Drug and Alcohol Rehabilitation: Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond.
Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond.
Filed under: Drug and Alcohol Rehabilitation
Front Pharmacol. 2013; 4: 5
Davidson D, Amrein L, Panasci L, Aloyz R
Many current chemotherapies function by damaging genomic DNA in rapidly dividing cells ultimately leading to cell death. This therapeutic approach differentially targets cancer cells that generally display rapid cell division compared to normal tissue cells. However, although these treatments are initially effective in arresting tumor growth and reducing tumor burden, resistance and disease progression eventually occur. A major mechanism underlying this resistance is increased levels of cellular DNA repair. Most cells have complex mechanisms in place to repair DNA damage that occurs due to environmental exposures or normal metabolic processes. These systems, initially overwhelmed when faced with chemotherapy induced DNA damage, become more efficient under constant selective pressure and as a result chemotherapies become less effective. Thus, inhibiting DNA repair pathways using target specific small molecule inhibitors may overcome cellular resistance to DNA damaging chemotherapies. Non-homologous end joining a major mechanism for the repair of double-strand breaks (DSB) in DNA is regulated in part by the serine/threonine kinase, DNA dependent protein kinase (DNA-PK). The DNA-PK holoenzyme acts as a scaffold protein tethering broken DNA ends and recruiting other repair molecules. It also has enzymatic activity that may be involved in DNA damage signaling. Because of its’ central role in repair of DSBs, DNA-PK has been the focus of a number of small molecule studies. In these studies specific DNA-PK inhibitors have shown efficacy in synergizing chemotherapies in vitro. However, compounds currently known to specifically inhibit DNA-PK are limited by poor pharmacokinetics: these compounds have poor solubility and have high metabolic lability in vivo leading to short serum half-lives. Future improvement in DNA-PK inhibition will likely be achieved by designing new molecules based on the recently reported crystallographic structure of DNA-PK. Computer based drug design will not only assist in identifying novel functional moieties to replace the metabolically labile morpholino group but will also facilitate the design of molecules to target the DNA-PKcs/Ku80 interface or one of the autophosphorylation sites.
HubMed – drug
Relapsed and refractory lymphoid neoplasms and multiple myeloma with a focus on carfilzomib.
Filed under: Drug and Alcohol Rehabilitation
Biologics. 2013; 7: 13-32
Nooka A, Gleason C, Casbourne D, Lonial S
Proteasomal inhibition revolutionized myeloma therapies in this decade of novel agents. The only US Food and Drug Administration approved proteasome inhibitor so far, bortezomib effectively targets the constitutive proteasome subunit ?5 of the 26S proteasome. Bortezomib induces high and quality response rates that are durable. However, myeloma cells acquire resistance to bortezomib through various mechanisms. Further, grade 3/4 peripheral neuropathy is seen in up to a quarter of patients treated with bortezomib. While the recent change in the mode of administration via the subcutaneous route is associated with a lower incidence of grade 3/4 peripheral neuropathy, it remains a major concern. The second generation proteasome inhibitors are promising, with increased preclinical efficacy and a better administration schedule. The current review spotlights the second generation proteasome inhibitors with special focus on the safety and efficacy of carfilzomib, an epoxyketone with lesser peripheral neuropathy, which exhibits irreversible proteasome inhibition. In this article, we review the pharmacology and preclinical and clinical efficacy and safety of carfilzomib alone and in combination with other chemotherapeutic agents in the various lymphoid neoplasms and multiple myeloma as well as ongoing clinical trials.
HubMed – drug
Bronchodilator Delivery During Simulated Pediatric Noninvasive Ventilation.
Filed under: Drug and Alcohol Rehabilitation
Respir Care. 2013 Feb 5;
White CC, Crotwell DN, Shen S, Salyer J, Yung D, Diblasi RM
Introduction:Noninvasive Ventilation (NIV) is usually applied using Bi-Level Positive Airway Pressure (Bi-PAP) devices and many of these devices use a single-limb patient circuit with an integrated leak port to purge the circuit of exhaled carbon dioxide. Sometimes, bronchodilator therapy is indicated in pediatric patients. However, there have been no forthcoming studies in the literature describing the optimal nebulizer position, with respect to leak during pediatric NIV. We hypothesized that there were no differences in albuterol delivery with a vibrating mesh nebulizer between three different positions/exhalation leak valve combinations within the patient circuit during simulated pediatric NIV.Methods:A simulated upper airway model was attached to a spontaneously breathing lung model (ASL 5000, Ingmar medical). A noninvasive ventilator equipped with heated wire circuit and heated humidifier was attached to the simulated patient via a pediatric oronasal mask. Albuterol (5 mg) was delivered with vibrating mesh nebulizers and at three different circuit position/leak condition combinations, including: 1) prior to the humidifier and leak valve; 2) between the humidifier and leak valve; and 3) integrated within the mask and after the leak. Albuterol was recovered from a filter and quantified using high-pressure liquid chromatography.Results:Greater Albuterol mass was delivered to the filter with the NIVO® nebulizer integrated into the mask than any other testing condition (P<0.01). In the conditions where the nebulizer was placed prior to the exhalation leak valve, greater drug delivery was observed when the nebulizer was placed proximal to the mask (Position 2) than when placed prior to the humidifier (Position 3, P<0.01).Conclusion:Albuterol delivery during simulated pediatric NIV is affected by the position of the nebulizer in relation to the expiratory leak valve and the distance the nebulizer is placed from the filter. A vibrating mesh nebulizer placed intra mask may provide a better alternative for medication delivery than those previously used during pediatric NIV. HubMed – drug
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