Lappaconitine trifluoroacetate contained polyvinyl alcohol nanofibrous membranes: Characterization, biological activities and transdermal application.

Lappaconitine (LA), a potent analgesic drug extracted from the root of natural aconitum species, has been clinically used for years because of its effectiveness and non-addictive properties. However, it is mainly limited in oral and intravenous administration in the form of Lappaconitine Hydrobromide (LAH). In this work, Lappaconitine trifluoroacetate (LAF), a new derivative of LA, was successfully obtained by introducing organofluorine group to LA. This new compound had a lower toxicity (LD50 of 21.14 mg·kg-1), improved analgesic effect and longer half-life (T1/2 of 2.24 h) when compared with LAH. Moreover, in vitro transdermal permeation (Jss of 206.82 µg·cm-2·h-1) of LAF was 30.54% higher than that of LAH, means that LAF can be conveniently used for transdermal drug delivery (TDD). Therefore, drug membranes with PVA solution (10 wt%) containing LAF in various amounts were fabricated by electrospinning. The in vitro release tests confirmed that up to 81.43% of LAF in the PVA/LAF nanofibrous membranes could be released in 72 h, accompanied by significant analgesic effect when compared with the blank control group. In conclusion, the prepared LAF-loaded membrane is a novel formulation for the treatment of chronic and long-term pain.

Application of Trifluoroacetic Acid as a Theranostic Agent for Chemical Ablation of Solid Tissue.

PURPOSE: To evaluate trifluoroacetic acid (TFA) as a theranostic chemical ablation agent and determine the efficacy of TFA for both noninvasive imaging and tissue destruction. MATERIALS AND METHODS: Fluorine-19 magnetic resonance imaging (19F-MRI) was optimized at 7 T using a custom-built volume coil. Fluorine images were acquired with both rapid acquisition with relaxation enhancement and balanced steady-state free precession (bSSFP) sequences with varying parameters to determine the optimal sequence for TFA. The theranostic efficacy of chemical ablation was examined by injecting TFA (100 µL; 0.25, 0.5, 1.0, and 2.0M) into ex vivo porcine liver. 19F and proton MRI were acquired and superimposed to visualize distribution of TFA in tissue and quantify sensitivity. Tissue damage was evaluated with gross examination, histology, and fluorescence microscopy. RESULTS: The optimal 19F-MRI sequence was found to be bSSFP with a repetition time of 2.5 ms and flip angle of 70°. The minimum imageable TFA concentration was determined to be 6.7 ± 0.5 mM per minute of scan time (0.63×0.63×5.00 mm voxel), and real-time imaging (temporal resolution of at least 1 s-1) was achieved with 2M TFA both in vitro and in ex vivo tissue. TFA successfully coagulated tissue, and damage was locally confined. In addition to hepatic cord disruption, cytoskeletal collapse and chromatin clumping were observed in severely damaged areas in tissues treated with 0.5M or higher TFA concentrations. CONCLUSIONS: TFA was determined to be a theranostic agent for chemical ablation of solid tissue. Ablation was both efficacious and imageable in ex vivo healthy tissue, even at low concentrations or with high temporal resolution.

Intracortical Administration of the Complement C3 Receptor Antagonist Trifluoroacetate Modulates Microglia Reaction after Brain Injury.

Worldwide, millions of individuals suffer an ischemic stroke each year, causing major disability, especially in the elderly, where stroke is the number one cause of disability. However, to date, no effective therapy exists that targets the functional recovery after stroke. After necrosis, neuroinflammation is a common feature of the acute stroke and a major obstacle to tissue restoration. In the lesioned area, the dying neurons release chemotactic signals, such as fractalkine/CX3CL1, which evoke "eat-me" signals that are recognized by microglia expressing complement C3a receptor (C3aR), resulting in phagocytosis of the dying but still viable neurons, known as secondary phagocytosis. Using a mouse model of stroke and two-photon microscopy, we aimed to attenuate poststroke phagocytosis of the dying but still viable neurons by using SB 290157, an antagonist of C3aR. We found that intracortical administration of SB 290157 reduced the number of inflammatory microglial cells expressing ED1 and Iba1 antigens at the lesion site. We could show, in vivo, that two days after a needle-induced cortical lesion there were less microglial cells present around the injury site, displaying less high-order branches and an increase in the lower order ones, suggesting an attenuated phagocytic phenotype in treated animals as compared with controls. We conclude that the C3aR antagonist, SB 290157, may be used in the future to limit the neuronal death by limiting secondary phagocytosis after stroke.

Sequential administrations of trifluoroacetate induce tolerance to Palicourea maccgravii, a monofluoroacetate-containing plant, in calves.

Monofluoroacetate (MFA) is considered one of the most toxic substances known. It is found naturally in plants, and causes sudden death syndrome in ruminants. Due to hyperacute evolution of poisoning and the absence of effective treatment, induction of resistance in animals might be the best tool to control MFA poisoning in ruminants. The objective of this study was to promote resistance in cattle against the toxic effects of MFA through its degradation by the ruminal microbiota after the administration of sodium trifluoroacetate (TFA). Ten calves were distributed into two groups: control group (n = 3) and treated group (n = 7). The calves in the treated group received 0.1 mg/kg live weight of TFA, whereas, those in the control group received water; both for 28 consecutive days. The calves were subjected to daily clinical evaluation and weekly blood biochemical determination to identify any signs of poisoning. After 28 d of administration of TFA or water, 2.0 g/kg body weight of Palicourea marcgravii leaves (containing 0.15% MFA) were administered using a stomach tube to determine the occurrence of resistance. The administration of TFA did not induce any clinical or biochemical changes in blood. The administration of P. marcgravii induced clinical changes in the calves of control group, but there was no change in the calves of the treated group. In conclusion, the administration of TFA to cattle can induce effective resistance against MFA poisoning.

Antitumor effects of rhodium (II) complexes on mice bearing Ehrlich tumors.

Rhodium (II) trifluoroacetate (TFARh), rhodium (II) trifluoroacetate adduct with sulfadiazine (TFARh.Sd) and rhodium (II) acetate adduct with sulfisoxazole (RhSx) were tested in mice for acute toxicity, antitumoral activity against Ehrlich ascites carcinoma and for viability of Ehrlich tumor cells in culture. At ip doses up to 60 mumol/kg (40-70 and 59 mg/kg, respectively), these compounds had no toxic effects up to 14 days. At ip doses of 10 mumol kg-1 day-1 for 5 days, TFARh and TFARh.Sd significantly increased the survival rate of mice bearing Ehrlich ascites cells (probability of survival to the end of 34th day, controls = 0.23, TFARh = 0.85, TFARh.Sd = 0.74). No significant effect was observed for RhSx. In vitro, these rhodium complexes at 40 microM significantly increased the number of dead cells in cultured Ehrlich tumor cells.

Antitumor effects of rhodium (II) complexes on mice bearing Ehrlich tumors

Rhodium (II) trifluoracetate (TFARh), rhodium (II) trifluoracetate adduct with sulfadiazine (TFARh.Sd) and rhodium (II) acetate adduct with sulfisoxazole (RhSx) were tested in mice for acute toxicity, antitumoral activity against Ehrlich ascites carcinoma and for viability of Ehrlich tumor cells in culture. At ip doses up to 60 µmg/kg (40-70 and 59 mg/kg, respectively), these coumpounds had no toxic effects up to 14 days. At ip doses of 10 µmol Kg-1 day-1 for 5 days, TFARh and TFARh.Sd significantly increased the survival rate of mice bearing Ehrlich ascites cells (probability of survival to the end of 34th day, controls = 0.23, TFARh = 0.85, TFARh.Sd = 0.74). No significant effect was observed for RhSx. In vitro, these rhodium complexes at 40 µM significantly increased the number of dead cells in cultured Ehrlich tumor cells

Cystic duct occlusion and transcatheter sclerosis of the gallbladder in the rabbit.

We have identified a reliable sclerosant of the gallbladder in rabbits. After ligating the cystic ducts with a silk ligature in 24 rabbits and aspirating the bile from the gallbladder, we instilled a mixture of 95% ethanol and either 2 M% trifluoroacetic acid (TFA) or 5 M% TFA into the gallbladder. The animals were killed after 6 or 8 weeks. Ethanol with TFA resulted in replacement of gallbladder lumen with fibrous tissue in 22 rabbits. The two sclerosants were equally reliable and produced quantitatively similar fibrosis in the rabbits. The tendency for normal biliary mucosa to repopulate a sclerosed gallbladder can be obviated by complete occlusion of the cystic duct. The parameters for successful transcatheter sclerosis of the gallbladder have now been defined in an animal model.

Transcatheter sclerosis of the gallbladder in rabbits. A preliminary study.

Catheter sclerosis of 56 rabbit gallbladders was attempted at laparotomy. The proximal cystic duct was occluded with a hemoclip and transcatheter administration of six different sclerosing agents and a saline control was performed. Eight animals were used for each agent, three being sacrificed after two weeks and the remainder after six weeks. Hot contrast and sotradecol were comparable with saline in their lack of effect on gallbladder mucosa. Alcohol alone, tetracycline, methylcyanoacrylate and alcohol plus trifluoroacetic acid were successful at two weeks in denuding the gallbladder epithelium and promoting fibrosis of the gallbladder wall. After six weeks, evidence of mucosal regeneration was present with all agents, and the epithelium appeared to have grown back from the occluded cystic duct. Late regeneration has not been previously reported and its significance when considering the application of the technique to the human gallbladder is discussed.

Humoral immunity to a metabolite of halothane, fluroxene, and enflurane.

Trifluoroacetate, a common metabolite of halothane, fluroxene, and enflurane, conjugated to guinea-pig albumin elicits specific serum antibody in guinea pigs. Two classes of antibodies were found: hemolytic, gamma-2, and anaphylactic, gamma-1. Repeated injections of the antigen, trifluoroacetyl-guinea pig albumin, often led to disappearance of circulating antibodies.