Differential Protective Effect of Zinc and Magnesium for the Hepatic and Renal Toxicity Induced by Acetaminophen and Potentiated with Ciprofloxacin in Rats.

Background and Objectives: The purpose of this study was to investigate the influence induced by magnesium chloride (MgCl2) and zinc gluconate (ZnG) supplementation on liver and kidney injuries experimentally induced with acetaminophen (AAPh) and potentiated by a ciprofloxacin addition in rats. Material and Methods: The experiment was performed on five animal groups: group 1-control, treated for 6 weeks with normal saline, 1 mL/kg; group 2-AAPh, treated for 6 weeks with AAPh, 100 mg/kg/day; group 3-AAPh + C, treated for 6 weeks with AAPh 100 mg/kg/day and ciprofloxacin 50 mg/kg/day, only in the last 14 days of the experiment; group 4-AAPh + C + Mg, with the same treatment as group 3, but in the last 14 days, MgCl2 10 mg/ kg/day was added; and group 5-AAPh + C + Zn, with the same treatment as group 3, but in the last 14 days, zinc gluconate (ZnG), 10 mg/kg/day was added. All administrations were performed by oral gavage. At the end of the experiment, the animals were sacrificed and blood samples were collected for biochemistry examinations. Results: Treatment with AAPh for 6 weeks determined an alteration of the liver function (increases in alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, and gamma-glutamyl transferase) and of renal function (increases in serum urea and creatinine) (p < 0.001 group 2 vs. group 1 for all mentioned parameters). Furthermore, the antioxidant defense capacity was impaired in group 2 vs. group 1 (superoxide dismutase and glutathione peroxidase activity decreased in group 2 vs. group 1, at 0.001 < p < 0.01 and 0.01 < p < 0.05, respectively). The addition of ciprofloxacin, 50 mg/kg/day during the last 14 days, resulted in further increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, and creatinine (0.01 < p < 0.05, group 3 vs. group 2). MgCl2 provided a slight protection against the increase in liver enzymes, and a more pronounced protection against the increase in serum urea and creatinine (0.001 < p < 0.01 group 4 vs. group 3). MgCl2 provided a slight protection against the decrease in superoxide dismutase (0.01 < p < 0.05 group 4 vs. group 3), but not against decrease of glutathione peroxidase. The improvement of mentioned parameters could also be seen in the case of ZnG, to a higher extent, especially in the case of alanine aminotransferase and lactic dehydrogenase (0.01 < p < 0.05 group 5 vs. group 4). Conclusions: This study presents further proof for the beneficial effect of magnesium and zinc salts against toxicity induced by different agents, including antibacterials added to the analgesic and antipyretic acetaminophen; the protection is proven on the liver and kidney's function, and the antioxidant profile improvement has a key role, especially in the case of zinc gluconate.

New ibuprofen derivatives with thiazolidine-4-one scaffold with improved pharmaco-toxicological profile.

BACKGROUND: Aryl-propionic acid derivatives with ibuprofen as representative drug are very important for therapy, being recommended especially for anti-inflammatory and analgesic effects. On other hand 1,3-thiazolidine-4-one scaffold is an important heterocycle, which is associated with different biological effects such as anti-inflammatory and analgesic, antioxidant, antiviral, antiproliferative, antimicrobial etc. The present study aimed to evaluated the toxicity degree and the anti-inflammatory and analgesic effects of new 1,3-thiazolidine-4-one derivatives of ibuprofen. METHODS: For evaluation the toxicity degree, cell viability assay using MTT method and acute toxicity assay on rats were applied. The carrageenan-induced paw-edema in rat was used for evaluation of the anti-inflammatory effect while for analgesic effect the tail-flick test, as thermal nociception in rats and the writhing assay, as visceral pain in mice, were used. RESULTS: The toxicological screening, in terms of cytotoxicity and toxicity degree on mice, revealed that the ibuprofen derivatives (4a-n) are non-cytotoxic at 2 µg/ml. In addition, ibuprofen derivatives reduced carrageenan-induced paw edema in rats, for most of them the maximum effect was recorded at 4 h after administration which means they have medium action latency, similar to that of ibuprofen. Moreover, for compound 4d the effect was higher than that of ibuprofen, even after 24 h of administration. The analgesic effect evaluation highlighted that 4 h showed increased pain inhibition in reference to ibuprofen in thermal (tail-flick assay) and visceral (writhing assay) nociception models. CONCLUSIONS: The study revealed for ibuprofen derivatives, noted as 4 m, 4 k, 4e, 4d, a good anti-inflammatory and analgesic effect and also a safer profile compared with ibuprofen. These findings could suggest the promising potential use of them in the treatment of inflammatory pain conditions.

Improvement in serum lipids and liver morphology after supplementation of the diet with fish oil is more evident under regular feeding conditions than under high-fat or mixed diets in rats.

BACKGROUND: Dietary n- 3 polyunsaturated fatty acids (PUFAs) have a role in preventing cardiovascular and hepatic diseases. However, their effects might differ significantly depending on individual dietary patterns. The aim of the present study was to evaluate the effects of dietary supplementation with ω-3 fatty acids (FA), administered in different schedules, on hepatic and aortic histological structure, lipid profile, and body weight (BW) in male Wistar rats under standard (SD), high-fat diet (HFD) and mixed feeding conditions. METHODS: PUFA treatment consisted of the administration of 50 mg/kg fish oil (FO) daily by oral gavage. HFD was obtained by adding a suspension of 4% cholesterol, thiouracil and cholic acid to the animals' drinking water. The rats were maintained on the diets for 6 weeks, and different schedules of PUFA administration were used. At 14, 28, and 42 days, the morphology of liver and aortic samples and the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) were assessed. RESULTS: The HFD groups exhibited significant hyperlipidemia and aortic inflammation, with progression to atherogenesis after 6 weeks. Administration of PUFAs slightly attenuated the aortic changes in these groups and reduced the liver's tendency to steatosis. FO-induced metabolic improvement was more evident in SD than in HFD rats. For instance, after the first 2 weeks, SD animals that received PUFAs had significantly increased HDL levels vs. controls (62.375 ± 4.10 vs. 52.625 ± 8.38 mg/dL, P < 0.05), but HFD rats did not, and decreased TG levels were observed exclusively in the SD rats (57.6 ± 4.09 vs. 66 ± 4.69 mg/dL, P < 0.05). After 6 weeks of n- 3 PUFA administration, LDL was significantly lower in the SD rats than in controls (13.67 ± 4.13 vs. 30.83 ± 2.86 mg/dL, P < 0.001), but the decrease in the HFD rats, although significant (49.17 ± 5.85 mg/dL vs. 57.17 ± 4.96 g/dL, P < 0.05), was not as marked. In the mixed-diet groups, administration of 50 mg/kg/day FO for 14 days under SD conditions following 4 weeks of HFD slightly decreased TG (86.625 ± 11.67 vs. 73 ± 4.52 mg/dL, P < 0.05) and increased HDL (45.875 ± 5.28 vs. 56 ± 3.16 mg/dL). However, in these animals, n-3 PUFA administration had no effect on LDL or TC. Administration of half of the above dose failed to improve any biochemical parameters. FO protected against excessive weight gain mainly under SD conditions. CONCLUSIONS: The results show that FO confers more protection against cardiovascular risk factors (increased LDL and TG, decreased HDL) and liver lipid accumulation when given to rats consuming regular diets than when given to rats consuming a high-fat diet. This argues that priority should be given to consumption of a healthy diet rather than to the use of supplements. The effectiveness of n-3 PUFAs might be reduced in the case of hyperlipidic intake or after consumption of a high-fat diet.

The safety profile of new antidiabetic xanthine derivatives and their chitosan based formulations.

The safety profile of new antidiabetic xanthine derivatives with thiazolidine­4­one scaffold (6, 7) and their new chitosan based formulations (CS-6, CS-7), administrated to diabetic rats, have been evaluated in terms of biochemical markers of liver and kidney function as well as of hematological markers. The effect on lipid profile and clinic parameters (body weight, food and water intake) has been also evaluated. The treatment of diabetic rats with xanthine derivatives (6, 7) and chitosan based formulations (CS-6, CS-7) was associated with lower liver enzymes (AST, ALT, LDH) and bilirubin (direct, total) values compared to the non-treated diabetic rats, that means the tested derivatives/formulations have improved the liver function injured in diabetes mellitus conditions. Also the kidney biochemical markers (creatinine, uric acid, urea) were significantly decreased in diabetic rats treated with 6, 7 and chitosan microparticles (CS-6, CS-7). The values of biochemical markers of liver and kidney functions were even better than the values recorded for pioglitazone, used as standard antidiabetic drug. The improving effect on kidney function was proved by the histopathological study. Moreover, the xanthine derivatives and their chitosan based formulation were associated with improved hematological markers compared to the non-treated diabetic rats which mean the improving of the hemorheological state. These results support the safety profile of new xanthine derivatives with thiazolidine­4­one scaffold (6, 7) and their new chitosan based formulations (CS-6, CS-7) and their potential applications for the treatment of diabetes mellitus syndrome.

Experimental Research Showing the Reduction of Naloxone-Place Aversion by Oral Zinc Administration in Rats.

Previous studies showed the attenuation of both morphine-dependence and morphine-place preference by zinc. Conditioned place preference and aversion are experimental models frequently used to test the reward-stimulating, respectively the aversive effects induced by different stimuli or substances. Addictive substances usually induce place preference (exhibit reward-stimulating properties), while their antagonists determine place-avoidance (aversion). The present study aimed to assess the effect determined by zinc sulphate oral administration (2 and 4 mg/kg/day, 14 days, prior to habituation) on the place aversion induced by two naloxone doses (1.5 and 2.5 mg/kg/administration). The results show a robust, dose-dependent reduction of the aversion determined by both naloxone doses (the aversion induced by 1.5 mg/kg naloxone was reduced with 15%-the lower zinc dose and with 24%-the higher zinc dose; the aversion induced by 2.5 mg/kg naloxone was reduced with 16%-the lower zinc dose and with 29%-the higher zinc dose). This represents a new proof of the interactions between zinc and opioidergic system and a further argument for dietary zinc supplementation in patients on opioids for cancer-related chronic pain.

Toxicity, Biocompatibility, pH-Responsiveness and Methotrexate Release from PVA/Hyaluronic Acid Cryogels for Psoriasis Therapy.

Poly(vinyl alcohol)/hyaluronic acid cryogels loaded with methotrexate were studied. The physical⁻chemical characterization of cryogels was performed by FT-IR spectroscopy, scanning electron microscopy, differential scanning calorimetry and dynamic mechanical thermal analysis. Acute toxicity and haematological parameters were determined by "in vivo" tests. The biocompatibility tests proved that the obtained cryogels showed significantly decreased toxicity and are biocompatible. The pH-responsiveness of the swelling behaviour and of the methotrexate release from the poly(vinyl alcohol)/hyaluronic acid (PVA/HA) cryogels were studied in a pH interval of 2⁻7.4. A significant change in properties was found at pH 5.5 specific for treatment of affected skin in psoriasis disease.

Zinc involvement in opioid addiction and analgesia--should zinc supplementation be recommended for opioid-treated persons?

INTRODUCTION: Zinc chelators were shown to facilitate some opioid-withdrawal signs in animals. Zinc deficiency, which affects more than 15% the world's population, is also common among opioid consumers and opioid-treated animals exhibit misbalances of zinc distribution. AIM: The present study focuses on how zinc ions interfere with opioid dependence/addiction and analgesia, trying to preliminary discuss if zinc supplementation in opioid-users should be recommended in order to reduce the risk of addiction. METHODS: All relevant literature was searched up to April 2015. The search was performed using the term "zinc" plus combinations of following terms: "opioid receptors", "opioid" or representatives of this class, "addiction", "dependence", "analgesia", and "pain". Human, animal, in vitro studies and reviews were including. RESULTS: Both human and animal studies revealed decreased serum zinc under opioid-administration conditions, attributed mainly to increased urinary elimination (humans) or redistribution (animals). Moreover, animal studies revealed decreased brain zinc levels in morphine-treated animals, with increased zinc hepatic levels, but also an enhancement of endogenous opioid system activity and a possible reduction of morphine withdrawal by zinc. In vitro studies revealed reduction of opioid ligands binding to receptors by zinc. However, the very few in vivo animal studies on opioid analgesia revealed controversial results, as zinc demonstrated clear analgesic effect, but zinc associated to opioids doesn't result in a potentiation of the analgesic effect. CONCLUSION: Zinc dietary supplementation in patients treated with opioids for cancer-related chronic pain should be considered, due to the high incidence of zinc deficiency, also well-documented in opioid consumers. The low toxicity of orally-administered zinc also pleads for this idea. The main contra-argument to zinc administration in opioid-treated persons is related to the way zinc influences opioid-induced analgesia.