukocytes, maintaining leukocytes' tropism towards inflamed endothelium. Leveraging on this technology, we aim to validate the therapeutic potential of Leuko in 3D OS tumor model (sarcospheres) and their ability to target primary murine OS model while concomitantly reducing the detrimental side effects. Given its biological relevance and ability to better recapitulate the tumor structure, a 3D tumor model was chosen to reproduce key properties, such as diffusion limitations and the cellular network of solid tumors that have significant impacts on cancer drug efficacy.In the sarcospheres model, we observed efficient penetration and internalization of NPs in both, murine (RF379, 577) and human PDX derived (PDX94, pPDX202) OS cell lines, where Leuko exhibited a 20% increase in targeting vs the control Liposome (Lipo). This difference was not detected in the control 2D model. Moreover, our data demonstrated a 2-fold increase in the Leuko cytotoxic effect in 3D compared to 2D systems. Murine OS cell viability was 20% lower in sarcospheres after treatment with the IC50 for Pon. In addition, NPs induced complete inhibition of murine sarcosphere formation in the extreme limiting dilution assay (ELDA). These findings were also confirmed using the PDX derived OS cell lines. Subsequently, an in vivo intratibial syngeneic orthotopic mouse model was utilized to determine the targeting and biodistribution of the NPs. Leuko showed an increased targeting and penetration in the tumor 1 and 3h post NPs injection as anticipated by the 3D in vitro studies. By exploiting the inflammatory conditions within the tumor, which increases the Leuko accumulation, these preliminary results advocate the translational potential of this innovative formulation as a new targeted drug delivery approach for OS. This promising platform could improve the clinical therapeutic approaches and lead to improved outcomes and reduced side effects for OS patients. Citation Format: Federica Giordano, Stefania Lenna, Riccardo Rampado, April Ewing, Gherardo Baudo, Matteo Massaro, Assaf Zinger, Enrica De Rosa, Jason T Yustein, Francesca Taraballi. Ponatinib loaded leukocyte-based nanoparticles for osteosarcoma treatment in sarcosphere tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 311.

The role of intranasal esketamine in treatment-resistant depression

IntroductionMajor depressive disorder (MDD) is a highly prevalent clinical condition with a leading cause of disability worldwide. Unfortunately, about 1/3 of patients with MDD fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression (TRD). Research showed abnormalities in glutamatergic transmission in neural circuits and antidepressant efficacy with the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine.ObjectivesThe authors elaborate a narrative literature review on the intranasal esketamine as a new-class antidepressant.MethodsPubMed database searched using the terms “treatment-resistant depression” and “esketamine”.ResultsKetamine, synthetized from PCP, acts as an antagonist of NMDA receptor, reducing Central Nervous System excitability. One limitation of ketamine for treating depression is that requires intravenous administration, reducing its applicability in outpatient settings. Esketamine, the S-enantiomer of ketamine, developed as an intranasal formulation has a higher affinity for the NMDA receptor. The evidence of the rapid antidepressant effect of intranasal esketamine was first made by Lapidus et al, that demonstrated intranasal esketamine ability to reduce depressive symptomatology. However, some recent studies reported significant acute cardiovascular, psychotomimetic and neurological side-effects. Thus, drug formulation, delivery device, insufflation technique, and individual factors seem to contribute importantly to the tolerability and efficacy of the intranasal administration rote.ConclusionsThere is the need to develop novel treatments providing effective, more rapid-acting, and sustained relief of depressive symptoms, especially in patients with TRD. Intranasal esketamine has shown antidepressant effects in patients with TRD but further investigation is required to strongly reinforce this potential and safety.

Metformin and Chemoprevention: Potential for Heart-Healthy Targeting of Biologically Aggressive Breast Cancer.

Currently, tamoxifen is the only drug approved for reduction of breast cancer risk in premenopausal women. The significant cardiovascular side effects of tamoxifen, coupled with lack of a survival benefit, potential for genotoxicity, and failure to provide a significant risk-reduction for estrogen receptor-negative breast cancer, all contribute to the low acceptance of tamoxifen chemoprevention in premenopausal women at high-risk for breast cancer. While other prevention options exist for postmenopausal women, there is a search for well-tolerated prevention agents that can simultaneously reduce risk of breast cancers, cardiovascular disease, and type-2 diabetes. Metformin is a well-tolerated oral biguanide hypoglycemic agent that is prescribed worldwide to over 120 million individuals with type-2 diabetes. Metformin is inexpensive, safe during pregnancy, and the combination of metformin, healthy lifestyle, and exercise has been shown to be effective in preventing diabetes. There is a growing awareness that prevention drugs and interventions should make the “whole woman healthy.” To this end, current efforts have focused on finding low toxicity alternatives, particularly repurposed drugs for chemoprevention of breast cancer, including metformin. Metformin's mechanisms of actions are complex but clearly involve secondary lowering of circulating insulin. Signaling pathways activated by insulin also drive biologically aggressive breast cancer and predict poor survival in women with breast cancer. The mechanistic rationale for metformin chemoprevention is well-supported by the scientific literature. Metformin is cheap, safe during pregnancy, and has the potential to provide heart-healthy breast cancer prevention. On-going primary and secondary prevention trials will provide evidence whether metformin is effective in preventing breast cancer.

Abstract 6381: NBS-1120: An e-NSAID with potent anti-cancer activity targets cell cycle proteins by generating polysulfides

Abstract Epidemiological and interventional human studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce cancer incidence and mortality. However, while NSAIDs are chemopreventive against cancer, they are not potent enough to be chemotherapeutic, and their long-term use may lead to significant gastrointestinal (GI), cardiovascular (CV) and renal side effects. In our search for a “better and safer NSAID”, we developed enhanced or e-NSAIDs. These are NSAIDs such as aspirin and naproxen, modified to release nitric oxide (NO) and hydrogen sulfide (H2S), both gaseous signaling molecules of biological relevance. NO and H2S have similar properties to prostaglandins within the GI mucosa, thus modulating the local mucosal defense systems, leading to reduced GI toxicity. Also, NO and H2S have protective roles in the CV and renal systems. NO and H2S signaling pathways regulate many mammalian physiological processes through post-translational cysteine persulfidation or nitrosylation. NO and H2S have a rich in vivo chemistry in which the molecules are transformed into short lived, bioactive species. They also react together to form highly bioactive persulfides. While both gasotransmitters have a complex role in tumor biology, their downstream effects have a profound impact on tumor growth and metastasis. e-NSAIDs and NBS-1120 in particular, have potent anti-tumor activity, demonstrated in in vivo models of colorectal, breast and pancreatic cancer. The activity of NBS-1120 is superior to the parent aspirin, NO releasing aspirin or H2S releasing aspirin. NBS-1120 has displayed the unexpected property of synergism: the sum of the parts (Aspirin+NO+H2S) does not equal the whole (NBS-1120). Here we report that NBS-1120 inhibits FOXM1, an important protein that plays a critical role in the cell cycle, is closely linked to p53 and controls the expression of cell cycle regulatory proteins. FOXM1's association with many solid tumors, its interactions with numerous signaling pathways, and its emerging role as a master regulator of DNA damage response and genotoxic agent resistance make it an important target for anticancer therapies. We describe the effects of NBS-1120 on p53, β-catenin, oxidative stress, NF-ΚB and COX1/2 through inhibition of FOXM1 by protein persulfidation and nitrosylation. Further, we report that the unique activity of e-NSAIDs is related to the simultaneous release of NO and H2S and their subsequent rapid reaction to form the highly bioactive polysulfides H2S2 and H2S3. NBS-1120 induced rapid polysulfide formation, however no evolution of H2S was detected. These data suggest that release of NO and H2S from NBS-1120 results in a very rapid reaction to form polysulfides. Mechanistically, the rapid formation of polysulfides may account for the potent activity of NBS-1120 compared to NSAIDs that release either NO or H2S alone. Citation Format: Jan J. Scicinski, Kenneth Olsen, Janet Stephens, Khosrow Kashfi. NBS-1120: An e-NSAID with potent anti-cancer activity targets cell cycle proteins by generating polysulfides [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6381.

Repeated intranasal ketamine for treatment-resistant depression - the way to go? Results from a pilot randomised controlled trial.

Ketamine research in depression has mostly used intravenous, weight-based approaches, which are difficult to translate clinically. Intranasal (IN) ketamine is a promising alternative but no controlled data has been published on the feasibility, safety and potential efficacy of repeated IN ketamine treatments. This randomised, double-blind, placebo-controlled pilot study compared a 4-week course of eight treatments of 100 mg ketamine or 4.5 mg midazolam. Each treatment was given as 10 separate IN sprays, self-administered 5 min apart. The study was stopped early due to poor tolerability after five treatment-resistant depressed participants were included. Feasibility, safety (acute and cumulative), cognitive and efficacy outcomes were assessed. Plasma ketamine and norketamine concentrations were assayed after the first treatment. Significant acute cardiovascular, psychotomimetic and neurological side effects occurred at doses < 100 mg ketamine. No participants were able to self-administer all 10 ketamine sprays due to incoordination; treatment time occasionally had to be extended (>45 min) due to acute side effects. No hepatic, cognitive or urinary changes were observed after the treatment course in either group. There was an approximately two-fold variation in ketamine and norketamine plasma concentrations between ketamine participants. At course end, one participant had remitted in each of the ketamine and midazolam groups. IN ketamine, with the drug formulation and delivery device used, was not a useful treatment approach in this study. Absorption was variable between individuals and acute tolerability was poor, requiring prolonged treatment administration time in some individuals. The drug formulation, the delivery device, the insufflation technique and individual patient factors play an important role in tolerability and efficacy when using IN ketamine for TRD.

Adenosine A3 receptor agonists: do recent findings offer new hope in chronic pain treatment?

Background Management of chronic pain is limited by inadequate effectiveness and undesirable safety profiles of currently available medi cations. There is growing evidence that adenosine (A1, A2A, A2B, A3) receptors can be promising therapeutic targets for treatment of chronic pain. A number of selective ligands for adenosine receptors have been introduced. Agents acting selectively at A1, A2A and A2B receptors have been effective in several preclinical animal models of pain and several have also entered into clinical development for neuropathic pain. Unfortunately, safety concerns related to significant cardiovascular side effects caused by systemic administration of some of these agents limited further development. In contrast, systemic administration of certain selective A3 receptor agonists is not associated with cardiac or hemodynamic side effects, making the A3

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Introduction: Prior studies have examined heart rate and cardiovascular effects in the setting of a loading dose followed by short term infusions of dexmedetomidine in adults and in children. We sought to describe the cardiac effects in critically ill children related to continuous infusion of dexmedetomidine without a loading dose for up to 24 hours of infusion. Hypothesis: Continuous infusion of dexmedetomidine without a loading dose will have minimal cardiac effects. Methods: Hemodynamically stable intubated patients in the pediatric critical care unit were infused at a rate of 0.7ug/kg/hour of dexmedetomidine for sedation prior to anticipated extubation attempt within 24 hours. Patients received a minimum of 6 hours of infusion of drug. Cardiovascular effects were monitored up to 24 hours or until infusion discontinuation. EKG was monitored continuously and HR, SBP, DBP, MAP, RR, and O2 sat were recorded at baseline, at 5, 10, 15, 25, 35, 45, 55, and 65 mins and then hourly thereafter up to 24 hours. Patients were predetermined to exit from study by predetermined HR and BPs set-points <5% for age. Changes in hemodynamic variables were compared to baseline by paired t-test and repeated measures ANOVA analysis. Results: A total of 17 intubated patients, mean age of 3yrs, (range 0.25 -17 yrs), mean weight 20kg (range 2.8-84kg) received a dexmedetomidine infusion for a mean of 16 hours (range 6 to 24 hours). There were no conduction abnormalities. 1 patient required discontinuation of infusion for predetermined low HR limits at hour 13 (baseline HR 64, discontinued at HR 57) coinciding with planned extubation. Mean HR decreased by 9 bpm at 65 mins (p<0.05) but HR changes were not statistically significant at any other time frame. Similarly, there was no significant change in SBP, MAP and DBP during the observed time periods. Conclusions: Significant cardiovascular side effects were not noted in continuous sedation of dexmedetomidine without a loading dose in critically ill children for infusions up to 24 hours. Consideration to withhold a loading dose may result in more patient tolerability and provider comfort with managing infusions.

Differential effects of estrogen receptor ligands on regulation of dihydrotestosterone-induced cell proliferation in endothelial and prostate cancer cells.

Androgen deprivation therapy of prostate cancer with estrogens shows significant cardiovascular side-effects. To develop effective prostate cancer therapeutic agent(s) with minimal cardiovascular side-effects, we compared the effects of various estrogen receptor (ER) ligands on the modulation of dihydrotestosterone (DHT) actions in LAPC-4 and LNCaP prostate cancer cells and human aortic endothelial cells (HAECs). DHT stimulated the proliferation of HAEC, LAPC-4 and LNCaP cells and induced PSA mRNA expression in LAPC-4 cells. These DHT actions were differentially modulated by ER ligands in a cell-dependent manner. In LAPC-4 cells, knockdown of ERβ expression partially eliminated the βE2 inhibition of DHT-induced LAPC-4 cell proliferation, and a parallel change was observed between ER ligand modulation of DHT-induced cell proliferation and cyclin A expression. The obtained data suggest that it is feasible to develop effective agent(s) for prostate cancer therapy with minimal cardiovascular side-effects and 17α-estradiol and genistein are such potential agents.

110 EFFECTS OF GENISTEIN ON REGULATION OF DIHYDROTESTOSTERONE-INDUCED CELL PROLIFERATION IN ENDOTHELIAL AND PROSTATE CANCER CELLS

Grant Supports: This study was supported in part by a grant from National Institutes of Health (NIH) (UL1 RR024996) and a grant from the National Natural Science Foundation of China (No. 30873126) and a grant from the National Basic Research Program of China (2011CB5120010. Background: Androgen deprivation therapy of prostate cancer with estrogens shows significant cardiovascular side effects. This study was to examine the effect of genistein comparing to 17β − estradiol on modulation of androgen actions in human aortic endothelial cells (HAECs) and prostate cancer LAPC-4 and LNCaP cells. Methods: MTS, RT-PCR, and Western blot were used to detect cell proliferation, mRNA and protein expression of estrogen receptor (ER) gene, and cyclin A genes, respectively. Specific ERβ siRNA was synthesized and transfected to knockdown ERβ expression in prostate cancer cells. Results: Dihydrotestosterone (DHT) produced a time and dose-dependent induction of cell proliferation in HAEC, LAPC-4 and LNCaP cells. These DHT actions were inhibited by genistein in LAPC-4 and LNCaP cells but not in HAEC cells. While βE2 only attenuated the DHT-induced cell proliferation in HAEC and LAPC-4 cells without any inhibition of DHT-induced LNCaP cell proliferation. In LAPC-4 cells, knockdown of ERβ expression partially eliminated the blockade of DHT-induced cell proliferation. Conclusion: This study demonstrates that genistein may be a potential agent for prostate cancer therapy since genistein inhibits DHT-induced LAPC-4 and LNCaP prostate cancer cell proliferation but not HAEC cell growth. 17β − estradiol completely blocked DHT-induced cell growth in HAECs while inhibiting LAPC-4 cell proliferation, accounting for the side-effect of cardiovascular in Androgen deprivation therapy of prostate cancer. DHT-induced LNCaP prostate cancer cell proliferation can’t be attenuated by 17β − estradiol, suggesting 17β − estradiol is inactive in treating metastasized prostate cancer. ERβ played an important role in the modulation of androgen receptor actions.

Abstract P4-11-01: Cardiovascular Effects of Postmastectomy Irradiation Evident after 15 Years. Results from the South Sweden Breast Cancer Group's Randomised Studies SBII:1 with 25 Years of Follow-Up of Pre-and Postmenopausal Women with Stage II Breast Cancer

Abstract Background: The importance of radiotherapy for local control after mastectomy and breast conservation surgery is well established with a reduction in loco-regional recurrences by two thirds. In early radiotherapy trials the reduction of loco-regional failures did not result in a reduction of mortality due to increased late non-breast cancer mortality. The 2005 overview of radiotherapy by EBCTCG did however show a significantly improved survival with the addition of radiotherapy. Patients and methods: From 1978 to 1985 1100 patients with breast cancer stage II were included in two randomized trials of radiotherapy and adjuvant systemic treatment, SBII:1 pre (Cyclophosphamide per os one year) and SB II:1 post (Tamoxifen 10 mg x 3 one year). The radiotherapy technique and the outcome of these studies have been published previously (Arwidi Å et al. Acta Radiol Oncol 18:273, 1979, Killander F et al. Eur J Cancer 43:2100, 2007, Killander F et al. The Breast 18:309, 2009). An efficient reduction of loco-regional recurrences but no improvement in survival was reported at 25 years of follow-up. Linkage to the following population based Swedish registries was obtained: 1. National Population Registry 2. National Cause of Death Registry, and 3. Swedish Hospital Discharge Registry. Per protocol treatment was administered to 1044 patients, which form the basis for the analyses. We have included both underlying and contributing causes of death due to heart, cerebrovascular and lung disease. Results: After 15 years a significantly increased cardiac mortality was observed in irradiated patients compared to patients given systemic treatment only, and this effect prevailed at 25 years of follow-up. However not until 15 years after radiotherapy significantly higher cardiovascular mortality was observed. When analysing cerebro-vascular mortality the same pattern was seen. Cumulative incidence of non-breast cancer mortality after postmastectomy radiation in pre-and For lung diseases no increase in mortality was discernible. An interesting observation was that in premenopausal patients cardiovascular and cerebrovascular mortality were less pronounced, and that the latency period was longer than for postmenopausal patients. Analyses of all hospital admissions during follow-up showed neither increased overall morbidity nor increased cardiovascular morbidity. Discussion: The significant cardiovascular side effects of radiation observed with the radiotherapy technique used in these studies underlines the importance of careful dose planning and reduction in the volumes of the heart and large vessels, that are exposed to radiation. Extended follow-up is necessary for detection of these late effects. The longer latency and lower cardiovascular mortality in premenopausal patients may reflect lower sensitivity for radiation of normal tissue compared to postmenopausal women. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-01.

Insights into cardiovascular side-effects of modern anticancer therapeutics

Modern anticancer therapeutics can be associated with significant cardiovascular side-effects. Detection, risk assessment, and treatment of these unwanted effects are an important task for treating physicians. The purpose of this review is to focus on approved novel cancer therapeutics and discuss the most important cardiovascular side-effects, prognosis, and potential treatment. We will contrast these effects to those of conventional cardiotoxic chemotherapeutics. Modern anticancer therapeutics can cause cardiovascular ischemia, arrhythmias, cardiac dysfunction, heart failure, and arterial hypertension. Anti-HER2 drugs, or more specifically trastuzumab, can induce cardiac dysfunction and heart failure. Newer data show that these effects occur predominantly during treatment and patients who experience the side-effects often have a good cardiovascular prognosis. Antiangiogenic agents can induce arterial hypertension, arterial and venous thromboembolism, and less frequently QTc prolongation. Recent findings indicate that a high rate of patients treated with antivascular endothelial growth factor drugs develop arterial hypertension and may experience related complications. Preventive strategies or optimal treatment have been tested but controlled studies are missing. Cardiovascular side-effects of modern anticancer drugs can be a serious problem and need careful attention, prevention, or treatment.

Propofol as an induction agent for endotracheal intubation can cause significant arterial hypotension in preterm neonates

Propofol is gaining increasing popularity as induction agent for pediatric endotracheal intubation. Recently, propofol has been described for the first time as induction agent for endotracheal intubation in preterm neonates. Propofol seemed to be efficient, safe and ideally suited for the INSURE (Intubation SURfactant Extubation) procedure in preterm neonates. The purpose of this study was to document intubating conditions, vital signs, extubation times and outcome in preterm neonates receiving propofol as induction agent for the INSURE procedure. Preterm neonates with a gestational age of 29-32 weeks and respiratory distress were eligible for INSURE with propofol if their postnatal age was <8 h. Exclusion criteria were any kind of disease not allowing early extubation. There were 13 inborn neonates enrolled for INSURE, mean gestational age was 30 weeks + 3 days, and mean birth weight was 1428 g (range 1170-1780 g). We stopped our observational study ahead of time as a result of significant cardiovascular side effects. Propofol generally offered good intubating conditions, but we encountered severe problems with arterial hypotension. A low propofol bolus of 1 mg kg(-1) caused a distinctive decline in mean arterial blood pressure from 38 mmHg (range 29-42 mmHg) prior premedication to 24 mmHg (22-40 mmHg) 10 min after propofol application. Our experience with propofol as induction agent for endotracheal intubation in preterm neonates reveals distinctive cardiovascular effects, which represent an important risk factor for serious complications of prematurity like intraventricular hemorrhage or periventricular leucomalacia. Propofol should be used with caution in very preterm neonates with respiratory distress during the first hours of life.

Comorbidities in heart failure: a key issue

Comorbidities in heart failure: a key issue

Updates on Cytochrome P450-Mediated Cardiovascular Drug Interactions

Cytochrome P (CYP) 450 is a superfamily of hemoproteins that play an important role in the metabolism of steroid hormones, fatty acids, and many medications. Many agents used for management of cardiovascular diseases are substrates, inhibitors, or inducers of CYP450 enzymes.When two agents that are substrates, inhibitors, or inducers of CYP450 are administered together, drug interactions with significant clinical consequences may occur. This review discusses CYP450-mediated cardiovascular drug interactions as well as noncardiovascular drug interactions that produced significant cardiovascular side effects. The principles in predicting drug interactions are also discussed.

Androgendeprivation in der Therapie des Prostatakarzinoms

Androgen deprivation (ADT) by medical or surgical castration represents the standard therapeutic approach for managing prostate cancer (PCA) with systemic or locoregional metastases. Although ADT has been successfully used for more than 60 years, there are still major controversies with regard to the initiation (early versus delayed), type (complete versus monotherapy), and duration (continuous versus intermittent) of treatment. It is the purpose of this review to critically present the results of the various ADT options. Bilateral orchiectomy and subcutaneous application of luteinising hormone-releasing hormone (LHRH) analogues represent the guideline-recommended standard treatment for metastatic PCA, whereas estrogens are no longer recommended because of significant cardiovascular side effects despite comparable therapeutic efficacy. Antiandrogen monotherapy with bicalutamide is comparable to LHRH analogues in men with minimal tumour burden. However, survival rates are inferior in patients with extensive metastatic disease, in whom medical or surgical castration should be favoured. Complete ADT results in a median survival benefit of about 5% in men with low metastatic tumour burden, and it cannot be recommended for routine use. Early ADT is associated with a significant advantage in terms of symptom-free survival and prevention of metastasis-associated complications, but it does not result in a prolonged progression-free and overall survival when compared with delayed ADT. Despite encouraging results, intermittent ADT remains an experimental therapeutic approach that should be considered on an individual basis in carefully selected patients. Adjuvant ADT is still discussed controversially for men after radical prostatectomy, whereas it has become the standard approach in patients who undergo external beam radiation for locally advanced PCA.

Local and Systemic Effects of Endoluminal Pelvic Perfusion of Isoproterenol: A Dose Response Investigation in Pigs

Isoproterenol (Sygehus Apotekerne Danmark, Copenhagen, Denmark) is a beta-adrenergic agonist known to cause upper urinary tract relaxation. We studied the local effect on pelvic pressure and the systemic effects of endoluminal perfusion with isoproterenol in a porcine model. Pigs weighing 40 kg were studied. Catheters were placed in the renal pelvis for pressure measurement and perfusion, and a catheter was used to drain the bladder. Blood pressure and heart rate were recorded. In 6 pigs in group 1 the pelvic pressure increase was examined at increasing flow rates of 0, 2, 5, 8, 10 and 15 ml per minute with saline containing 0, 10(-3), 10(-2), 10(-1), 1 and 10 microg/ml isoproterenol. Blood values of isoproterenol were analyzed. In 6 pigs in group 2 the pelvis was perfused at a flow rate of 8 ml per minute with saline containing 0, 10(-5), 10(-4), 10(-3), 10(-2), 10(-1), 1 and 10 microg/ml isoproterenol. In group 1 endoluminal perfusion with isoproterenol inhibited the pelvic pressure increase due to perfusion at all concentrations of isoproterenol. At a perfusion rate of 8 ml per minute the maximal effect (a 78% decrease) was achieved using 0.1 microg/ml isoproterenol without cardiovascular side effects. In group 2 all isoproterenol concentrations caused significant inhibition of the pressure-flow relationship in a dose dependent matter. A 64% decrease in the pressure increase due to saline perfusion was achieved at 0.1 microg/ml isoproterenol without concomitant significant cardiovascular side effects. Isoproterenol was only detected in plasma during perfusion with 1 and 10 microg/ml isoproterenol, which caused significant cardiovascular side effects in the latter case. Isoproterenol significantly inhibits the pressure increase due to perfusion in the normal porcine renal pelvis without concomitant cardiovascular side effects. Isoproterenol is a safe drug in this porcine model and, hence, it is potentially useful during endourological procedures.

E.02.01 Psychopharmaca in the management of the consequences of disasters

This article reviews the cardiovascular effects of antidepressants drugs. Tricyclic antidepressants (TCAs) have the most significant cardiovascular side effects of any of the antidepressant agents. TCA side effects may be particularly burdensome or even life-threatening in patients with preexisting cardiovascular disease. Orthostatic hypotension is the most common cardiovascular side effect, and conduction disturbances and ventricular arrhythmias are the most life-threatening ones. TCAs' quinidine-like effects account for these conduction and rhythm disturbances. Monoamine oxidase inhibitors (MAOIs) commonly induce orthostatic hypotension. Hypertensive crises and the serotonin syndrome are the most serious problems associated with MAOI administration. MAOIs require dietary and concomitant drug restrictions to minimize adverse effects. Rarely, spontaneous severe hypertension may occur during MAOI administration. Bupropion administration may increase patients' blood pressure, particularly in those with preexisting hypertension. Trazodone may provoke ventricular arrhythmias. Nefazodone and the selective serotonin reuptake inhibitors (SSRIs) may contribute to drug-drug interactions that have significant cardiovascular adverse effects as a part of those interactions. Also, concomitant administration of SSRIs and MAOIs may produce the serotonin syndrome and vasomotor instability. Venlafaxine may increase supine diastolic blood pressure. According to the manufacturer, subjects taking this agent require blood pressure monitoring. Considering what we know about all antidepressants, periodic blood pressure assessment should be a routine part of the practice of psychiatry.

Effects of selective beta2 and beta3-adrenoceptor agonists on detrusor hyperreflexia in conscious cerebral infarcted rats.

We evaluated the effects of beta-adrenoceptor agonists on detrusor hyperreflexia in cerebral infarcted rats. To produce cerebral infarction in Sprague-Dawley rats the left middle cerebral artery was occluded by introducing a monofilament nylon thread into the artery. In sham operated rats the same artery was exposed but not occluded. After these operations cystometric and cardiovascular experiments were performed with no anesthesia or restraint. After the operation bladder capacity was significantly decreased and voiding pressure was significantly increased in cerebral infarcted but not in sham operated animals. The difference in cerebral infarcted and sham operated rats was significant for each parameter (p <0.01). Post-void residual urine volume was not affected in either group. In the cerebral infarction group intravenous administration of CL316243 ([R,R]-5-2-[[2-(3-chlorophenyl-2-hydroxyethyl]-amino]propyl] -1,3-benzodioxole-2,2-dicarboxylate) (Kissei Central Laboratories, Hotaka, Japan) a selective beta3-adrenoceptor agonist, significantly increased bladder capacity at 10 and 100 microgram./kg. without affecting voiding pressure or post-void residual urine volume. Procaterol, a selective beta2-adrenoceptor agonist, significantly increased bladder capacity and post-void residual urine volume at 10 microgram/kg. intravenously without affecting voiding pressure. In separate experiments procaterol (1 to 100 microgram./kg. intravenously) decreased mean blood pressure and increased heart rate in a dose dependent manner. In contrast, the effects of CL316243 (0.1 to 100 microgram./kg. intravenously) on mean blood pressure and heart rate were minimal. These results indicate that in cerebral infarcted rats detrusor hyperreflexia can be suppressed by the selective beta3-adrenoceptor agonist CL316243 without increasing post-void residual volume and without significant cardiovascular side effects. If the current results hold true in humans, selective beta3-adrenoceptor agonists may prove useful for treating detrusor hyperreflexia associated with cerebral infarction.

SEROTONIN 5-HT2C RECEPTOR AGONISTS: POTENTIAL FOR THE TREATMENT OF OBESITY

Obesity continues to be a burgeoning health problem worldwide. Before their removal from the market, fenfluramine and the more active enantiomer dexfenfluramine were considered to be among the most effective of weight loss agents. Much of the weight loss produced by fenfluramine was attributed to the direct activation of serotonin 5-HT(2C) receptors in the central nervous system via the desmethyl-metabolite of fenfluramine, norfenfluramine. Norfenfluramine, however, is non-selective, activating additional serotonin receptors, such as 5-HT(2A) and 5-HT(2B), which likely mediated the heart valve hypertrophy seen in many patients. Development of highly selective 5-HT(2C) agonists may recapitulate the clinical anti-obesity properties observed with fenfluramine while avoiding the significant cardiovascular and pulmonary side effects.

Tropisetron does not induce arrhythmia in chemo-naive otherwise healthy cancer patients

8259 Background: Chemotherapy induced emesis is one of the most distressing side effects of chemotherapy. Serotonin antagonists revolutionized its management. Although they are considered as relatively safe agents, they have significant cardiovascular side effects: Ondansetron and dolasetron are known to prolong corrected QT interval (QTc), which is a good predictor of arrhythmia. Package insert of tropisetron carries a warning against cardiovascular events and data on its cardiovascular effects are sparse. Our aim was to investigate the effects of tropisetron alone before combination chemotherapy on electrocardiographic parameters of patients with cancer. Methods: All the patients were monitorized with high resolution holter monitor (Ela Medical Inc.). Approximately 10 minutes after holter monitoring onset, 5 mg tropisetron was given intravenously, then 1 hour was allowed to elapse until chemotherapy administration to compare baseline values of QTc and QT dispersion with those during injection and the following 1 hour period in chemo-naive otherwise healthy cancer patients. Eleven patients, median age 45 years, without prior cardiovascular co-morbidities were enrolled. Ten (91%) patients were females with breast cancer and 1 (9%) was male with lymphoma. Results: In pre-tropisetron period, 3 patients (27.3%) had non-significant arrhythmias (2 supravetricular extrasystole [SVES] and 1 ventricular extrasystole [VES]). In during- and after-tropisetron period, 2 additional patients developed SVES and 3 developed bradycardia below 50 beats/minute (collectively 72.7%). Patients were asymptomatic and there was no statistical significance (Mc Nemar, p=0.063) in frequencies. QTc before (375msecs) and after (370 msecs) tropisetron injection were not different (Wilcoxon Signed Ranks Test, p=0.098), as was QT dispersion (30 vs. 40msecs, Wilcoxon Signed Ranks Test, p=0.180). There were no life threatening arrhythmias observed. Conclusions: Tropisetron did not seem to induce significant or non-significant arrhythmias. Predictors of arrhythmias were not affected, either. However, the number of patients is few and we continue to enroll patients. No significant financial relationships to disclose.