Comparative antidopaminergic properties of thioridazine, mesoridazine and sulforidazine on the corpus striatum

The functional antidopaminergic potencies of the atypical antipsychotic drug thioridazine (THD), as well as its active metabolites mesoridazine (MES) and sulforidazine (SUL), were assessed by testing their blockade of the inhibitory effects of endogenous dopamine (DA) or apomorphine on the electrically evoked release of radiolabeled DA and acetylcholine (ACh) from perfused rabbit striatal slices. These functional comparisons (reflecting presynaptic and postsynaptic DA receptors, respectively) were correlated with potency estimations of these drugs in competing for D2 DA receptors (i.e., [3H]spiperone binding sites) in rabbit striatal homogenates. Similar orders of potency (SUL greater than MES much greater than THD) were found for blockade of pre- and postsynaptic DA receptors modulating DA and ACh release, respectively, as well as in competing for [3H]spiperone binding sites in the striatum. MES, SUL and haloperidol were 2 to 3 times more potent at DA release modulatory receptors than postsynaptic DA receptors. In contrast, THD was 8 times more potent at antagonizing the apomorphine-induced inhibition of DA release than against apomorphine's effect on ACh release. THD was virtually inactive in antagonizing the inhibition of ACh release induced when nomifensine was used to increase endogenous synaptic DA, despite significantly antagonizing these effects on DA release in the same slices. Together, these data indicate that: 1) MES and SUL are responsible for a significant part of the antidopaminergic effects attributed to THD; 2) THD should produce less cholinergic activation than other neuroleptics; and 3) that nonreceptor-mediated effects at high THD concentrations may mask effects due to receptor blockade.     

Ginseng on hyperglycemia: effects and mechanisms

It has been reported that American ginseng attenuates hyperglycemia and may present itself as a supplement to diabetes therapy. However, the lack of standardization in the usage of ginseng root leads to inconclusive results when applied to diabetes treatment. The mechanisms of American ginseng root in the treatment of diabetes remains a mystery. This greatly limits the effective utilization of American ginseng in facilitating diabetic therapy. Initiating studies have shown that American ginseng increases insulin production and reduces cell death in pancreatic beta-cells. Also, studies have revealed American ginseng's ability to decrease blood glucose in type II diabetes patients as well as in streptozotocin-induced diabetic animals (STZ-diabetic mice). These data suggest that effects of ginseng in improving hyperglycemia may alter mitochondrial function as well as apoptosis cascades to ensure cell viability in pancreatic islet cells. This review briefly summarizes current knowledge of ginseng components and clinical studies related to diabetes. Further research will be needed to explore and identify the component(s) of ginseng, which may be responsible for the beneficial effects observed in animal studies which could then be extrapolated to human islets.     

Selective vulnerability of glutathione metabolism and cellular defense mechanisms in rat striatum to manganese

The present findings provide experimental evidence for the hypothesis that compromised cellular defense mechanisms, i.e., glutathione (GSH), GSH-peroxidase and catalase in the brain may be involved in neuronal degeneration caused by manganese (Mn) neurotoxicity. Moreover, data are presented demonstrating that the striatum is particularly susceptible to the deleterious effects of Mn. Specifically, exposure to subchronic MnCl2 produced significant reductions in GSH-peroxidase activity in the cytosol and mitochondrial fractions of the whole brain and the striatum. The decrease in GSH-peroxidase was most pronounced in the mitochondrial fraction of the striatum where the activity was reduced to 35% of the control. Catalase activity was also decreased in the striatum of rats treated with Mn but not in the whole brain. GSH content was markedly depleted (20% of the control) in the striatum, although only modestly decreased in whole brain (80% of the control). The alterations in the above parameters were accompanied by depletion of dopamine and dopamine metabolites in the striatum. The treatment of rats with Mn also decreased the activity of oxidized glutathione-reductase; the same treatment increased the activity of gamma-glutamyltranspeptidase. The activity of gamma-glutamylcysteine synthetase was not altered by Mn. The possible relevancy of the findings of this study to understanding the mechanism of Mn neurotoxicity of dopamine systems is discussed.     

Studies on the interaction between phagocytes and tubercle bacilli. III. Some metabolic effects in guinea pigs associated with infection with tubercle bacilli

In continuing studies concerning the interactions between phagocytes and tubercle bacilli the effect of tuberculous infection on respiration and glucose utilization was investigated in guinea pigs. Peritoneal exudates rich in polymorphonuclear leucocytes, derived from guinea pigs infected with tubercle bacilli, had a significantly higher rate of respiration than the same cells from normal animals. The difference between cells from normal and infected animals was greater when the animals were infected with a virulent strain (Vallée) than when infected with an attenuated one (R1Rv or BCG). By the use of glucose labelled with C¹⁴ at position 1 or 6, or uniformly labelled glucose, it was established that this difference in oxygen uptake between normal and infected cells was probably not caused by a difference in the pathway of glucose utilization. Similarly, the respiration of liver and kidney slices from normal and infected guinea pigs was compared and it was found that liver slices showed differences similar to those shown by leucocytes, but that the kidney slices did not. The possibility has not been ruled out that the difference in rate of respiration of liver slices due to infection might be caused by tuberculous lesions in the livers of infected animals. The mononuclear cells which invade the liver have a higher rate of oxygen uptake than liver cells. The rate of glucose utilization and the total amount of CO₂ produced was also determined in intact guinea pigs. Both functions were found not to differ significantly in normal and infected animals. The rate of production of CO₂ from C₁ and C₆ of glucose was the same in both groups of animals. The ratio of the rate of production of C¹⁴O₂ from C₁ and C₆ of glucose by the whole animal was found to be about 1.35. It was found to be much higher with polymorphonuclear leucocytes (C₁/C₆ = 8 in the absence of serum). During the process of phagocytosis this ratio increased from about 25 to about 130 (in the presence of 2 per cent serum) indicating an increase in the direct oxidative pathway of glucose utilization during stimulated cellular activity.     

Molecular mechanisms in the actions of morphine and viminol (R2) on rat striatum.

Analgesic doses of morphine and viminol R2 increase the turnover rate of dopamine (DA) in rat striatum but fail to increase the striatal concentration of adenosine 3',5'-monophosphate (cAMP) or the affinity of tyrosine hydroxylase (TH) for the pteridine cofactor. When morphine is added to striatal homogenates, it changes neither the basal activity of adenylate cyclase nor the enzyme activation by DA. Similarly to morphine, haloperidol enhances the turnover rate of striatal DA, but unlike morphine it increases the affinity of TH for the pteridine cofactor and blocks the in vitro activation of striatal adenylacte cyclase by DA. Morphine (52 mumol/kg i.p.), viminol R2 (7 mumol/kg i.p.) or haloperidol (2.6 mumol/kg i.p.) fails to increase the striatal cAMP contrations. However (+)-amphetamine (4.8 mumol/kg i.p.) increases DA turnover rate and the striatal cAMP content, but, in doses up to 12.8 mumol/kg i.p., it fails to change the affinity of TH for the pteridine cofactor. This study shows that although (+)-amphetamine, haloperidol and morphine increase the turnover rate of striatal DA each drug possesses a specific profile in its action on molecular mechanisms that control the function of striatal dopaminergic synapses.     

Comparison of the effects of clonidine,loperamide and metoclopramide in two models of gastric emptying in the rat

Several methods are used to evaluate gastric emptying (GE) in rats, which is an important endpoint in preclinical drug development. Although phenol red model or monitoring of plasma acetaminophen levels are well‐established procedures for GE assessment, their capacity to detect the effects of pharmacological agents has rarely been compared. This study was therefore designed to evaluate clonidine with loperamide and metoclopramide in the two test models. Rats were administered phenol red or acetaminophen test meals. The remaining amount of phenol red in the stomach or the time course of plasma acetaminophen levels was then measured. In the phenol red test, loperamide (8 mg/kg, p.o.) and clonidine (100 μg/kg, s.c.) decreased GE (?88 and ?42%, P < 0.001 and P < 0.01, respectively). Metoclopramide (10 mg/kg, s.c.) accelerated GE (+42%, P < 0.01). Loperamide reduced acetaminophen plasma levels (?45% at T15 min, P < 0.05), suggesting a delayed GE. Clonidine and metoclopramide increased acetaminophen plasma levels (+115 and +152% at T15 min, P < 0.05 and P < 0.001, respectively), suggesting an accelerated GE. The three substances did not affect plasma acetaminophen levels when acetaminophen was subcutaneously injected, thereby suggesting that acetaminophen metabolism/excretion was not modified. Whereas the phenol red test allows the evaluation of GE at a single time point, the measurement of plasma acetaminophen levels over the time would appear more informative. Nevertheless, the fact that clonidine, in contrast to expectation, increased plasma acetaminophen levels, suggests that data obtained with the acetaminophen method should be interpreted with caution for new chemical entities susceptible to modify absorption of acetaminophen from the small intestine.     

The effects of metoclopramide in modifying the response of isolated guinea-pig ileum to various agonists.

Metoclopramide has a dual effect on intestinal smooth muscle. Low concentrations of metoclopramide cause potentiation of the responses to substance P, acetylcholine, histamine and barium chloride on the guinea-pig ileum. Higher concentrations produce a depression of smooth muscle responses which is characteristic of the tertiary amine local anesthetics. Neural pathways are involved in the mechanism of potentiation, since the enhancement of the responses to the agonists is abolished by tetrodotoxin. Atropine partially antagonizes the potentiating effect of metoclopramide implying that activation of muscarinic receptors is a contributing factor, but this does not fully explain the potentiation.     

Subcutaneous metoclopramide in the treatment of symptomatic gastroparesis: clinical efficacy and pharmacokinetics

We investigated the safety and efficacy of short-term s.c. administration of metoclopramide in the treatment of symptomatic gastric stasis. Ten patients with gastroparesis, documented by abnormal solid phase radionuclide gastric emptying study, were treated with 10 mg (2 ml) of s.c. metoclopramide every 6 hr for 3 days. Patients gave themselves the injections as outpatients. Questionnaires were then completed concerning symptom relief, local side effects and adverse reactions. A repeat gastric emptying study was obtained immediately after the last dose of metoclopramide. Serum metoclopramide concentrations were obtained at trough, 1, 2, 3, 4 and 5 hr postadministration and serum prolactin levels at trough, 1 and 3 hr. Pharmacokinetic analysis showed mean peak metoclopramide concentration at 30 min of 99.7 +/- 47.1 ng/ml with measured levels of 93.9 +/- 106.83 ng/ml at 60 min and return to trough values by 4 hr; trough prolactins remained elevated above normal values. Gastric stasis improved from a base-line retention of 78.7% of radioisotope at 2 hr to 72.5% after 3 days of therapy (P = .65). Eight patients reported significant improvement in symptomology and two patients reported lessening of symptoms such as nausea, vomiting, bloating, abdominal pain, heartburn and vomiting. The side effects were minimal and did not interfere with completion of the protocol. We demonstrated that s.c. administration of metoclopramide was well accepted by patients and resulted in subjective and objective improvement of gastric stasis. In addition, serum metoclopramide concentrations were comparable with other parenteral routes of administration. Furthermore, serum prolactin levels may provide both a bioassay of efficacy and a marker for monitoring compliance.     

Placebo and nocebo effects on itch: effects,mechanisms, and predictors

Placebo and nocebo effects have been extensively studied in the field of pain and more recently also on itch. In accordance with placebo research on pain, expectancy learning via verbal suggestion or conditioning has shown to induce placebo and nocebo effects on itch, in which the combination of both procedures seems most promising. Moreover, itch can also be transferred ‘contagiously’ in which suggestion and social behavioural learning seem to play a role. With regard to predictors of placebo and nocebo responding on itch and contagious itch, preliminary evidence suggests a role for individual psychological characteristics and personality traits regarding negative outcome expectancies. Although findings on placebo and nocebo effects on itch seem comparable to pain, we have only just begun to understand the underlying mechanisms and predictors of placebo and nocebo effects on itch.     

Chronic pelvic pain: causes, mechanisms and effects

This article outlines the causes, mechanisms and effects of chronic pelvic pain. It provides a basic overview of the biopsychosocial treatment options delivered by a multidisciplinary team. The focus is on actively listening to patients to validate their pain experience and provide information on their condition. A combination of pain management psychology and pain management physiotherapy, medical interventions and medication are used to improve the quality of life of patients with this distressing condition.     

Stem cell mechanisms and paracrine effects: potential in cardiac surgery

Heart disease remains the leading cause of death in the industrialized world. Stem cell therapy is a promising treatment modality for injured cardiac tissue. A novel mechanism for this cardioprotection may include paracrine actions. Cardiac surgery represents the unique situation where preischemia and postischemia treatment modalities exist that may use stem cell paracrine protection. This review (1) recalls the history of stem cells in cardiac disease and the unraveling of its mechanistic basis for protection, (2) outlines the pathways for stem cell-mediated paracrine protection, (3) highlights the signaling factors expressed, (4) explores the potential of using stem cells clinically in cardiac surgery, and (5) summarizes all human stem cell studies in cardiac disease to date.     

Antioxidation of 2-phenylbenzofuran derivatives: structural-electronic effects and mechanisms

Stilbenoid-type 2-phenylbenzofuran derivatives, which are widely distributed in nature, are now promising antioxidant agents. In the present study, a quantum computational approach principally based on the DFT/B3LYP method with the 6-311++G(d,p) basis set was used to shed light on free radical scavenging for the isolated compounds stemofurans A-K and S-W. On the basis of the findings and from a thermodynamic perspective, the antioxidant activity of all studied compounds in the gaseous phase was mostly controlled by the O–H bond dissociation enthalpy (BDE), consistent with the hydrogen atom transfer (HAT) mechanism. The solvent effect was investigated, and the hydroxyl radicals of these studied compounds possessed the lowest proton affinity (PA) enthalpy and the sequential proton loss electron transfer (SPLET) pathway occurred in water, methanol and acetone. The studied compounds interacted with DPPH radicals, which is kinetic evidence of the involvement of two intermediates and one transition state. From both thermodynamics and kinetics perspectives, it can be proposed that stemofuran U is likely to be a leader compound in antioxidant drug development due to the presence of a 4′-OH moiety. Regarding the structure–bioactivity relationship, methylation can lead to a decrease in BDE.

The plausible antioxidative mechanism of 2-phenylbenzofurans based on DFT calculation.     

Cisapride and metoclopramide in the treatment of gastroesophageal reflux disease

In a double-blind, randomized study, the clinical effects of 5 mg and 10 mg of cisapride three times daily were compared with those of 10 mg of metoclopramide three times daily in 114 patients with symptoms of gastroesophageal reflux, mainly diurnal and nocturnal heartburn and regurgitation. The symptoms significantly (P less than 0.001) improved in the three groups; the mean severity score decreased by at least 78% after four weeks of treatment. Initial symptoms were more severe in the cisapride-treated patients, especially in those receiving 10 mg three times daily; however, the patients' condition after four weeks was similar in the three groups. Central nervous system side effects were reported by one patient from each of the cisapride-treated groups and by nine of the 43 metoclopramide-treated patients (P less than 0.02). Six metoclopramide-treated patients and one cisapride-treated patient dropped out of the study because of side effects. These findings favor the use of cisapride when prokinetic treatment of gastroesophageal reflux is considered.     

Vasopressin receptor antagonists: mechanisms of action and potential effects in heart failure

Increased arginine vasopressin (AVP) secretion in heart failure may lead to vasoconstriction, left ventricular remodeling, and water retention-actions that promote afterload, preload, and hyponatremia and thereby cause disease progression. Interfering with AVP-mediated signaling pharmacologically may be beneficial in heart failure. Selective antagonism of the vasopressin 2 (V2) receptor may facilitate a safe diuresis and normalize low serum sodium levels, as demonstrated in preliminary clinical trials. Pure V2 antagonism, however, may stimulate AVP secretion and enhance V1a signaling, while pure V1a receptor antagonism may lead to unwanted V2 stimulation and secondary water retention and volume expansion. Combined V1a and V2 receptor antagonism could potentially prove advantageous as a therapy for heart failure by acting synergistically to facilitate diuresis and improve hemodynamics.     

Vascular effects of adiponectin: molecular mechanisms and potential therapeutic intervention

Adiponectin is a major adipocyte-secreted adipokine abundantly present in the circulation as three distinct oligomeric complexes. In addition to its role as an insulin sensitizer, mounting evidence suggests that adiponectin is an important player in maintaining vascular homoeostasis. Numerous epidemiological studies based on different ethnic groups have identified adiponectin deficiency (hypoadiponectinaemia) as an independent risk factor for endothelial dysfunction, hypertension, coronary heart disease, myocardial infarction and other cardiovascular complications. Conversely, elevation of circulating adiponectin concentrations by either genetic or pharmacological approaches can alleviate various vascular dysfunctions in animal models. Adiponectin exerts its vasculoprotective effects through its direct actions in the vascular system, such as increasing endothelial NO production, inhibiting endothelial cell activation and endothelium-leucocyte interaction, enhancing phagocytosis, and suppressing macrophage activation, macrophage-to-foam cell transformation and platelet aggregation. In addition, adiponectin reduces neointima formation through an oligomerization-dependent inhibition of smooth muscle proliferation. The present review highlights recent research advances in unveiling the molecular mechanisms that underpin the vascular actions of adiponectin and discusses the potential strategies of using adiponectin or its signalling pathways as therapeutic targets to combat obesity-related metabolic and vascular diseases.