Therapeutic Effects of Procainamide on Endotoxin-Induced Rhabdomyolysis in Rats.

Overt systemic inflammatory response is a predisposing mechanism for infection-induced skeletal muscle damage and rhabdomyolysis. Aberrant DNA methylation plays a crucial role in the pathophysiology of excessive inflammatory response. The antiarrhythmic drug procainamide is a non-nucleoside inhibitor of DNA methyltransferase 1 (DNMT1) used to alleviate DNA hypermethylation. Therefore, we evaluated the effects of procainamide on the syndromes and complications of rhabdomyolysis rats induced by lipopolysaccharide (LPS). Rhabdomyolysis animal model was established by intravenous infusion of LPS (5 mg/kg) accompanied by procainamide therapy (50 mg/kg). During the experimental period, the changes of hemodynamics, muscle injury index, kidney function, blood gas, blood electrolytes, blood glucose, and plasma interleukin-6 (IL-6) levels were examined. Kidneys and lungs were exercised to analyze superoxide production, neutrophil infiltration, and DNMTs expression. The rats in this model showed similar clinical syndromes and complications of rhabdomyolysis including high levels of plasma creatine kinase, acute kidney injury, hyperkalemia, hypocalcemia, metabolic acidosis, hypotension, tachycardia, and hypoglycemia. The increases of lung DNMT1 expression and plasma IL-6 concentration were also observed in rhabdomyolysis animals induced by LPS. Treatment with procainamide not only inhibited the overexpression of DNMT1 but also diminished the overproduction of IL-6 in rhabdomyolysis rats. In addition, procainamide improved muscle damage, renal dysfunction, electrolytes disturbance, metabolic acidosis, hypotension, and hypoglycemia in the rats with rhabdomyolysis. Moreover, another DNMT inhibitor hydralazine mitigated hypoglycemia, muscle damage, and renal dysfunction in rhabdomyolysis rats. These findings reveal that therapeutic effects of procainamide could be based on the suppression of DNMT1 and pro-inflammatory cytokine in endotoxin-induced rhabdomyolysis.

Electro-acupuncture at 'Neiguan' (PC6) attenuates liver injury in endotoxaemic rats.

BACKGROUND: Intravenous injection of lipopolysaccharide (LPS) stimulates macrophages to release proinflammatory cytokines and nitric oxide (NO). This results in hypotension, vascular hyporeactivity and multiple organ failure (eg, liver injury) in rats. In rats with endotoxin shock, electro-acupuncture (EA) of 'Neiguan' (PC6) retrieved blood pressure and reduced plasma concentrations of NO. The authors evaluated whether EA at PC6 could alleviate the development of liver injury and dysfunction in endotoxic rats. METHODS: A total of 28 male adult Wistar rats were included in this study. Rats received intravenous LPS (10 mg/kg for 4 h) or saline for 4 h followed by EA at PC6 acupuncture point. RESULTS: Elevated biochemical parameters of liver injury and marked infiltration of neutrophils into liver tissues caused by LPS were significantly attenuated by EA. However, hypotension, tachycardia and raised production of plasma NO were not suppressed by EA at PC6. CONCLUSIONS: These results indicate that EA at PC6 should be further investigated as a possible adjuvant therapy for endotoxin-induced liver dysfunction. Its mechanism of action needs further investigation.

Characteristics and dissemination of mosaic penicillin-binding protein 2-harboring multidrug-resistant Neisseria gonorrhoeae isolates with reduced cephalosporin susceptibility in northern Taiwan.

Among 254 Neisseria gonorrhoeae isolates from a sexually transmitted infection (STI) clinic in northern Taiwan, 69 isolates were found to contain the mosaic penA (MA) gene and were associated with elevated cefixime and ceftriaxone MICs. Most of these MA gene-harboring isolates were also resistant to penicillin (71.4%) and ciprofloxacin (100%) and were from men who have sex with men (MSM) or from bisexual men (81.2%). Three major sequence types (ST835, ST2180, and ST2253) constituted 55.7% of these isolates. The major sequence types harboring the mosaic penA gene may represent major sexual networks responsible for the emergence/introduction and the spread of the multidrug-resistant clones in Taiwan.

A study of the formulation design of acoustically active lipospheres as carriers for drug delivery.

Acoustically active lipospheres (AALs) were prepared using perfluorocarbons and coconut oil as the cores of inner phase. These AALs were stabilized using coconut oil and phospholipid coatings. A lipophilic antioxidant, resveratrol, was the model drug loaded into the AALs. AALs with various percentages of perfluorocarbons and oil were prepared to examine their physicochemical and drug release properties. Co-emulsifiers such as Brij 98 and Pluronic F68 (PF68) were also incorporated into AALs for evaluation. AALs with high resveratrol encapsulation rates ( approximately 90%) were prepared, with a mean droplet size of 250-350nm. The AALs produced with perfluorohexane as the core material had larger particle sizes than those with perfluoropentane. Resveratrol in these systems exhibited retarded drug release in both the presence and absence of plasma in vitro; the formulations with high oil and perfluorocarbon percentages showed the lowest drug release rates. The addition of PF68 slightly but significantly reduced resveratrol delivery from the AALs. Ultrasound treatment of 1MHz produced an increase in the drug release from the systems, illustrating the drug-targeting effect of the combination of AALs and ultrasound.

The effect of oil components on the physicochemical properties and drug delivery of emulsions: tocol emulsion versus lipid emulsion.

An emulsion system composed of vitamin E, coconut oil, soybean phosphatidylcholine, non-ionic surfactants, and polyethylene glycol (PEG) derivatives (referred to as the tocol emulsion) was characterized in terms of its physicochemical properties, drug release, in vivo efficacy, toxicity, and stability. Systems without vitamin E (referred to as the lipid emulsion) and without any oils (referred to as the aqueous micelle system) were prepared for comparison. A lipophilic antioxidant, resveratrol, was used as the model drug for emulsion loading. The incorporation of Brij 35 and PEG derivatives reduced the vesicle diameter to <100nm. The inclusion of resveratrol into the emulsions and aqueous micelles retarded the drug release. The in vitro release rate showed a decrease in the order of aqueous micelle system>tocol emulsion>lipid emulsion. Treatment of resveratrol dramatically reduced the intimal hyperplasia of the injured vascular wall in rats. There was no significant difference in this reduction when resveratrol was delivered by either emulsion or the aqueous micelle system. The percentages of erythrocyte hemolysis by the emulsions and aqueous micelle system were approximately 0 and approximately 10%, respectively. Vitamin E prevented the aggregation of emulsion vesicles. The mean vesicle size of the tocol emulsion remained unchanged during 30 days at 37 degrees C. The lipid emulsion and aqueous micelle system, respectively, showed 11- and 16-fold increases in vesicle size after 30 days of storage.