In vitro antioxidant properties of pentoxifylline, piracetam, and vinpocetine

Oxygen-free radicals play an important role in several physiologic and pathophysiologic processes. In pathologic circumstances, they can modify and damage biologic systems. Because oxygen-free radicals are involved in a wide range of diseases (cerebrovascular, cardiovascular, etc.), scavenging these radicals should be considered as an important therapeutic approach. In our in vitro study, we investigated the antioxidant capacity of three drugs: pentoxiphylline (Sigma Aldrich, St. Louis, MO, USA) piracetam (Sigma Aldrich), and vinpocetine (Richter Gedeon RT, Budapest, Hungary). Phenazine methosulphate was applied to generate free radicals, increasing red blood cell rigidity. Filtration technique and potassium leaking were used to detect the cellular damage and the scavenging effect of the examined drugs. According to our results, at human therapeutic serum concentration, only vinpocetine (Richter Gedeon RT) had significant (p < 0.01) scavenging activity with a protective effect that increased further at higher concentrations. Pentoxiphylline (Sigma Aldrich) and piracetam (Sigma Aldrich) did not have significant antioxidant capacity at therapeutic concentrations, but increasing their concentrations (pentoxiphylline at 100-times, and piracetam at 10-times higher concentrations) led to a significant (p < 0.01) scavenger effect. Our findings suggest that this pronounced antioxidant effect of vinpocetine and even the milder scavenging capacity of pentoxiphylline and piracetam may be of value in the treatment of patients with cerebrovascular disorders, but merits further investigations.     

Putative role of 67 kDa elastin-laminin receptor in tumor invasion

Cellular regulatory mechanisms normally maintain a delicate balance between cell proliferation, quiescence and death. The imbalance between these functions resulting from molecular intracellular changes is a key factor in tumorigenesis. Tumor cells detaching from the primary tumor possess a propension for invasion and metastasis formation. These tumor cells can attach, migrate, proliferate and grow in host tissue. The surrounding extracellular matrix (ECM) modulates these functions. It is now widely accepted that cell-matrix interactions play an important role in these processes. Most investigators concentrated their attention on the role of integrins in the above processes. There are, however, only scant data on the role of elastin and its receptors in tumor invasion. Nevertheless, experimental evidence indicates that the 67 kDa elastin-laminin receptor (ELR) subunit plays an important role in tumor invasion by mediating essential tumor cell functions leading to metastases. In this review we will concentrate on the putative role of the 67 kDa ELR subunit in tumor invasion.     

Changing Effect of i.c.v. IL-1β on Vasopressin Release in Anaesthetized, Female Rats at Different Stages of Lactation: Role of Prostaglandins and Noradrenaline

lnterleukin-1β stimulates oxytocin and vasopressin release in conscious, male rats and causes a rise in blood pressure. These experiments were done to: A) examine the effect of i.c.v. interieukin-1 β (1 ng/μl) on circulating levels of vasopressin in female rats at different stages of lactation and B) determine if α-adrenergic mechanisms and/or prostaglandins were involved as mediators. Urethane-anaesthetized non-lactating rats and rats at Day 7, 10, 20 and 26 of lactation were set up for arterial blood sampling and i.c.v. injections. One mL blood samples were obtained in one min periods before, and at 1, 2.5, 5, 10, 30, 60 and 120 min after the following treatments: i.c.v. treatment with either interleukin-1β (1 ng in 1 μl PBS-BSA) or PBS-BSA (1 μl) as a vehicle control; or i.c.v. treatment with interleukin-1β following pretreatment with either phentolamine (1.7 ng/μl i.c.v.) or indomethacin (1 ng/μl i.c.v.). As blood was sampled, isotonic saline was infused (1 mL per min) and blood pressure was monitored to minimize any hypovolemic effects due to sampling. Extracted plasma was assayed using a specific vasopressin radioimmunoassay, lnterleukin-1 β i.c.v. stimulated the release of vasopressin above that elicited by PBS-BSA alone in non-lactating rats resulting in an approximate 1.2 to 2-fold increase in plasma hormone levels. Throughout the first half of lactation, vasopressin responsiveness to i.c.v. interleukin-1β treatment was markedly attenuated. In latter stages of lactation, the response recovered and resembled that of non-lactators around the time of weaning. Prostaglandins consistently mediate a stimulatory action of interleukin-1β on vasopressin release whereas α-adrenergic mechanisms mediate a depression of interleukin-1β-induced vasopressin release during the early to middle stages of lactation. It is possible that the depression in interleukin-1β-stimulation of vasopressin release in early to mid-lactation is conducive for nursing to occur and that the increase in vasopressin responsiveness towards the latter stages of lactation represents a component of the weaning process.     

Dysregulation of T-cell function in the elderly : scientific basis and clinical implications

The function of the immune system is to maintain body integrity by defending against infections, cancers, autoimmune diseases and inflammation-related chronic diseases. The immune response is known to become defective with aging, leading to decreased longevity and appearance of age-related disease. The most important changes occur in T-cell immunity, and are manifested particularly as altered clonal expansion of cells of limited antigen specificity. The causes of these alterations are multifactorial, and include thymic involution, T-cell subset changes and signal transduction alterations. The clinical consequences of these changes are not well defined, except for their extremely important negative impact on defence against infections, especially by new pathogens, and decreased responses to vaccination. Considering the public health consequences of decreased immune competence in old age, strategies for immune response modulation are desirable to decrease the health burden for the elderly and improve their quality of life.     

Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents

OBJECT: Clinical application of the convection-enhanced delivery (CED) technique is currently limited by low infusion speed and reflux of the delivered agent. The authors developed and evaluated a new step-design cannula to overcome present limitations and to introduce a rapid, reflux-free CED method for future clinical trials. METHODS: The CED of 0.4% trypan blue dye was performed in agarose gel to test cannula needles for distribution and reflux. Infusion rates ranging from 0.5 to 50 microl/minute were used. Agarose gel findings were translated into a study in rats and then in cynomolgus monkeys (Macacafascicularis) by using trypan blue and liposomes to confirm the efficacy of the reflux-free step-design cannula in vivo. Results of agarose gel studies showed reflux-free infusion with high flow rates using the step-design cannula. Data from the study in rats confirmed the agarose gel findings and also revealed increasing tissue damage at a flow rate above 5-microl/minute. Robust reflux-free delivery and distribution of liposomes was achieved using the step-design cannula in brains in both rats and nonhuman primates. CONCLUSIONS: The authors developed a new step-design cannula for CED that effectively prevents reflux in vivo and maximizes the distribution of agents delivered in the brain. Data in the present study show reflux-free infusion with a constant volume of distribution in the rat brain over a broad range of flow rates. Reflux-free delivery of liposomes into nonhuman primate brain was also established using the cannula. This step-design cannula may allow reflux-free distribution and shorten the duration of infusion in future clinical applications of CED in humans.     

Slow and wide QRS complex tachycardia as a unique complication following radiofrequency catheter ablation of a left-sided accessory pathway in a child

Radiofrequency lesions can, theoretically, be the substrate for new persistent arrhythmias. As far as we know, this has never previously been encountered after transcatheter ablation of accessory pathways. A child with Wolff-Parkinson-White syndrome was referred for radiofrequency catheter ablation of a left-sided accessory pathway. After successful ablation of the accessory pathway using a retrograde transaortic approach, the child developed an incessant wide QRS complex tachycardia at slow rate that was resistant to pharmacologic interventions. The focus of the tachycardia was identical to the ventricular site of insertion of the eliminated accessory pathway.     

Galanin and its receptors in neurological disorders

Galanin is a highly inducible neuropeptide, showing distinct up-regulation after pathological disturbance within the nervous system. Significant increase in galanin expression is observed after peripheral nerve injury, in the basal forebrain in Alzheimer’s disease (AD), during neuronal development, and after stimulation with estrogen, while seizure activity deplete galanin in the hippocampus. A wide distribution of galanin and its receptors is seen in the nervous system, often in co-localization with classical neurotransmitters and other neuromodulators. Galanin acts predominantly as an inhibitory, hyperpolarizing neuromodulator on neurotransmitter and glucose-induced insulin release and stimulates growth hormone and prolactin secretion. Galanin has been implicated in several higher order physiological functions including cognition, feeding, nociception, mood regulation, and neuroendocrine modulation. The effects of galanin are mediated via three G protein-coupled receptors with different functional coupling. Moderate to low pharmacological effects are seen by galanin under physiological conditions, in contrast to its dramatic effects on the nervous system after neuronal disturbance. This pathophysiological heavy function of the galaninergic system renders it an interest for disorders such as AD, depression, and epilepsy in terms of side effects. Some properties of the galaninergic system are of particular importance in the context of neurodegeneration. Galanin is highly inducible, 10- to 100-fold, upon nerve injury, whereas most neuropeptides are induced 1.5- to 2-fold. Galanin is strongly neurotrophic during development as well as subsequent to injury. Whereas other neurotrophic neuropeptides like VIP and PACAP activate cAMP synthesis, galanin suppresses its synthesis, yet it is a strong neurotrophic as well as neuroprotective agent. As we delineate which galanin receptor subtype mediates neuroprotective and neurotrophic effects and which mediates synaptic inhibition, pharmacological use of receptor-selective galaninergic ligands for treatment in neurodegenerative diseases are coming closer.     

The role of PAF, TLR, and the inflammatory response in neonatal necrotizing enterocolitis

The pathogenesis of neonatal necrotizing enterocolitis remains poorly understood. Recent evidence suggests that PAF (platelet activating factor) and human toll-like receptors (TLRs) contribute to the pro-inflammatory response that is characteristic of NEC pathology. Understanding the regulation of these molecular interactions may provide new approaches for prevention or treatment of this dreaded condition.