Identification of Factors Causing Sudden Coagulation in Patients with Acute Myocardial Infarction

Background: Coronary artery disease (CAD) evolving to acute myocardial infarction (AMI) is due to the thrombotic occlusion of coronary vessels in the presence of destabilized atheroma, rich in inflammatory cells secreting proteolytic enzymes that induce the development of thrombosis. The aim of this study was to analyse the plasma of AMI patients for the detection of proteases or factors that may cause fast coagulation. Methods: The patients were analysed for the presence in plasma of cardiac troponin T (c-TnT) or proteases as neutrophil gelatinase-associated lipocalin (NGAL) using ELISA method and matrix metalloproteinase-9 (MMP-9) utilising flow cytometry technique and interleukin-8 (IL-8) using flow cytometry methodology. Results: The presence of AMI was demonstrated by high levels of c-TnT; in comparison with controls the AMI patients displayed a significant increase in the values of MMP-9 and low levels of antithrombin III: these markers were negatively correlated: MMP-9 appeared to cause the coagulation activity documented by the consumption of antithrombin III. The same patients also showed high levels of NGAL, which is known to modulate MMP-9 activity and to be involved in coagulation process: patients also exhibited an increased amount of IL-8 which appears to be associated with high levels of NGAL: this cytokine seems to affect the values of NGAL which is linked to coagulation process. Conclusion: The high levels of MMP-9, NGAL and IL-8 in AMI patients seemed to be interrelated and connected with the process leading to rapid coagulation. These markers may be measured in absence of AMI, particularly in CAD patients, as their detection may reveal a risk of sudden coronary coagulation

Quantitative evaluation of opioid withdrawal signs in rats repeatedly treated with morphine and injected with naloxone, in the absence or presence of the antiabstinence agent clonidine

An opioid withdrawal syndrome was induced in rats by repeated morphine administration and final naloxone injection. The withdrawal causes alteration of several physiological signs. The aim of the study was to describe a quantitative opioid abstinence syndrome to validate the methodology by utilizing clonidine, a well-known antiwithdrawal agent, and propose the procedure for the screening of antiabstinence drugs. In particular, rats were treated with saline, morphine, naloxone, morphine and naloxone and four doses of clonidine (0, 0.04, 0.1, and 0.25 mg/kg orally). In rats repeatedly exposed to morphine and then injected with naloxone, signs like excretion of feces and urine, salivation, behavioral jumping and wet dog shakes, rectal temperature, and pain threshold have been observed. Consequently, the objective symptoms observed in morphine plus naloxone-treated animals have been taken as markers of opioid withdrawal. These factors have been quantitatively measured and grouped to form a standardized procedure of opioid abstinence syndrome. In addition, it is possible to observe that the antiabstinence drug clonidine exerted effects on modified physiological signs appearing in morphine-dependent rats treated with naloxone, like fecal excretion, levels of rectal temperature, latency times, salivation as well as jumping behavior. The effects exerted by clonidine in this procedure and in other methods are compared and appear to be similar. In addition, comparative observations referring to both the previous methods and the present procedure related to the type of signs studied, the modality of evaluation, and suppressive activity exerted by the antiwithdrawal agent, clonidine, are performed: the greater accuracy of the proposed method becomes apparent. Thus, this experimental model, validated by the antiabstinence agent clonidine, is proposed as a useful screen for drugs affecting opioid withdrawal syndrome

Effects of alpha-lipoic acid administration on plasma glucose levels, total malondialdehyde values and withdrawal signs in rats treated with morphine or morphine plus naloxone

Morphine (CAS 57-27-2) administration or its removal induces alterations in glucose levels and oxidative status or behaviour signs, which may be hypothetically closely related; if this is correct, controlling glucose changes may lead to modifications in peroxide levels and in behaviour profile. It therefore seems important to rind a drug able to control alterations of glucose metabolism, peroxide generation and behaviour symptoms in morphine or morphine withdrawal animals. This paper describes the effects of morphine or morphine plus naloxone (CAS 51481-60-8) on the plasma levels of glucose, malondialdehyde (MDA) (CAS 100683-54-3) and behavioural signs in rats treated or not with alpha-lipoic acid (CAS 1077-28-7), known to interfere with glucose and peroxide levels.The administration of morphine or its removal by naloxone alters plasma glucose levels, increases MDA values, and also affects signs such as pain threshold values, fecal excretion and jumping behaviour.The injection of alpha-lipoic acid decreases glycemia in rats treated with morphine or morphine plus naloxone. This result may be due to the capacity of alpha-lipoic acid to facilitate glucose transport and its utilization. The administration of alpha-lipoic acid to rats given morphine or morphine plus naloxone lowers total MDA levels because of its peroxide scavenging capacity. In animals injected with morphine plus naloxone, which show altered pain thresholds, high fecal excretion and jumping behaviour, treatment with alpha-lipoic acid increases latency times, decreases fecal excretion and reduces jumping. These effects can be attributed to the capacity of alpha-lipoic acid to interfere with mediators or peroxides involved in the modified behaviour. The glycemia levels, MDA values and behavioural signs seem to be interconnected in the reported experiments. The administration of alpha-lipoic acid is demonstrated to control the alterations in plasma glucose levels, peroxide values or behavioural profile in animals receiving morphine or morphine plus naloxone

Effects of ondansetron administration on opioid withdrawal syndrome observed in rats

This study tested whether a 5-HT3 receptor antagonist could reverse the signs of precipitated opioid withdrawal. Rats were treated with either saline or morphine for 4 days. After the four days, half of the rats in each group received naloxone and half received saline. Each animal also received one of four doses of ondansetron (0, 1, 2 and 4 mg/kg i.p.). Administration of ondansetron to rats receiving naloxone after chronic morphine decreased the intensity of withdrawal signs such as increased defecation, jumping and wet-dog shakes, elevated the nociceptive threshold values which were decreased by precipitated withdrawal, but produced no change in urination, rectal temperature or salivation. The effects exhibited by ondansetron administration may be explained through interference of its 5-HT3 receptor antagonist activity with serotoninergic mechanisms involved in the regulation of these withdrawal symptoms. The use of this drug is thus suggested as a possible treatment of opioid withdrawal signs in heroin addicts

Plasma malondialdehyde levels and opiate withdrawal signs observed in rats treated with morphine plus naloxone: effects of \u3b1-lipoic acid administration

A number of experimental studies have found that reactive oxygen species are involved during morphine treatment or withdrawal. The aims of this study were to analyse whether morphine administration and/or removal are related to peroxide generation and/or signs of withdrawal in rats, and whether the changes in antioxidant status induced by the administration of an antioxidant may modify peroxide levels and behavioural signs. We injected morphine or morphine and naloxone into rats and evaluated the plasma levels of peroxide malondialdehyde (MDA) and the appearance of withdrawal signs. We also investigated the effects on these parameters induced by the administration of the antioxidant \u3b1-lipoic acid (LA). Morphine treatment increased MDA levels. Abrupt naloxone-induced morphine withdrawal caused a further and significant increase in MDA, and the appearance of withdrawal signs such as abnormal fecal excretion, shortened latency times and jumping. The administration of LA lowered MDA levels in the rats treated with morphine or morphine plus naloxone, and also decreased MDA values and abstinence signs in the animals treated with morphine plus naloxone. The effects of LA were attributed to its capacity to scavenge peroxides and interfere with the biogenesis of the arachidonic acid metabolites involved in the expression of abstinence symptoms

Effects exerted by otilonium bromide administration on precipitated opioid withdrawal syndrome in rats

An opioid withdrawal syndrome was induced in rats by repeated morphine administration and final naloxone injection. The withdrawal causes alteration of several physiological signs. The aim of the study was to prevent the altered physiological profiles by utilising otilonium bromide. Morphine was administered in three daily i.p. injections for 4 days at doses of 9, 16 and 25 mg/kg (1st day), 25, 25 and 50 mg/kg (2nd day), 50, 50 and 50 mg/kg (3rd day) and 50, 50 and 100 mg/kg (4th day). Naloxone was injected (30 mg/kg) i.p. 180 min after the last morphine injection. Otilonium bromide was administered orally at 0, 2, 4 and 8 mg/kg, 120 min before the naloxone administration. Signs like faecal and urine excretion, rectal temperature and pain threshold levels, salivation, jumping and wet dog shakes were affected in different ways. Notably the administration of otilonium bromide in rats receiving morphine together with naloxone decreased the intensity of certain withdrawal symptoms, such as excretion of faeces, wet dog shake behaviour, and elevated the nociceptive threshold values. The effects exhibited by otilonium bromide administration may be explained through its calcium antagonist activity interfering with a mechanism involved in the regulation of these previously mentioned withdrawal symptoms. The use of this drug is thus suggested as a possible control of some acute opioid withdrawal signs in heroin addicts

Activated partial thromboplastin time correlates with methoxyhydroxyphenylglycol in acute myocardial infarction patients : therapeutic implications for patients at cardiovascular risk

BACKGROUND/AIM: Acute myocardial infarction (AMI) is associated with increased coagulation which in the presence of unstable atheroma or endothelial damage leads to occlusive coronary vessel thrombosis. AMI is usually characterized by increased levels of catecholamines. It is possible there may be a link between catecholamines and hypercoagulation, but this still remains to be determined. In the current study we sought to verify whether hypercoagulation is associated with hypersympathetic activity in AMI patients, and whether there is a correlation between increased Methoxyhydroxyphenylglycol (MOPEG) levels (a metabolite of catecholamines) and shorter APTT (a marker of hypercoagulation). RESULTS: Shorter APTT values were detected in the plasma of AMI patients, which had also increased MOPEG levels. A linear correlation between APTT and MOPEG values was observed. High levels of the coagulation marker prothrombin (fragments 1+2) were also found. CONCLUSION: Shortened APTT demonstrates hypercoagulation and high MOPEG levels indicate increased catecholamine metabolism. A direct correlation between APTT and MOPEG was found herein, demonstrating a link between catecholamines and the process of coagulation. Catecholamines may interact with the \u3b12-adrenergic receptors located on platelets and convert factor XII to XIIa or through the kallikrein-kinin system, they may activate factor XII. The activation of factor XII initiates the intrinsic coagulation pathway, which is monitored by APTT. It is suggested to control patients with a shortened APTT and increased sympathetic activity with the aim of preventing secondary coagulation and cardiovascular accidents by administering anti-thrombotic and anti-adrenergic agents

Effects of tizanidine administration on precipitated opioid withdrawal signs in rats

An opioid withdrawal syndrome was precipitated by naloxone administration in rats treated with morphine. The withdrawal caused alteration of several physiological signs. The aim of the study was to investigate whether the altered physiological profiles were modified by utilising tizanidine, an alpha 2 adrenergic receptor agonist which is capable of affecting faecal and urinary excretion, rectal temperature, pain threshold levels and salivation. To induce an opioid withdrawal syndrome, morphine was administered in three daily intraperitoneal injections for four days at doses of 9, 16 and 25 mg/kg (1st day), 25, 25 and 50 mg/kg (2nd day), 50, 50 and 50 mg/kg (3rd day) and 50, 50 and 100 mg/kg (4th day): naloxone was injected (30 mg/kg) i.p. 180 min after the last morphine injection. Tizanidine was administered orally at 0.17, 0.35 and 0.7 mg/kg, 60 min after the last morphine injection. Signs such as faecal and urine excretion, rectal temperature and latency times to thermal stimulus, salivation, jumping and wet dog shakes were affected in different ways by morphine, naloxone, tizanidine and by the combination of these agents. Notably, the administration of tizanidine in rats receiving morphine and naloxone decreased the intensity of certain withdrawal symptoms, including altered excretion of faeces and urine, salivation and wet dog shake behavior. Body temperature levels and nociceptive threshold values were also modified. The effects caused by tizanidine administration may be due to its alpha 2 receptor agonist activity interfering with a mechanism involved in the regulation of these previously mentioned withdrawal symptoms. Thus, the use of this drug may be indicated as a possible control of the acute phase of opioid withdrawal in heroin addicts

Effects of carbamazepine treatment on pain threshold values and brain serotonin levels in rats

The administration of carbamazepine to rats caused a significant increase in pain threshold values. Furthermore, treatment with carbamazepine lowered the concentration of tryptophan bound to plasma proteins and elevated the brain serotonin values. The high brain serotonin levels, observed in carbamazepine-treated rats, are probably attributable to an increased availability of brain tryptophan, since this amino acid has been substantially removed from the plasma protein compartment by carbamazepine treatment, which exhibits a high binding capacity to plasma proteins. The analgesic effects caused by carbamazepine administration have been attributed to increased levels of brain serotonin which is involved in the control of pain transmission

Effects of administration of phentonium bromide on opioid withdrawal syndrome in rats

This study has tested whether phentonium bromide, a quaternary ammonium anti-muscarinic agent, could reverse the signs of precipitated opioid withdrawal. Rats were treated with either saline or morphine for 4 days, after which half the rats received naloxone and half saline. Each animal also received one of four doses of phentonium bromide (0, 1, 3 and 9 mg kg(-1), i.p.). Administration of phentonium bromide in rats receiving naloxone after chronic morphine treatment reduced the intensity of withdrawal signs such as increased defecation or micturition, salivation and wet-dog shakes, and elevated the nociceptive threshold values. The effects of administration of phentonium bromide might result from its anti-muscarinic activity interfering peripherally with the mechanisms involved in the regulation of the withdrawal symptoms. The use of this drug is thus suggested as a possible means of controlling some of the signs observed during the acute phase of opioid withdrawal in heroin addicts