The bisphosphonate alendronate improves the damage associated with trinitrobenzenesulfonic acid-induced colitis in rats

BACKGROUND AND PURPOSE: The nitrogen-containing bisphosphonates are drugs used successfully in the treatment of osteoporosis. They act inhibiting farnesyl diphosphate synthase. This mechanism may also produce anti-inflammatory effects. The therapeutic activity of alendronate was tested in vivo using a model of inflammatory bowel disease. EXPERIMENTAL APPROACH: The trinitrobenzenesulfonic acid model of colitis in the rat was used. Rats were treated orally with alendronate and its efficacy compared with that of oral sulphasalazine or vehicle, starting 2 h after colitis induction. The status of the animals was assessed 5 days later. KEY RESULTS: Alendronate treatment (25 or 75 mg kg(-1) day(-1)) resulted in a decrease in the colonic damage score and loss of body weight (at 25 mg kg(-1) day(-1) only). This was associated to a dramatic reduction in the mRNA levels of interleukin 1 beta (IL-1 beta), monocyte chemoattractant protein 1 (MCP-1) and interleukin 1 receptor antagonist (IL-1 ra). The magnitude of the beneficial effect was comparable to that of sulphasalazine (at a 6-20 fold higher dose). Thus sulphasalazine post-treatment reduced the mRNA levels of IL-1 beta/IL-1 ra and MCP-1 to the same extent as alendronate and additionally lowered colonic alkaline phosphatase activity, but failed to affect body weight loss or colonic damage score. Alendronate failed to exert beneficial effects when administered intraperitoneally. CONCLUSIONS AND IMPLICATIONS: Oral but not intraperitoneal alendronate significantly protected the colon in experimental rat colitis. Inflammatory bowel disease patients might benefit from exposure to oral alendronate.     

Nanoparticles: pharmacological and toxicological significance

Nanoparticles are tiny materials (<1000 nm in size) that have specific physicochemical properties different to bulk materials of the same composition and such properties make them very attractive for commercial and medical development. However, nanoparticles can act on living cells at the nanolevel resulting not only in biologically desirable, but also in undesirable effects. In contrast to many efforts aimed at exploiting desirable properties of nanoparticles for medicine, there are limited attempts to evaluate potentially undesirable effects of these particles when administered intentionally for medical purposes. Therefore, there is a pressing need for careful consideration of benefits and side effects of the use of nanoparticles in medicine. This review article aims at providing a balanced update of these exciting pharmacological and potentially toxicological developments. The classes of nanoparticles, the current status of nanoparticle use in pharmacology and therapeutics, the demonstrated and potential toxicity of nanoparticles will be discussed.     

Anxiety, depression, and behavioral symptoms of executive dysfunction in ecstasy users: contributions of polydrug use

BACKGROUND: Given ecstasy's (MDMA) potential serotonergic neurotoxicity, it is plausible that regular ecstasy users would have an elevated prevalence of behavioral executive dysfunction or mood symptoms. However, recent studies have found that the relationship between ecstasy use and psychological symptoms was no longer significant after controlling for marijuana use (e.g., Morgan et al., 2002). The goal of the present study was to examine the relationship between ecstasy exposure and self-reported executive functioning and psychological symptoms after controlling for gender, ethnicity, and other drug use. METHODS: Data were collected from 65 men and women with a wide range of ecstasy use (including 17 marijuana-using controls). Participants were administered the Frontal Systems Behavioral Scale, State-Trait Anxiety Inventory for adults, and the Beck Depression Inventory-2nd edition. RESULTS: Although 19-63% of the ecstasy users demonstrated clinically elevated psychological symptoms, frequency of ecstasy use did not predict the psychological symptoms. No gender differences or interactions were observed. CONCLUSIONS: These results revealed that, although ecstasy users demonstrate elevated levels of psychological symptoms and executive dysfunction, these symptoms are not statistically associated with their ecstasy consumption. Instead, other drug use (alcohol, marijuana, opioids, and inhalants) significantly predict psychological symptoms in this sample of polydrug users.     

Comparative evaluation of powder and tableting properties of low and high degree of polymerization cellulose I and cellulose II excipients

Low and high degree of polymerization (DP) cellulose II powders have been prepared from Avicel PH-102 and Solka Floc 40NF (low and high DP cellulose I powders, respectively), respectively, by treatment with sodium hydroxide (5N) for 24h and their powder and tableting properties investigated. Cellulose II powders, compared to the respective cellulose I counterpart, exhibited lower crystallinity, true density, and specific surface area. They were denser and showed higher moisture uptake. The Heckel analyses revealed both low and high DP cellulose II powders to be less ductile than the low DP cellulose I powder and more ductile compared to the high DP cellulose I powder. The crushing strengths of low and high DP cellulose II powders were comparable to that of the high DP cellulose I powder but lower than the low DP cellulose I powder. When compressed to comparable crushing strengths, the low and high DP cellulose II compacts disintegrated faster in comparison to the corresponding cellulose I compacts. Low DP cellulose I and II powders, compared to the high DP cellulose I counterparts were more sensitive to magnesium stearate. Magnesium stearate decreased the disintegration times of low DP cellulose I compacts but had no effect on the low and high DP cellulose II and high DP cellulose I compacts. In conclusion, low and high DP cellulose II powders, despite their different powder properties, show similar tableting properties, leading to the formation of rapidly disintegrating compacts. The low and high DP cellulose I excipients, in contrast, differ in their powder properties as well as tableting characteristics.     

Lead exposure effect on angiotensin II renal vasoconstriction

Low levels of chronic lead exposure can produce hypertension and endothelial dysfunction, which could be associated with oxidative stress, changes in vascular tone and an imbalance of endothelial-derived vasoconstriction and vasodilator factors. The aim was to investigate the effect of chronic lead-exposure on angiotensin II-induced vasoconstriction in isolated perfused kidney and microvessels. Male Wistar rats (230-250 g) were treated for 12 weeks with lead acetate (100 ppm, Pbgroup) or pure water (control group). We evaluated the vascular reactivity in the kidneys and renal microvessels in the presence and absence of N(omega)-nitro-L-arginine methyl ester (L-NAME) in both groups. The nitrite concentration in renal perfusate was measured as an index of NO released, renal abundance of 3-nitrotyrosine was measured as well as endothelial NO synthase (eNOS) expression. Oxidative stress was measured by using the oxidative fluorescence dye dihydroethidium (DHE) to evaluate in situ production of superoxide and identified by confocal microscopy. Lead-exposure significantly increased blood pressure, eNOS protein expression, oxidative stress and vascular reactivity to angiotensin II. L-NAME potentiated vascular response to angiotensin II in control group but had no effect on the Pb-group. Nitrites released from the kidney of lead-group was lower compared to the control group while 3-nitrotyrosine was higher. This data suggest that lead-induced hypertension could be caused partially by an altered NOsystem.     

Sleep architecture in adolescent marijuana and alcohol users during acute and extended abstinence

This study examined sleep changes following cessation of marijuana and alcohol use during late adolescence. Twenty-nine heavy marijuana and alcohol users and 20 matched controls were studied during a 28-day monitored abstinence period. Sleep was examined as a function of prior substance use during Nights 1–2 and Nights 27–28. On Night 2, percent rapid eye movement sleep was predicted by past month alcohol use, whereas percent slow wave sleep was predicted by marijuana intake. By Night 28, neither alcohol nor marijuana use predicted any sleep architecture measure. However, on Night 28, indices of period limb movements (PLMs) in sleep were predicted by marijuana and alcohol intake. Results indicate that in adolescents: (1) cessation of heavy marijuana and alcohol use may influence sleep; (2) most sleep abnormalities abate within several weeks of abstinence; and (3) PLMs may increase following abstinence.     

Hesperidin, a flavonoid glycoside with sedative effect, decreases brain pERK1/2 levels in mice

The aim of this work was to evaluate if the intraperitoneal administration of the natural compound hesperidin, in a sedative dose, and neo-hesperidin, a hesperidin structural analog that exerts minor sedative effect, were able to induce changes in intracellular signaling cascades in different areas of the brain.The systemic administration of hesperidin produced a marked reduction in the phosphorylation state of extracellular signal-regulated kinases 1/2 (ERK 1/2), but not of Ca⁺²/calmodulin-dependent protein kinase II α subunit (αCaMKII), in the cerebral cortex, cerebellum and hippocampus. In contrast, neo-hesperidin did not markedly affect the activity of ERK 1/2 in both the cortex and the cerebellum.Taken together, these results demonstrated that intracellular signalling involving a selective decrease in ERK1/2 activation accompanied the depressant action of hesperidin. Even more, the low sedative action of neo-hesperidin correlates with a negligible decrease in phosphorylation state of ERK 1/2 (pERK 1/2), suggesting that low levels of pERK 1/2 in CNS could be a marker of sedative efficacy of flavonoids.     

Synergistic interaction between the Potyvirus, Turnip mosaic virus and the Crinivirus, Lettuce infectious yellows virus in plants and protoplasts

Lettuce infectious yellows virus (LIYV), the type member of the genus Crinivirus in the family Closteroviridae, is specifically transmitted by the sweet potato whitefly (Bemisia tabaci) in a semipersistent manner. LIYV infections result in a low virus titer in plants and protoplasts, impeding reverse genetic efforts to analyze LIYV gene/protein functions. We found that synergistic interactions occurred in mixed infections of LIYV and Turnip mosaic virus (TuMV) in Nicotiana benthamiana plants, and these resulted in enhanced accumulation of LIYV. Furthermore, we examined the ability of transgenic plants and protoplasts expressing only the TuMV P1/HC-Pro sequence to enhance the accumulation of LIYV. LIYV RNA and protein titers increased by as much as 8-fold in these plants and protoplasts relative to control plants. LIYV infections remained phloem-limited in P1/HC-Pro transgenic plants, suggesting that enhanced accumulation of LIYV in these plants was due primarily to increased replication efficiency, not to greater spread.