Nitric oxide (NO)-induced death of gram-negative bacteria from a light-controlled NO-releasing platform.

A NO-delivery platform has been fabricated from polydimethylsiloxane (PDMS) and Pluronic(®) F127 gel that contains the light-sensitive NO donor, [Mn(PaPy(3))(NO)]ClO(4). The material was assembled layer-by-layer. First, a thin PDMS membrane was cast. It was then layered with cold 25% (w/v) Pluronic(®) F127 gel mixed with [Mn(PaPy(3))(NO)]ClO(4). Finally, it was covered with a thick layer (nearly impermeable to NO) of PDMS (=polydimethoxysiloxane) to allow release of NO only from the thinner side upon exposure to light. Light-induced NO release from this layered material has been confirmed via NO-specific electrode and by a modified soft Griess-agar assay. Incorporation of ca. 8 mg/g of [Mn(PaPy(3))(NO)]ClO(4) in the Pluronic gel layer affords a material that drastically reduces the microbial loads of Acinetobacter baumannii and Pseudomonas aeruginosa via the antibiotic effects of the photoreleased NO. Application of this flexible layered NO-donating composite as bandage material has been proposed.

Accelerated photorelease of NO from {Ru-NO}6 nitrosyls containing carboxamido-N and carboxylato-O donors: syntheses, structures, and photochemistry.

Three ruthenium nitrosyls, namely, [(Me(2)bpb)Ru(NO)(OAc)], [(Me(2)bpb)Ru(NO)(OBz)] (1), and [(Me(2)Qb)Ru(NO)(qca)](BF(4)) (2), have been synthesized from designed ligands with carboxamido-N donors. In all three complexes, a carboxylato-O donor is trans to the bound NO. The structures of 1 and 2 have been determined by X-ray crystallography. The nearly linear Ru-N-O bond angles [175.18(18) degrees and 175.0(3) degrees, respectively] and diamagnetism of the two nitrosyls are indicative of the {Ru-NO}(6) configuration. All three complexes exhibit nu(NO) in the range 1830-1890 cm(-1). When solutions of 1 and 2 are exposed to low-intensity (milliwatts) UV light, rapid release of NO is observed. The results of photochemical measurements indicate that the placement of the carboxylato-O donor trans to NO promotes the photorelease of NO in these nitrosyls much like Cl(-) and py. The presence of the carboxamido-N donor is, however, essential for the observed NO photolability because the structurally similar nitrosyl [(pyca)(2)Ru(NO)(Cl)] (3) (with carboxylato-O trans to NO) does not release NO upon exposure to UV light. Extension of conjugation in the ligand frame (quinoline rings in place of pyridine rings) increases both the rate of NO photorelease and the quantum yield of 2 compared to 1. The results of this investigation confirm that the combination of carboxamido-N donor(s) in the ligand frame and carboxylato-O trans to NO is a new structural motif in photoactive {Ru-NO}(6) nitrosyls.

Characterization of pHEMA-based hydrogels that exhibit light-induced bactericidal effect via release of NO.

A light-activated NO donor, [Mn(PaPy(3))(NO)]ClO(4) (1a), has been incorporated into HEMA-based polymer hydrogel and the nitrosyl-polymer conjugate materials 1a(x) · HG and 1a(x) · HG(MB) have been characterized. The NO releasing properties and antibacterial capabilities of these materials in conjunction with growth attenuators such as hydrogen peroxide and methylene blue (MB) are reported. Since the nitrosyl releases NO only upon exposure to light, materials like 1a(x) · HG(MB) could be used as wound dressings that deliver NO under controlled conditions.

Mitragyna speciosa: Balancing Potential Medical Benefits and Abuse.

Mitragyna speciosa, also known as kratom, has the potential meet the need for pain medications that lack the addictiveness and overdose risk of classical opioid analgesics, such as morphine. This need is urgent because opioid addiction and overdose deaths have risen throughout diverse segments of U.S. society. Some opioid addicts have found relief in kratom preparations. The use of kratom as an analgesic has been validated by historical accounts and contemporary pharmacological research. Although kratom is a promising source of analgesic candidates, it is a euphoriant with potential for both abuse and addiction. However, kratom appears to be less addictive and to have milder withdrawal symptoms than opioid drugs. Thus, there is a need to balance the potential medical benefits and abuse of M. speciosa.

High Drug Prices Hurt Everyone.

Turing Pharmaceuticals raised the price of Daraprim 5,500%, illustrating how the absence of competition in the sale of low-volume, low-price drugs can lead to price gouging. For patented medicines, society allows supracompetitive pricing to incentivize innovation. However, Gilead's decision to sell Sovaldi for $84,000 per course of treatment raised the question whether society must accept any price set by the patent holder. Unfortunately, these incidents illustrate a broader trend in which pharmaceutical prices are greater in the United States than abroad, placing the United States at the top in per capita expenditures on pharmaceuticals. The Canadian and Indian approaches to balancing patient access to medicines with other policy objectives, including stimulating investment in R&D, point to a multifaceted solution. Proposed solutions include prevention, increasing pharmaceutical coverage, and increasing transparency. Strategic policy requires access to information regarding R&D costs, private listing agreements (prices charged to different customers), and patient outcomes.

Synthesis, characterization, and light-controlled antibiotic application of a composite material derived from polyurethane and silica xerogel with embedded photoactive manganese nitrosyl.

The synthesis of a light-sensitive polyurethane-based composite material (PUX-NO) is described. In its polyurethane medium, PUX-NO contains entrapped silica xerogel particles in which a photoactive manganese nitrosyl has been incorporated. Green flexible films of PUX-NO readily release nitric oxide (NO) only when exposed to low power (mW) visible light. Incorporation of the nitrosyl in the xerogel not only retains the nitrosyl (NO donor) within the composite material but also provides the right extent of hydration. Pre-swelled films of PUX-NO have water content close to 30 Wt % and such films can be stored for months under slightly moist condition without loss in NO-delivering capacity. The NO-releasing parameters of the film have been determined. The NO-releasing capacity of PUX-NO films can be conveniently altered by changing the amount of the nitrosyl as well as the thickness of the films. Patches of PUX-NO film have been successfully employed to reduce drastically bacterial loads of both gram-positive and gram-negative bacteria including methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii under the total control of light. Effective control of infections by these bacterial pathogens via delivery of proper doses of NO only to the sites of infection appears feasible with PUX-NO films.

Eradication of Pathogenic Bacteria by Remote Delivery of Nitric Oxide via Light-Triggering of Nitrosyl-Containing Materials.

Although nitric oxide (NO) delivery systems have been fabricated with sol-gel-based materials, remote control of such systems with light has not been achieved. In this work, a fiber optic-based NO delivery system is described in which the photoactive metal-nitrosyl, [Mn(PaPy(3))(NO)]ClO(4) (1), has been employed in a sol-gel material. The material (1*FO) contains the manganese-nitrosyl which releases NO upon illumination with visible light. The NO-releasing capacity of 1*FO has been measured with an NO-sensitive electrode and the spatial diffusion of NO in solution has been visualized using the Griess reaction. The utility of 1*FO has been demonstrated in effective reduction of bacterial loads of Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus (MRSA). The results suggest that a device that releases NO via illumination by optical fiber may have clinical applications in combating infections with both Gram-positive, Gram-negative and to some degree antibiotic resistant bacteria.

Incorporation of a designed ruthenium nitrosyl in PolyHEMA hydrogel and light-activated delivery of NO to myoglobin.

A ruthenium nitrosyl with 4-vinylpyridine (4-vpy) as one ligand, namely, [Ru(Me2bpb)(NO)(4-vpy)](BF4) (1), has been synthesized and structurally characterized. This diamagnetic {Ru-NO}6 nitrosyl is photoactive and readily releases NO upon exposure to low-intensity (5-10 mW) UV light (quantum yield at 300 nm = 0.18). Radical-induced copolymerization of 2-hydroxyethyl methacrylate (HEMA) and ethyleneglycol dimethacrylate (EGDMA) in the presence of 1 has afforded a 1-pHEMA, a transparent hydrogel in which 1 is covalently attached to the polymer backbone. Exposure of 1-pHEMA to UV light (5-10 mW) results in rapid release of NO (detected by NO electrode) that can be delivered to biological targets such as myoglobin. The photoactivity of 1-pHEMA is strictly dependent on exposure to UV light.