Antidotal efficacies of the cyanide antidote candidate dimethyl trisulfide alone and in combination with cobinamide derivatives.

Formulation optimization and antidotal combination therapy are the two important tools to enhance the antidotal protection of the cyanide (CN) antidote dimethyl trisulfide (DMTS). The focus of this study is to demonstrate how the formulation with polysorbate 80 (Poly80), an excipient used in pharmaceutical technology, and the combinations with other CN antidotes having different mechanisms of action enhance the antidotal efficacy of the unformulated (neat) DMTS. The LD50 for CN was determined by the statistical Dixon up-and-down method on mice. Antidotal efficacy was expressed as antidotal potency ratio (APR). CN was injected subcutaneously one minute prior to the antidotes' injection intramuscularly. The APR values of 1.17 (dose: 25 mg/kg bodyweight) and 1.45 (dose: 50 mg/kg bodyweight) of the neat DMTS were significantly enhanced by the Poly80 formulation at both investigated doses to 2.03 and 2.33, respectively. The combination partners for the Poly80 formulated DMTS (DMTS-Poly80; 25 and 50 mg/kg bodyweight) were 4-nitrocobinamide (4NCbi) (20 mg/kg bodyweight) and aquohydroxocobinamide (AHCbi; 50, 100, and 250 mg/kg bodyweight). When DMTS-Poly80 (25 and 50 mg/kg bodyweight; APR = 2.03 and 2.33, respectively) was combined with 4NCbi (20 mg/kg bodyweight; APR = 1.35), significant increase in the APR values were noted at both DMTS doses (APR = 2.38 and 3.12, respectively). AHCbi enhanced the APR of DMTS-Poly80 (100 mg/kg bodyweight; APR = 3.29) significantly only at the dose of 250 mg/kg bodyweight (APR = 5.86). These studies provided evidence for the importance of the formulation with Poly80 and the combinations with cobinamide derivatives with different mechanisms of action for DMTS as a CN antidote candidate.

Method development for detecting the novel cyanide antidote dimethyl trisulfide from blood and brain, and its interaction with blood.

The antidotal potency of dimethyl trisulfide (DMTS) against cyanide poisoning was discovered and investigated in our previous studies. Based on our results it has better efficacy than the Cyanokit and the Nithiodote therapies that are presently used against cyanide intoxication in the US. Because of their absence in the literature, the goal of this work was to develop analytical methods for determining DMTS from blood and brain that could be employed in future pharmacokinetic studies. An HPLC-UV method for detection of DMTS from blood, a GC-MS method for detection of DMTS from brain, and associated validation experiments are described here. These analytical methods were developed using in vitro spiking of brain and blood, and are suitable for determining the in vivo DMTS concentrations in blood and brain in future pharmacokinetic and distribution studies. An important phenomenon was observed in the process of developing these methods. Specifically, recoveries from fresh blood spiked with DMTS were found to be significantly lower than recoveries from aged blood spiked in the same manner with DMTS. This decreased DMTS recovery from fresh blood is important, both because of the role it may play in the antidotal action of DMTS in the presence of cyanide, and because it adds the requirement of sample stabilization to the method development process. Mitigation procedures for stabilizing DMTS samples in blood are reported.

Intravascular Residence Time Determination for the Cyanide Antidote Dimethyl Trisulfide in Rat by Using Liquid-Liquid Extraction Coupled with High Performance Liquid Chromatography.

These studies represent the first report on the intravascular residence time determinations for the cyanide antidote dimethyl trisulfide (DMTS) in a rat model by using high performance liquid chromatography coupled with ultraviolet absorption spectroscopy (HPLC-UV). The newly developed sample preparation included liquid-liquid extraction by cyclohexanone. The calibration curves showed a linear response for DMTS concentrations between 0.010 and 0.30 mg/mL with R2 = 0.9994. The limit of detection for DMTS via this extraction method was 0.010 mg/mL, and the limit of quantitation was 0.034 mg/mL. Thus this calibration curve provided a tool for determining DMTS in the range between 0.04 and 0.30 mg/mL. Rats were given 20 mg/kg DMTS dose (in 15% Polysorbate 80) intravenously, and blood samples were taken 15, 60, 90, 120, and 240 min after DMTS injections. The data points were plotted as DMTS concentration in RBCs versus time, and the intravascular residence time was determined graphically. The results indicated a half-life of 36 min in a rat model, suggesting that the circulation time is long enough to provide a reasonable time interval for cyanide antagonism.

Morphology control of nanofibril donor-acceptor heterojunction to achieve high photoconductivity: exploration of new molecular design rule.

Donor-acceptor nanofibril composites have been fabricated, and the dependence of their photocurrent response on the structure and morphology of the donor part has been systematically investigated. The nanofibril composites were composed of template nanofibers, assembled from an electron acceptor molecule, perylene tetracarboxylic diimide (PTCDI), onto which (through drop-casting) various electron donor molecules (D1-D4) were coated. The donor molecules have the same π-conjugated core, but different side groups. Due to the different side groups, the four donor molecules showed distinctly different propensity for intermolecular aggregation, with D1-D3 forming segregated phases, while D4 prefers homogeneous molecular distribution within the film. It was found that the nanofibril composites with D4 exhibit the highest photocurrent, whereas those with aggregation-prone D1-D3 exhibited much lower photocurrent under the same illumination condition. Solvent annealing is found to further enhance the aggregation of D1-D3 but facilitate more uniform molecular distribution of D4 molecules. As a result, the photocurrent response of PTCDI fibers coated with D1-D3 decreased after vapor annealing, whereas those coated with D4 further increased. The detrimental effect of the aggregation of donor molecules on the PTCDI fiber is likely due to the enhanced local electrical field built up by the high charge density around the aggregate-nanofiber interface, which hinders the charge separation of the photogenerated electron-hole pair. The results reported in this study give further insight into the molecular structural effect on photoconductivity of hybrid materials, particularly those based on donor-acceptor composites or interfaces, and provide new molecular design rules and material processing guidelines to achieve high photoconductivity.