Response After Repeated Ketamine Injections in a Rat Model of Neuropathic Pain.

Ketamine, an N-methyl-D-aspartate antagonist, reduces pain by decreasing central sensitization and pain windup. However, chronic ketamine use can cause tolerance, dependency, impaired consciousness, urinary symptoms, and abdominal pain. This study aimed to investigate the effects of repeated ketamine injections and ketamine readministration after discontinuation in a rat model of neuropathic pain. To induce neuropathic pain, partial sciatic nerve ligation (PSNL) was performed in 15 male Wistar rats, and these animals were divided into three groups: PSNL (control), PSNL + ketamine 5 mg/kg (K5), and PSNL + ketamine 10 mg/kg (K10; n=5 each). Ketamine was injected intraperitoneally daily for 4 weeks, discontinued for 2 weeks, and then readministered for 1 week. Following PSNL, the mechanical withdrawal threshold was determined weekly using the Von Frey. The K10 group showed a significant increase in the mechanical withdrawal threshold, presented here as the target force (in g), at 21 and 28 days compared to the time point before ketamine injection (mean±SE, 276.0±24.0 vs. 21.6±2.7 and 300.0±0.0 vs. 21.6±2.7, respectively; P<0.01) and at 14, 21, and 28 days compared to the control group (108.2±51.2 vs. 2.7±1.3, 276.0±24.0 vs. 2.5±1.5, and 300.0±0.0 vs. 4.0±0.0, respectively; P<0.05). However, in the K10 group, the ketamine effects decreased significantly at 7 days after readministration compared to those after 28 days of repeated injections (P<0.05). In the K10 group, repeated ketamine injections showed a significant increase in antinociceptive effect for >2 weeks, but this ketamine effect decreased after drug readministration.

Application of the combined use of ultrasonic homogenization and electro-spraying in the formation of nano carrier systems.

Chitosan-coated nano-liposomes containing etofenprox were prepared by ultrasonic homogenization (UH) and a combined use of UH and electro-spraying. The physicochemical properties of the resulting samples were examined and compared. The two methods yielded similar values and tendencies, except for encapsulation efficiency that differed by an average of 15%. In the coating process, as the chitosan concentration increased (0.1-0.5%, w/v) and the degree of deacetylation increased (chitosans A, B and C), the surface charge of the nano carrier likewise increased and carrier size distribution was altered. The encapsulation efficiency as measured by gas chromatography decreased slightly with the increasing chitosan concentration (0.1-0.5%, w/v). The results indicate that diverse preparation conditions could affect the physicochemical properties of the resulting nano carrier systems.

Influence of chitosan coating on the liposomal surface on physicochemical properties and the release profile of nanocarrier systems.

Chitosan-coated nanoliposomes containing etofenprox or alpha-cypermethrin prepared by ultrasonic homogenization maintained a size distribution in the nanometre range. Nanoliposomes were constructed using different types and concentrations of chitosan to regulate the mean size and surface charge. As the chitosan concentration (0.1-0.5%, w/v) and the degree of deacetylation increased, surface charge also increased. The encapsulation efficiency and release profile were measured by gas chromatography. Encapsulation efficiency decreased slightly as chitosan concentration increased (0.1-0.5%, w/v). As the intrinsic surface charge or concentration of the coating material increased, the release period of the entrapped core material was extended (chitosans A and B; 0.1 and 0.3%, w/v). The results indicate that diverse preparation conditions could affect the physicochemical properties and release profile of the resulting nanocarrier systems.

Plasma nitroglycerin concentrations and hemodynamic effects of sublingual, ointment, and controlled-release forms of nitroglycerin.

After a sublingual test dose, 12 healthy men aged 21 to 29 yr were treated with controlled-release transdermal nitroglycerin skin patches designed to deliver 10 mg/day nitroglycerin and with nitroglycerin ointment (2%) (1-in amount from the tube spread over 50 cm2) for 24 hr in a double-blind crossover study. Assessment was by measurement of nitroglycerin in plasma, blood pressure, and pulse rate. The mean plasma concentration of nitroglycerin during ointment dosing was approximately 200% to 400% that during skin patch dosing. Levels during ointment dosing were closer to those from sublingual dosing than were those during skin patch dosing. Blood pressure and pulse rate changes were much the same during both transdermal treatments. Calculations showed that delivery of nitroglycerin from the skin patches would have to be over 40 to 80 cm2 of the skin to achieve nitroglycerin exposure of the order of that induced by 1 in of ointment spread over 50 cm2 or from sublingual dosing.

Pharmacokinetics of nitroglycerin and its metabolites after administration of sustained-release tablets.

Nitroglycerin was administered to eight healthy volunteers in the form of sublingual tablets, oral sustained-release tablets, and an oral solution. Blood samples were collected for measurement of nitroglycerin and its two isomeric glyceryl dinitrate metabolites. Blood pressure and pulse rate were monitored; subjective evaluations of headache, dizziness, facial flushing, skin irritation, and gastrointestinal upset were made. Nitroglycerin itself was virtually undetectable after the solution and tablet preparations; the metabolites were consistently detectable from a few minutes after dosing to 24 h later. Mean total (nitroglycerin plus metabolite) concentrations were comparable in the 15 min following sublingual administration, and the 8 h following tablet administration. The relative bioavailability of the tablets in comparison with the oral solution was 70 per cent based on metabolite concentrations. Nitroglycerin sustained-release tablets appear to exert their beneficial effects in the prolonged prophylaxis of angina through active metabolites.

Plasma concentrations and hemodynamic effects of intravenous, sublingual, and aerosolized nitroglycerin in patients undergoing cardiac catheterization.

Intravenous, sublingual, or aerosolized nitroglycerin was administered to 19 patients with coronary artery disease during clinically indicated cardiac catheterization. Eight blood samples were collected over 15 min from each patient, and analyzed for content of nitroglycerin, 1,2-glycerol dinitrate, and 1,3-glycerol dinitrate. Simultaneously, heart rate (HR), systolic blood pressure (SBP), and left ventricular end-diastolic pressure (LVEDP) were recorded. Plasma concentrations of nitroglycerin were highest after intravenous injection and lowest after sublingual tablets. Metabolite concentrations were highest after intravenous injection at early time-points; at later time-points, no between-group differences could be detected. SBP was minimally affected by intravenous nitroglycerin but was significantly reduced by sublingual and aerosolized formulations. Minor fluctuations in HR were observed in association with all three formulations. LVEDP was reduced by all three formulations of nitroglycerin but most rapidly by the intravenous form. Overall, no differences were detected in hemodynamic responses caused by sublingual and aerosolized nitroglycerin. Efficacy of sublingual and aerosolized nitroglycerin in patients undergoing cardiac catheterization is equivalent.