Antinociceptive effect of systemically administered dipyrone (metamizol), magnesium chloride or both in a murine model of cancer.

BACKGROUND: Opioid effectiveness to treat cancer pain is often compromised by the development of tolerance and the occurrence of undesirable side effects, particularly during long-term treatment. Hence, the search for more efficient analgesics remains a necessity. The main goal of this study was to relieve neuropathic symptoms associated with tumour growth by administering the non-opioid analgesic dipyrone (DIP) alone or in combination with magnesium chloride (MgCl2 ), an adjuvant that blocks the NMDA receptor channel. METHODS: Mice were inoculated with a melanoma cell line (B16-BL6) in the left thigh and two protocols were used to evaluate the effect of DIP (270 mg/kg), MgCl2 (200 mg/kg), or the combination DIP-MgCl2 . In the therapeutic protocol the drugs, alone or combined, were administered once tumour had promoted increased nociception. In the preventive protocol, drugs were administered prior to the appearance of the primary tumour. Tumour growth was assessed with a caliper and nociception was determined using behavioural tests. RESULTS: DIP promoted antinociception only at the beginning of both protocols due to the development of tolerance. The combination DIP-MgCl2 improved the antinociceptive effect, avoiding tolerance and reducing tumour growth in the preventive treatment, more efficiently than each compound alone. CONCLUSIONS: These results suggest that DIP-MgCl2 may represent a safe, affordable and accessible option to reduce tumour growth and to treat cancer pain avoiding the risk of tolerance, without the typical complications of opioids agents, particularly when long-term treatment is required. SIGNIFICANCE: This study shows a non-opioid analgesic combined with an adjuvant as a therapeutic option to treat cancer pain. The avoidance of antinociceptive tolerance when repeated administration is required, as well as tumor growth reduction, are additional advantages to be considered.

IL-1 and TNF receptor-deficient mice show decreased inflammation in an immune complex model of uveitis.

PURPOSE: To determine the role of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in the induction of uveitis by a reverse passive Arthus reaction (RPAR). METHODS: Human serum albumin (HSA) antiserum was injected into the vitreous of "knockout" or "double knockout" mice genetically deficient in IL-1 receptor type I (IL-1RI-/-), TNF receptors p55 and p75 (TNFR p55-/-/p75-/-), IL-1RI and TNFR p55 (IL-1RI-/-/TNFR p55-/-), and controls. Twenty-four hours later, animals were challenged with intravenous HSA. Eyes were enucleated 4 hours after antigen challenge, and inflammation was quantitated by counting cells on histologic sections. Interleukin-6 in aqueous humor was measured with a B9 cell bioassay. The distribution of immune complexes in eyes was observed by immunohistochemical staining for IgG and complement component C3. RESULTS: Four hours after antigen challenge, immune complexes were localized at the ciliary body and iris of receptor-deficient mice. A transient uveitis was most severe at this time. A significant reduction in the median number of infiltrating cells was found in TNFR p55-/-/p75-/- mice (4.8, n = 15), compared with controls (14.2, n = 20, P < 0.05). The median number of infiltrating cells was significantly reduced in IL-1RI-/- mice (knockout 2.6, n = 11; controls 7.4, n = 8, P < 0.005). Interleukin-1RI-/-/TNFR p55-/- mice had a strong reduction in infiltrating cells (knockout 1.6, n = 11; controls 27.3, n = 12, P = 0.002). Interleukin-6 activity in aqueous humor was reduced in IL-1RI-/-/TNFR p55-/- mice (P = 0.03) but not in TNFR p55-/-/p75-/- (P = 0.40) mice. Most IL-1RI-/-mice had no detectable aqueous humor IL-6, but this group was not statistically different from controls. CONCLUSIONS: In contrast to endotoxin-induced uveitis, both IL-1 and TNF appear to have critical roles in RPAR uveitis. When receptors for these cytokines were deleted, the severity of immune complex-induced uveitis was profoundly reduced.

Murine endotoxin-induced uveitis, but not immune complex-induced uveitis, is dependent on the IL-8 receptor homolog.

PURPOSE: To determine the roles of the murine interleukin-8 receptor homolog (mIL-8Rh, neutrophil chemokine CXC receptor 2) and macrophage inflammatory protein-1alpha (MIP-1alpha, a CC chemokine) in two eye inflammation models: endotoxin-induced uveitis (EIU) and immune complex-induced uveitis (reverse passive Arthus reaction (RPAR) uveitis). METHODS: For the EIU model, 250 ng E.coli endotoxin was injected into the vitreous of mIL-8Rh-/- mice or heterozygous littermate mIL-8Rh+/- controls and into MIP-1alpha-/- mice or congenic MIP-1alpha+/+ controls. Eyes were harvested after 24 h for histologic characterization of infiltrating cells and IL-6 bioassays. For the RPAR model, mouse antiserum against human serum albumin (HSA) was injected into the vitreous of mIL-8Rh-/-, mIL-8Rh+/-, MIP-1alpha-/-, and MIP-1alpha+/+ mice. Twenty-four hours later, animals were challenged with intravenous HSA. Eyes were harvested after 4 h for analysis. RESULTS: RPAR resulted in the deposition of immune complexes at the ciliary area and iris with the subsequent development of uveitis. Genetic deficiency of mIL-8Rh reduced the median number of infiltrating cells in EIU by 63% (p < 0.01) but had no effect on RPAR-induced inflammation. In the EIU model, macrophages comprised a much higher percentage (45%) of infiltrating cells in mice lacking mIL-8Rh than in controls (17%). Loss of the MIP-1alpha gene had no apparent effect on RPAR uveitis and a 39% reduction of infiltrating cells in EIU that was not statistically significant. IL-6 activity in aqueous humor was much less in mice with RPAR uveitis than in those with EIU. Neither gene deletion had a significant impact on IL-6 levels in either disease model. CONCLUSIONS: Chemokines acting via mIL-8Rh have a significant role in the induction of neutrophil infiltration during EIU but not during RPAR uveitis. MIP-1alpha is not critical for either EIU or RPAR-induced uveitis. The differential dependence on IL-8-like chemokines is in accord with the two forms ofuveitis having different etiologies and, therefore, potentially different optimal therapies.

Increased lipopolysaccharide-induced tumour necrosis factor levels and death in hypercholesterolaemic rabbits.

Nutritional-induced hypercholesterolaemia in New Zealand rabbits causes increased susceptibility to experimental infections. Rabbits fed cholesterol (0.5 g%) for 8 weeks were injected intravenously with varying doses of Escherichia coli 0127: B8 lipopolysaccharide (LPS; 3-100 micrograms/kg). The levels of cholesterol, triglycerides, tumour necrosis factor (TNF), and the survival rates of treated rabbits were then measured. Rabbits fed either normal chow or chow impregnated with sesame oil were used as controls. LPS induced higher serum TNF levels in hypercholesterolaemic rabbits than in normal rabbits or rabbits fed with chow containing sesame oil. TNF levels rose faster in hypercholesterolaemic rabbits than in normal rabbits, reaching maximum levels at 60 min and 120 min, respectively, after LPS injection. The survival rate of hypercholesterolaemic rabbits (1/11) was lower than in normal rabbits (6/7) or rabbits fed with the sesame oil chow (4/4) at the higher LPS doses. No death occurred at lower doses. One possible interpretation of these results, also supported by neutralization experiments, is that increased TNF secretion in hypercholesterolaemic rabbits raises the host's susceptibility to experimental endotoxaemia and possibly to Gram-negative infection.

Iron overload augments the development of atherosclerotic lesions in rabbits.

Iron, a major oxidant in vivo, could be involved in atherosclerosis through the induction of the formation of oxidized LDL, a major atherogenic factor. This study was designed to test this hypothesis experimentally. Four groups of New Zealand White rabbits were included: iron-overloaded/hypercholesterolemic (group A, n = 8), iron-overloaded (group B, n = 6), hypercholesterolemic (group C, n = 6), and untreated (group D, n = 6). Iron overload was achieved by the intramuscular administration of 1.5 g of iron dextran divided in 30 doses. Hypercholesterolemia was produced by feeding rabbit chow enriched with 0.5% (wt/wt) cholesterol. Serum iron, ferritin, cholesterol, triglycerides, and lipoperoxides in serum were measured throughout the study. Lipoperoxides were measured at the end of the study in liver, aorta, and spleen homogenates. Aortas of groups A and C had multiple lesions; however, group A had greater lesional involvement than group C (P < .05). Lesions were not observed in rabbits fed normal chow (group D). As expected, serum iron and ferritin were above normal levels in groups A and B. Serum cholesterol increased in groups A and C. Lipoperoxides in liver and spleen homogenates of iron-overloaded rabbits were increased. Interestingly, iron deposits were seen by ultrastructural studies in the arterial walls of rabbits in groups A and B. Our study suggests that iron overload augments the formation of atherosclerotic lesions in hypercholesterolemic rabbits.