fumaric-acid and Disease-Models--Animal

Topical administration is a promising clinical strategy to avoid serious gastrointestinal adverse reactions of loxoprofen sodium (LOX), a new non-steroidal anti-inflammatory drug. Small molecule organic acids had been reported with the ability of promoting transdermal rate of several drugs. In this article, the effect of small molecule organic acids on the transdermal delivery of LOX was studied, and the possible mechanism was also explored by Fourier infrared spectroscopy, differential scanning calorimetry, tape stripping, etc. The results showed that lactic acid and fumaric acid could significantly increase the penetration rate of LOX and reduce time lag even without the help of acidic environment. The preliminary mechanism investigation inferred that fumaric acid could increase LOX's distribution in stratum corneum and might change its complexation state, but had little effect on the drug structure and skin's lipids and proteins configuration. The topical LOX gel using fumaric acid as penetration enhancer had higher transdermal rate, significant anti-inflammatory effect and no obvious skin irritation. This study proved the promising application of small molecule organic acids in transdermal enhancing and provided a potential strategy for transdermal delivery of LOX combined with fumaric acid.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Disease Models, Animal; Female; Fumarates; Gels; Inflammation; Lactic Acid; Male; Phenylpropionates; Rabbits; Rats, Sprague-Dawley; Skin; Skin Absorption; Swine; Swine, Miniature; Time Factors

Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.

Topics: Adenosine Monophosphate; Animals; Aspartic Acid; Citric Acid Cycle; Disease Models, Animal; Electron Transport; Electron Transport Complex I; Fumarates; Ischemia; Malates; Male; Metabolomics; Mice; Mitochondria; Myocardial Infarction; Myocardium; Myocytes, Cardiac; NAD; Reactive Oxygen Species; Reperfusion Injury; Stroke; Succinate Dehydrogenase; Succinic Acid

The present study aimed to develop and characterize new formulations of dipyridamole (DP), a pH-dependent poorly soluble drug, employing an acidic pH-modifier for improving dissolution and absorption under hypochlorhydric condition. Granule formulations of DP (DPG) with and without fumaric acid (FA) were prepared with wet granulation, physicochemical properties of which were characterized focusing on morphology, dissolution and stability. Pharmacokinetic profiling of orally dosed DPG or DPG with 60% loading of FA (DPG/FA60) was carried out in omeprazole-treated rats as a hypochlorhydric model. Although pH-dependent dissolution behavior was observed in DPG, DPG/FA exhibited high rate and extent of dissolution in both acidic and neutral media. Complete supersaturation was achieved with a 2 h testing period in pH6.8 medium, and co-existing fumaric acid had no impact on the chemical/photochemical stability of DP in solid-state. After oral administration of DPG or DPG/FA60 (10 mg-DP/kg), there was ca. 40% reduction of AUC(0-3) for DPG in omeprazole-treated rats as compared to that in normal rats; however, AUC(0-3) for DPG/FA60 under hypochlorhydria was almost identical to that of DPG in normal rats. Given the improved systemic exposure early after oral administration in hypochlorhydric rats, the DPG/FA might provide better clinical outcomes in hypochlorhydric patients.

Topics: Achlorhydria; Administration, Oral; Animals; Area Under Curve; Biological Availability; Chemistry, Pharmaceutical; Chromatography, Liquid; Crystallization; Crystallography, X-Ray; Dipyridamole; Disease Models, Animal; Drug Compounding; Drug Stability; Fumarates; Half-Life; Hydrogen-Ion Concentration; Male; Metabolic Clearance Rate; Microscopy, Electron, Scanning; Omeprazole; Phosphodiesterase Inhibitors; Powder Diffraction; Rats; Rats, Sprague-Dawley; Solubility; Spectrometry, Mass, Electrospray Ionization; Technology, Pharmaceutical

2,3-Dimethoxy-5-methyl-1,4-benzoquinone (Q0), an analogue of ubiquinone, irreversibly paralyses the adult and microfilariae of the cattle filarial parasite Setaria digitata. The same concentration of Q0 that paralyses the microfilariae of S. digitata also paralyses the microfilariae of the human filarial parasite Wuchereria bancrofti within the same duration. Thus the experiments done in the model S. digitata system can well be extended to the human filarial system. A drug at the level of the quinone-centered energy generating system, perhaps an analogue of quinone like Q0, can inactivate the filarial parasites and may prove to be an effective drug to control filariasis.

Topics: Animals; Benzoquinones; Cattle; Disease Models, Animal; Dose-Response Relationship, Drug; Electron Transport; Filariasis; Fumarates; Glucose; Humans; Malates; Movement; NAD; Setaria Nematode; Setariasis; Sodium Lactate; Time Factors; Wuchereria bancrofti

Anticarcinogenic effects of the fumaric acid was studied in two rat models of carcinogenesis. Tumors of the esophagus, forestomach, tongue and throat were induced by peroral instillation of 35 mg/kg body weight N-methyl-N-benzylnitrosamine, and neurogenic and renal ones--by transplacental injection of 75 mg/kg body weight N-ethyl-N-nitrosourea. The fumaric acid given in drinking water in the dose of 1 g/l at the postinitiation stage of the carcinogenesis was shown to inhibit the development of esophageal papilloma, brain glioma and mesenchymal tumors of the kidney.

Topics: Animals; Anticarcinogenic Agents; Carcinogens; Chi-Square Distribution; Dimethylnitrosamine; Disease Models, Animal; Drug Screening Assays, Antitumor; Esophageal Neoplasms; Ethylnitrosourea; Female; Fumarates; Kidney Neoplasms; Male; Nervous System Neoplasms; Pregnancy; Prenatal Exposure Delayed Effects; Rats