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694 Pharmacology

phosphate deglycase [201]. The use of these enzymes or development of stable analogues for

A number of AGE inhibitors were synthesized and screened for their AGEs inhibitory effects by Rahbar et al. [173, 202, 203]. These are derivatives of aryl ureido and aryl carboxaminido phenoxy isobutyric acids and were derived from some known AGEs inhibitors. These compounds act at multiple stages of the AGEs formation process. Some of these compounds have AGEs breaking properties. More studies are needed for these

The AGEs which have undergone cross-linking are very stable products and their concentration, especially in long-lived matrix proteins, increases with age. AGEs inhibitors are ineffective against formed AGEs and compounds which can break the cross-links are required. The AGEs breaker compounds can prove invaluable to slow down the aging process, and in the treatment of established stages of diseases such as diabetes, Alzheimer's,

The first AGEs breaking compound reported was phenacylthiazolium bromide (PTB) in 1996. PTB breaks the covalent cross-links of AGEs [204]. Administration of PTB (10 mg/kg/day, intraperitoneal for 4 wks) reduced the amount of IgG bound to the surface of

The search for a stable derivative of PTB resulted in the synthesis of ALT 711 (4,5 dimethylthiazolium) [205]. ALT 711 (now known as alagebrium) reduced arterial stiffness in streptozotocin-induced diabetic rats [205]. In aging rats, ALA (10 mg/kg for 16 weeks) also increased glutathione peroxidase and superoxide dismutase activities and reduced oxidative stress [206]. Alagebrium improved impaired cardiovascular function in older rhesus monkeys [207]. Alagebrium demonstrated promising results and a good safety profile in phase 2 clinical trials. In a clinical study involving 93 subjects, 50 yrs and older, with evidence of vessel stiffness (pulse pressure ≥60 mm Hg, systolic blood pressure ≥140 mm Hg, and large artery compliance ≤1.25 mL/mm Hg), alagebrium (210 mg, once per day for 56 days) improved arterial compliance [208]. In another group of 13 patients aged 65±2 yrs with systolic hypertension (systolic blood pressure > 140 mmHg, diastolic blood pressure <90 mm Hg), alagebrium (210 mg/kg twice a day for 8 weeks) reduced vascular fibrosis and markers of inflammation [209]. Alagebrium (administered for 16 weeks) decreased left ventricular mass and improved left ventricular diastolic filling in another trial in 23 patients

However, in a recent study [212] involving 102 patients (aged 62 ± 11 years) with heart failure (left ventricular ejection fraction (LVEF ≤0.45), alagebrium (400 mg/day/36 wks) did not improve exercise tolerance and systolic dysfunction, and no changes were observed in a number of secondary endpoints. Thus, the authors could not verify the claims that

Alagebrium has been reported to be a weak inhibitor of thiamine diphosphokinase and is unlikely to interfere with thiamine metabolism at therapeutic concentrations [213]. However, the authors urge caution when new AGE-crosslink breakers based on thiamine are designed, to make sure they are not potent inhibitors of thiamine diphosphokinase.

compounds to establish their specificity and safety for therapeutic use.

red blood cells in diabetic rats [153]. However, PTB is not stable.

alagebrium has beneficial effects in systolic heart failure [212].

deglycation therapy remains speculative .

atherosclerosis and rheumatoid arthritis.

with diastolic heart failure [210, 211].

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**31** 

*Brazil* 

Silvânia Vasconcelos et al.\*

**Ethanol Interference on Adenosine System** 

It is well documented in literature a wide range of behavioral and physiological effects arising from ethanol intake (Spinetta et al., 2008; Soares et al., 2009; Brust, 2010). Because it is a substance that affects differently and simultaneously several neurotransmitter systems, covering different brain areas (Dahchour & De Witte, 2000; Vasconcelos et al., 2008; Vengeliene et al., 2008), it becomes complex to reveal the mechanism of action that governs its effects, being still a challenge for researchers. In addition, ethanol has a biphasic behavioral presenting

Among the wide range of pathways in central nervous system that are modified by ethanol, it is important to highlight those that explain ethanol diverse effects, like the ones releasing gamma-amynobutiric acid (GABA), glutamate, dopamine and norepinephrine (Kaneyuki et al., 1991; Vasconcelos et al., 2004). Moreover, another pathway that is rising on researches about ethanol effects is the adenosinergic system (Prediger et al., 2006; Thorsell et al., 2007). Adenosine was described as a potent depressor of neuronal activity (Dunwiddie & Haas, 1985), and acts mainly via A1 receptor, which is a presynaptic inhibitor of the release of neurotransmitters such as dopamine, GABA, glutamate, acetylcholine and norepinephrine (Fredholm et al., 2001; Dunwiddie & Masino, 2001). Moreover, adenosine is involved in behavioral processes like motor function, anxiety, depression, reward and drug addiction, and human disorders such as Parkinson disease and schizophrenia (Moreau and Huber, 1999).

In addition, there is strong evidence of an involvement of the adenosinergic system on ethanol effects, including the extracellular increase of adenosine after acute exposure to ethanol (Krauss et al., 1993; Nagy et al., 1990), the accentuation or blockade of ethanolinduced motor incoordination provided by adenosine receptor agonists or antagonists, respectively (Dar, 2001; Soares et al., 2009), and the reduction of anxiogenic-like behavior in acute ethanol withdrawal (Prediger et al., 2006). Adenosine antagonists, like caffeine, are implicated in alcohol tolerance (Fillmore, 2003), and retrograde memory impairment caused by ethanol (Spinetta et al., 2008). Thus, adenosine receptors seem to modulate some of the

Sarah Escudeiro1, Ana Luíza Martin1, Paula Soares1, Antônio Vieira Filho2, Larissa Silva2,

Kátia Cilene Dias1, Danielle Macêdo1, Francisca Cléa Sousa1, Marta Fonteles1

*1Federal University of Ceará, Department of Physiology and Pharmacology, Brazil 2College of Medicine Christus, Brazil* 

an excitatory feature in the early stages and a depressant feature in its chronic use.

**1. Introduction** 

 \*

and Manoel Cláudio Patrocínio2

*Federal University of Ceará, Department of Physiology and Pharmacology* 

