Sertraline Causes Strong Coronary Vasodilation: Possible Relevance for Cardioprotection by Selective Serotonin Reuptake Inhibitors

Summary Objective: Although Selective Serotonin Reuptake Inhibitors (SSRIs) are important antidepressant drugs, knowledge of their vaso active effects is limited. Vaso active effects of the SSRI sertraline were studied in rings of rat aorta, human Internal Mammary Arteries (IMAs) and in Langendorff perfused rat hearts.Methods: The effects of sertraline (0.1 to 300 mol L^{– 1}) on precontracted rat aortic and IMA rings were evaluated in organ bath chambers. Precontraction was elicited by serotonin (5-HT; 10 mol L^{– 1}), phenylephrine (PE; 10 mol L^{– 1}) and potassium chloride (KCl; 50 mmol L^{– 1}). In addition, the effects of sertraline on PE induced contraction curves were established by subjecting vascular rings to increasing doses of PE (1 nmol L^{– 1} to 10 mol L^{– 1}) in the presence of sertraline or vehicle. Finally, the effects of sertraline on ex vivo coronary flow in rat hearts were examined using a retrograde Langendorff perfusion model.Results: Sertraline elicited dose-dependent relaxation, independent of the substance used for precontraction (p < 0.025). Sertraline showed a rightward shift of dose-response curves to PE (p < 0.01). Vasodilatory effects of SSRIs were endothelium independent. In perfused rat hearts, sertraline (0.3 to 10 mol L^{– 1}) showed a concentration-dependent increase in coronary flow that returned to baseline levels after wash-out of the antidepressant (p = 0.005).Conclusions: One of the SSRIs, sertraline, showed marked vasodilatory effects in rat aorta and human IMAs. Sertraline elicited vasodilatation in coronary arteries during perfusion of rat hearts. These hemodynamic effects may explain the observed beneficial effects in myocardial ischemia and infarction.     

A case of gastic antral vascular ectasia—increase of neuroendocrine cells in the antrum

We report an 82-year-old woman with severe iron deficiency anemia who was found to have gastric antral vascular ectasia (GAVE). As the required repeated blood transfusion for the anemia and did not respond to various medical treatments, she was referred for antrectomy. The pathogenesis of GAVE is still obscure and may involve many factors. In our patient, immunohistochemical studies of the resected stomach disclosed a marked increase of neuroendocrine cells. The majority of these hyperplastic neuroendocrine cells, furthermore, showed immunoreactivity for 5-hydroxytryptamine (serotonin). These findings suggest that neuroendocrine mediators, serotonin in particular, may have been responsible for the local vasodilatation.     

儿宝颗粒对厌食症大鼠模型血中5-HT、NO及空肠段SP、VIP、SS表达的影响

[目的]从胃肠激素水平探讨健脾运脾复方儿宝颗粒治疗小儿厌食症的作用机制.[方法]用饮食不当法复制小儿厌食症大鼠模型,通过观察外周血中5-羟色胺(5-HT)、一氧化氮(NO)、肠内P物质(SP)、血管活性肠肽(VIP)、生长抑制素(SS)水平的变化,以及胃肠病理形态学改变,观察儿宝颗粒的作用.[结果]儿宝颗粒可以改善厌食症大鼠外周血5-HT、NO、SP、SS、VIP水平变化及胃肠黏膜病理形态.[结论]儿宝颗粒可改善厌食症大鼠胃肠黏膜的病理形态学改变,并对5-HT、NO、SP、SS、VIP具有调节与平衡作用.     

Substance P analogs displace sigma binding differentially in the brain and spinal cord of the adult mouse

We have previously observed similarities in the behavioral effects produced by the NH₂-terminus of the undecapeptide substance P (SP) and by 1,3-di(2-tolyl)-guanidine (DTG) in the adult mouse. The present series of experiments indicate differences in the rank-order of potency of sigma ligands [DTG; haloperidol (HAL)], SP analogs [SP; SP(1-7); SP(5-11); [D-Pro², D-Phe⁷]-SP(1-7) (D-SP(1-7))] and miscellaneous compounds [morphine (MOR), naloxone (NAL)] at competing for [³H]-DTG binding sites in the mouse brain and spinal cordin vitro: Brain; DTG = HAL SP = MOR = NAL SP(1-7) D-SP(1-7) SP(5-11): Spinal cord; DTG = HAL SP(1-7) = MOR = NAL SP D-SP(1-7) = SP(5-11). The observed difference in the rank-order potencies of the displacing ligands at these same binding sites supports the notion of two distinct populations of sigma binding sites in these tissues in the adult mouse. Given the low (micromolar) potency of SP analogs at displacing [³H]-DTG binding in the present series of experiments, it is unlikely that the similar behavioral effects we have previously observed elicited by SP(1-7) and DTG in the adult mouse are a result of a direct action of SP(1-7) at the sigma binding site.     

PCTH: A Novel Orally Active Chelator for the Treatment of Iron Overload Disease

Our laboratories have prepared a novel class of iron (Fe) chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) class. This article will review the iron chelation efficacy of this series of chelators, both in cell culture and in animal models. Several PCIH analogs were shown to be effective at inducing iron mobilization and preventing iron uptake from the iron-transport protein, transferrin. Moreover, several of these ligands were effective at permeating the mitochondrion and inducing iron release. Studies in mice demonstrated that the PCIH analog, PCTH, was orally active and well tolerated by mice at doses ranging from 50 to 100 mg kg^?1, twice daily (b.d.). A dose-dependent increase in fecal ⁵⁹Fe excretion was observed in the PCTH-treated group. This level of iron excretion was similar to that found for the orally effective chelators, pyridoxal isonicotinoyl hydrazone (PIH) and deferiprone (L1). The PCIH group of ligands clearly has the potential for the treatment of β-thalassemia (thal) and Friedreich's Ataxia (FA).     

Current view: intestinal stem cells and signaling

Studies using mice have yielded significant amounts of information regarding signaling pathways, such as Wnt, bone morphogenic protein, PtdIns(3,4,5) kinase, and Notch, involved in intestinal development and homeostasis, including stem cell regulation and lineage specification and maturation. However, attempts to model signals definitively that control intestinal stem cells have been difficult because of a long-standing and recently reenergized debate surrounding their location. Although crypt-based columnar cells have been recently shown to display self-renewal and multipotential capacity, a large body of evidence supports long-term label-retaining cells, located on average at the +4 position just above the Paneth cells, as putative stem cells. Herein, we propose that both these cell types represent true intestinal stem cells maintained in different states (quiescent vs actively cycling), presumably via interactions with different microenvironments. Finally, we review current findings regarding the roles of Wnt, bone morphogenic protein, PtdIns(3,4,5) kinase, and Notch pathways within the intestine.     

Gastric metastases from invasive primary mucosal epithelioid malignant melanoma of the hard palate: report of the first case in the English literature

Information on the 5-hydroxytryptamine type 3 receptor antagonist cilansetron is scarce and most studies have only been published in abstract form. Results from preclinical and two dose-finding studies have suggested that cilansetron could be effective in the treatment of patients with diarrhea-predominant irritable bowel syndrome. Two large efficacy and safety trials extending over 3 and 6 months revealed a superiority of cilansetron 2 mg orally three-times daily over placebo reflected by numbers needed to treat of 4.8 and 5.6, respectively, for the parameter proportion of patients reporting adequate symptom relief. Dose-ranging studies showed no dose–response relationship. Cilansetron tended to induce constipation but, apart from transient ischemic colitis in four out of 1484 cases, no serious adverse effects were observed. Further trials are underway to fully determine the role of cilansetron in the treatment of diarrhea-predominant irritable bowel syndrome.     

Serotonergic function, behavioral disinhibition, and negative affect in children of alcoholics: the moderating effects of puberty

BACKGROUND: Serotonergic (5-HT) dysfunction has been implicated in both behavioral disinhibition and negative affect in adults. Although our group's previous work found decreased whole blood 5-HT in high versus low behavior problem children of alcoholics, some child/adolescent studies report conflicting results, and 5-HT's role in negative affect has been largely unexamined. Age-related developmental factors may play a role in these relationships. METHODS: This report is from an ongoing prospective study of the development of risk for alcohol abuse/dependence and other problematic outcomes in a sample of families subtyped by father's alcoholism classification. The present study extends previous work and examines relationships between whole blood 5-HT and both child behavioral disinhibition (an aggression index from the Child Behavior Checklist) and negative affect (Child Behavior Checklist Anxious/Depressed scale) in offspring from 47 families (N = 45 boys and 17 girls; mean age = 10.88+/-2.03 yr). RESULTS: The most important finding was that puberty moderated relationships between 5-HT and both behavioral disinhibition and negative affect with a relationship for pubescent children (n = 14, r = -0.54, p = 0.05: r = -0.57,p = 0.04, respectively) but no relationship for prepubescent children (n = 48, r = 0.05, p = 0.75; r = -0.15, p = 0.31, respectively). CONCLUSIONS: The moderating effects of puberty may help clarify inconsistencies in child/adolescent literature. Furthermore, there appears to be a relationship between 5-HT and negative affect which parallels that between 5-HT and behavioral disinhibition. Pubertal status may be an important variable to evaluate as a moderator in relation to the developmental context of the role 5-HT dysfunction may play in various models of behavior related to alcoholism over the early life course.     

The surface glycoconjugates of parasitic protozoa: potential targets for new drugs

Protozoan parasites are the cause of many diseases in humans and their domestic livestock. Glycoconjugates (i.e. glycoproteins, glycolipids) on the cell surface of these extremely diverse and very primative eukaryotes play a crucial role in determining the specificity of the host-parasite interaction and in protecting the parasites within their respective hosts. These molecules frequently share a common structural feature in that they are attached to the plasma membrane via a glycosylphosphatidylinositol (GPI) glycolipid. While GPI protein-membrane anchors are ubiquitous among the eukaryotes, they are used with exceptionally high frequency in the protozoa. Some kinetopastidparasites also synthesise very high levels of GPI-related glycolipids that are not linked to protein. Thus GPI-anchored molecules or free GPI glycolipids tend to dominate the cell surface molecular architecture of these organisms. The highly elevated levels and specialised nature of GPI metabolism in the kinetoplastid and other parasites suggests that the GPI biosynthetic pathway might be a good target for the development of new chemotherapeutic agents. This article reviews the wide range of functions that GPI protein anchors and GPI-related glycolipids are thought to perform in these organisms and some aspects of their biosynthesj?     

Exploring the Human Cytomegalovirus Core Nuclear Egress Complex as a Novel Antiviral Target: A New Type of Small Molecule Inhibitors

Nuclear egress is an essential process in the replication of human cytomegalovirus (HCMV), as it enables the migration of newly formed viral capsids from the nucleus into the cytoplasm. Inhibition of the HCMV core nuclear egress complex (core NEC), composed of viral proteins pUL50 and pUL53, has been proposed as a potential new target for the treatment of HCMV infection and disease. Here, we present a new type of small molecule inhibitors of HCMV core NEC formation, which inhibit the pUL50-pUL53 interaction at nanomolar concentrations. These inhibitors, i.e., verteporfin and merbromin, were identified through the screening of the Prestwick Chemical Library^® of approved drug compounds. The inhibitory effect of merbromin is both compound- and target-specific, as no inhibition was seen for other mercury-organic compounds. Furthermore, merbromin does not inhibit an unrelated protein–protein interaction either. More importantly, merbromin was found to inhibit HCMV infection of cells in three different assays, as well as to disrupt HCMV NEC nuclear rim formation. Thus, while not being an ideal drug candidate by itself, merbromin may serve as a blueprint for small molecules with high HCMV core NEC inhibitory potential, as candidates for novel anti-herpesviral drugs.     

Barnidipine, a Novel Calcium Antagonist for Once-Daily Treatment of Hypertension: A Multicenter, Double-Blind, Placebo-Controlled, Dose-Ranging Study

The antihypertensive effects and tolerance of once-daily barnidipine, a novel dihydropyridine calcium antagonist, were evaluated. A total of 190 patients with a sitting diastolic blood pressure (DBP) of 95–114 mmHg were investigated in this multicenter, double-blind, placebo-controlled, dose-ranging study. After a 4-week single-blind placeborun-in period, patients were randomized to placebo or barnidipine (10 mg, 20 mg, or 30 mg modified release capsules) once daily for 6 weeks. Nonresponders (sitting DBP ≥90 mmHg and a decrease of <10 mmHg) were treated for an additional 6 weeks with a dose increase of 10 mg. At each clinic visit, sitting and standing blood pressure and heart rate were measured approximately 24 hours after the last dose of study drug was taken. Compared with placebo, barnidipine lowered blood pressure, with a trend toward a dose–response relationship over the dose range 10–30 mg. A dose increment of 10 mg in nonresponders resulted in additional reductions in blood pressure. At the end of the active treatment period, the responder rates were 41% and 57% for 10 mg and 20 mg barnidipine, respectively. Heart rate in both sitting and standing positions was not affected by barnidipine. Treatment with barnidipine was well tolerated, and the incidence of adverse events was dose related and consistent with vasodilatation. In conclusion, barnidipine (10–30 mg) administered once daily is well tolerated and reduces blood pressure inpatients with mild to moderate hypertension. On behalf of the Dutch Barnidipine Multicenter Study Group On behalf of the Dutch Barnidipine Multicenter Study Group This revised version was published online in July 2006 with corrections to the Cover Date.     

A stepwise protocol for the treatment of refractory gastroesophageal reflux-induced chronic cough

Background

Refractory gastroesophageal reflux-induced chronic cough (GERC) is difficult to manage. The purpose of the study is to evaluate the efficacy of a novel stepwise protocol for treating this condition.

Methods

A total of 103 consecutive patients with suspected refractory reflux-induced chronic cough failing to a standard anti-reflux therapy were treated with a stepwise therapy. Treatment commences with high-dose omeprazole and, if necessary, is escalated to subsequent sequential treatment with ranitidine and finally baclofen. The primary end-point was overall cough resolution, and the secondary end-point was cough resolution after each treatment step.

Results

High-dose omeprazole eliminated or improved cough in 28.1% of patients (n=29). Further stepwise of treatment with the addition of ranitide yielded a favorable response in an additional 12.6% (n=13) of patients, and subsequent escalation to baclofen provoked response in another 36.9% (n=38) of patients. Overall, this stepwise protocol was successful in 77.6% (n=80) of patients. The diurnal cough symptom score fell from 3 [1] to 1 [0] (Z=6.316, P=0.000), and the nocturnal cough symptom score decreased from 1 [1] to 0 [1] (Z=–4.511, P=0.000), with a corresponding reduction in the Gastroesophageal Reflux Diagnostic Questionnaire score from 8.6±1.7 to 6.8±0.7 (t=3.612, P=0.000). Conversely, the cough threshold C2 to capsaicin was increased from 0.49 (0.49) µmol/L to 1.95 (2.92) µmol/L (Z=–5.892, P=0.000), and the cough threshold C5 was increased from 1.95 (2.92) µmol/L to 7.8 (5.85) µmol/L (Z=–5.171, P=0.000).

Conclusions

Sequential stepwise anti-reflux therapy is a useful therapeutic strategy for refractory reflux-induced chronic cough.     

Involvement of nerves and calcium channels in the intestinal response to Clostridium difficile toxin A: an experimental study in rats in vivo

BACKGROUND: The involvement of nerves and calcium channels in the intestinal response to Clostridium difficile toxin A (luminal concentration 1 or 15 microg/ml) was studied in the small intestine of rats in vivo. METHODS: Inflammation was quantified by estimating myeloperoxidase (MPO) activity in the intestinal lumen, extravascular accumulation of Evan's blue (EB) in the intestine, and number of red blood cells (RBCs) in veins in histological sections. Intestinal damage was estimated using a histological grading system. In some experiments net fluid transport was recorded using a gravimetric technique. RESULTS: In acutely denervated intestines, toxin A caused marked destruction of the villi, increased luminal release of MPO activity, and augmentation of intestinal content of EB and venous RBCs. Denervating the intestine 3-4 weeks prior to the actual experiment prevented the development of villus damage and significantly decreased the number of RBCs in intestinal veins in experiments with a low toxin concentration, whereas no effect was demonstrated on luminal MPO activity. Using a high toxin concentration, chronic denervation decreased only the number of RBCs. Pretreatment with hexamethonium (low toxin concentration; acute denervation) attenuated the effect of toxin A on morphology, luminal MPO activity, and number of RBCs. Pretreatment with nifedipine (low toxin concentration; acute denervation) significantly decreased intestinal MPO activity and number of RBCs. Tissue accumulation of EB was not influenced by experimental manipulation. Net fluid transport was measured in experiments exposing the intestinal mucosa to a high toxin concentration. Fluid secretion caused by the toxin was significantly attenuated by intravenous hexamethonium whereas no effect was observed after administration of nifedipine or granisetron. CONCLUSIONS: At a low toxin concentration, intramural reflexes are involved in the inflammatory response whereas axon reflexes contribute to tissue damage. At a high toxin concentration no nervous involvement in the toxin A response was demonstrated except for fluid secretion evoked by the toxin.     

NS5A inhibitors for the treatment of hepatitis C infection

Today, we are witnessing a new era for the treatment of hepatitis C with excellent rates of virologic response and very good safety profiles. Among the many classes of direct‐acting antivirals, the inhibitors of nonstructural protein 5A are particularly interesting. NS5A is a phosphorylated protein with a relevant role in viral replication. HCV‐NS5A inhibitors show high potency, very good safety profile and high barrier to resistance. The amazing in vitro effectiveness of this class is associated with great efficacy in clinical trials in combination protocols with antivirals of other classes, with sustained virological response (SVR) obtained in more than 90% of patients. Herein, we sought to review the current knowledge regarding the NS5A protease complex inhibitors with special emphasis on clinical efficacy and development of viral resistance.