172 research outputs found
Injectable local anaesthetic agents for dental anaesthesia
Background: Pain during dental treatment, which is a common fear of patients, can be controlled successfully by local anaesthetic. Several different local anaesthetic formulations and techniques are available to dentists. / Objectives: Our primary objectives were to compare the success of anaesthesia, the speed of onset and duration of anaesthesia, and systemic and local adverse effects amongst different local anaesthetic formulations for dental anaesthesia. We define success of anaesthesia as absence of pain during a dental procedure, or a negative response to electric pulp testing or other simulated scenario tests. We define dental anaesthesia as anaesthesia given at the time of any dental intervention.
Our secondary objective was to report on patients' experience of the procedures carried out. / Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2018, Issue 1), MEDLINE (OVID SP), Embase, CINAHL PLUS, WEB OF SCIENCE, and other resources up to 31 January 2018. Other resources included trial registries, handsearched journals, conference proceedings, bibliographies/reference lists, and unpublished research. / Selection criteria: We included randomized controlled trials (RCTs) testing different formulations of local anaesthetic used for clinical procedures or simulated scenarios. Studies could apply a parallel or crossâover design. / Data collection and analysis: We used standard Cochrane methodological approaches for data collection and analysis. / Main results: We included 123 studies (19,223 participants) in the review. We pooled data from 68 studies (6615 participants) for metaâanalysis, yielding 23 comparisons of local anaesthetic and 57 outcomes with 14 different formulations. Only 10 outcomes from eight comparisons involved clinical testing.
We assessed the included studies as having low risk of bias in most domains. Seventyâthree studies had at least one domain with unclear risk of bias. Fifteen studies had at least one domain with high risk of bias due to inadequate sequence generation, allocation concealment, masking of local anaesthetic cartridges for administrators or outcome assessors, or participant dropout or exclusion.
We reported results for the eight most important comparisons. / Success of anaesthesia: When the success of anaesthesia in posterior teeth with irreversible pulpitis requiring root canal treatment is tested, 4% articaine, 1:100,000 epinephrine, may be superior to 2% lidocaine, 1:100,000 epinephrine (31% with 2% lidocaine vs 49% with 4% articaine; risk ratio (RR) 1.60, 95% confidence interval (CI) 1.10 to 2.32; 4 parallel studies; 203 participants; lowâquality evidence).
When the success of anaesthesia for teeth/dental tissues requiring surgical procedures and surgical procedures/periodontal treatment, respectively, was tested, 3% prilocaine, 0.03 IU felypressin (66% with 3% prilocaine vs 76% with 2% lidocaine; RR 0.86, 95% CI 0.79 to 0.95; 2 parallel studies; 907 participants; moderateâquality evidence), and 4% prilocaine plain (71% with 4% prilocaine vs 83% with 2% lidocaine; RR 0.86, 95% CI 0.75 to 0.99; 2 parallel studies; 228 participants; lowâquality evidence) were inferior to 2% lidocaine, 1:100,000 epinephrine.
Comparative effects of 4% articaine, 1:100,000 epinephrine and 4% articaine, 1:200,000 epinephrine on success of anaesthesia for teeth/dental tissues requiring surgical procedures are uncertain (RR 0.85, 95% CI 0.71 to 1.02; 3 parallel studies; 930 participants; very lowâquality evidence).
Comparative effects of 0.5% bupivacaine, 1:200,000 epinephrine and both 4% articaine, 1:200,000 epinephrine (odds ratio (OR) 0.87, 95% CI 0.27 to 2.83; 2 crossâover studies; 37 participants; lowâquality evidence) and 2% lidocaine, 1:100,000 epinephrine (OR 0.58, 95% CI 0.07 to 5.12; 2 crossâover studies; 31 participants; lowâquality evidence) on success of anaesthesia for teeth requiring extraction are uncertain.
Comparative effects of 2% mepivacaine, 1:100,000 epinephrine and both 4% articaine, 1:100,000 epinephrine (OR 3.82, 95% CI 0.61 to 23.82; 1 parallel and 1 crossâover study; 110 participants; lowâquality evidence) and 2% lidocaine, 1:100,000 epinephrine (RR 1.16, 95% CI 0.25 to 5.45; 2 parallel studies; 68 participants; lowâquality evidence) on success of anaesthesia for teeth requiring extraction and teeth with irreversible pulpitis requiring endodontic access and instrumentation, respectively, are uncertain.
For remaining outcomes, assessing success of dental local anaesthesia via metaâanalyses was not possible. / Onset and duration of anaesthesia: For comparisons assessing onset and duration, no clinical studies met our outcome definitions.
Adverse effects (continuous pain measured on 170âmm HeftâParker visual analogue scale (VAS))
Differences in postâinjection pain between 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine are small, as measured on a VAS (mean difference (MD) 4.74 mm, 95% CI â1.98 to 11.46 mm; 3 crossâover studies; 314 interventions; moderateâquality evidence). Lidocaine probably resulted in slightly less postâinjection pain than articaine (MD 6.41 mm, 95% CI 1.01 to 11.80 mm; 3 crossâover studies; 309 interventions; moderateâquality evidence) on the same VAS.
For remaining comparisons assessing local and systemic adverse effects, metaâanalyses were not possible. Other adverse effects were rare and minor. / Patients' experience: Patients' experience of procedures was not assessed owing to lack of data. / Authors' conclusions: For success (absence of pain), lowâquality evidence suggests that 4% articaine, 1:100,000 epinephrine was superior to 2% lidocaine, 1:100,000 epinephrine for root treating of posterior teeth with irreversible pulpitis, and 2% lidocaine, 1:100,000 epinephrine was superior to 4% prilocaine plain when surgical procedures/periodontal treatment was provided. Moderateâquality evidence shows that 2% lidocaine, 1:100,000 epinephrine was superior to 3% prilocaine, 0.03 IU felypressin when surgical procedures were performed.
Adverse events were rare. Moderateâquality evidence shows no difference in pain on injection when 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine were compared, although lidocaine resulted in slightly less pain following injection.
Many outcomes tested our primary objectives in simulated scenarios, although clinical alternatives may not be possible.
Further studies are needed to increase the strength of the evidence. These studies should be clearly reported, have low risk of bias with adequate sample size, and provide data in a format that will allow metaâanalysis. Once assessed, results of the 34 âStudies awaiting classification (full text unavailable)â may alter the conclusions of the review
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Cancer Regulation Through Splice Modulation
RNA splicing plays a central role in cell regulation, development, and disease progression, but the complexity of this macromolecular assembly process has left RNA splicing underexplored in cancer. In recent years, it has become clear that alternative RNA splicing becomes mis-regulated in and plays a role in the progression of a wide range of cancers. Therefore, drugs that regulate RNA splicing could serve as powerful therapeutics for cancer. Splice modulators (SPLMs) are a class of chemotherapeutics that regulate aberrant splicing profiles in tumors, thereby inducing tumor cell apoptosis. SPLMs interfere with the overused splicing machinery that cancer cells become dependent upon for expansion, thereby limiting the tumorâs ability to produce proteins necessary for growth and survival. Understanding the relationship between splicing and cancer progression will allow for expansion of our therapeutic arsenal in tackling cancer.In my graduate studies, I evaluated splice modulator regulation of the cell cycle genes Aurora kinase (AURK) and Polo-like kinase 1 (PLK-1). Next, I leveraged the SPLM FD- 895âs regulation of the cell cycle to develop a splicing-based combination therapy capable of targeting a wide range of tumor types. This co-dosing approach relied on use of the splice modulator FD-895 to reduce cell cycle RNA, followed by treatment with a cell cycle protein inhibitor to further reduce cell cycle protein expression. This combination therapy was found to be effective against a range of tumor types, including cervical, ovarian, and colorectal tumor cell lines, indicating that this approach has wide therapeutic applications. These studies suggest the potential to engage small molecule SPLM pretreatment as a therapeutic tool to edit the levels of therapeutically targeted proteins by mis-splicing their RNAs. SPLM combination therapy may be particularly useful for enhancing clinical agents that suffer from off-target effects or dose-limiting toxicity and could therefore allow for previously abandoned lead molecules (therapeutics) to re-enter the clinic.
Next, I synthesized analogs of the splice modulator FD-895 to investigate structure- activity relationships (SARs) for this class of compound. Structural differences from one SPLM to another lead to significant changes in splicing activity based on SPLM orientation within the spliceosome binding pocket. Therefore, although most SPLMs affect the splicing of the same category of genes, each SPLM affects the splicing of individual genes to a different extent. Through these efforts, we have been able to synthesize splice modulators like 17S-FD-895 with enhanced stability compared to their parent natural products [Villa 2013]
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Development of synthetic glycosaminoglycan glycoconjugates and their application to manipulate cellular signaling events
Growth factor signaling is a key determinant of cellular decisions ranging fromstem cell fate, to metabolic behavior. As such, gaining control over these signalingevents is of critical importance to the field of regenerative medicine, which iscontinuously seeking novel means to tailor the cellular microenvironment to direct cellstowards medically advantageous outcomes. Heparan sulfate (HS) glycosaminoglycans(GAGS) are sulfated polysaccharides found on the cell surface and in the extracellularmatrix which are responsible for the engagement of growth factors as well as growthfactor receptors as a means to spatiotemporally direct cell signaling events. Despite theobvious potential associated with controlling HS GAG-growth factor interactions, HSGAG-based approaches to manipulate cellular signaling has been minimal due to thecomplex nature of this class of sulfated polysaccharides. Sulfated GAGs like HS have anon-template driven synthesis, that is, their structure is not dictated by a genetic blueprint. During assembly, the GAGs undergo a series of sulfations, isomerizations, andacetylations which give rise to their specific binding capacity, but it is this samecomplexity that poses a significant hurdle for synthetic or chemoenzymatic approachesgeared at producing these structures for study and medical application. As a result,novel approaches must be developed to hone control over cell signaling using GAGswhile circumventing the structural obstacle posed by the complexity of their structure. Inthis dissertation, I present a variety of accessible methods for the preparation ofsynthetic HS GAG glycoconjugates, and demonstrate their efficacy in several contexts.In chapter 2, I introduce a HS GAG presenting, membrane incorporating, polymer whichutilizes a multivalent display of commercially available HS GAG disaccharides to exertcontrol over stem cell fate in a structure dependent manner. In chapter 3 I reveal therole of HS GAG in the metabolic programming of adipocytes, and then apply thesepolymers to enhance glucose clearance capacity in adipocytes, bearing implications forthe treatment of type 2 diabetes. In chapter 4, I developed a highly efficient âclickâbased method for the conjugation of full length GAGs to protein substrates, and appliedthese glycoconjugates to manipulate the growth rates of human stem cells from theextracellular matrix. Finally, in chapter 5, I apply the synthetic polymers and proteinglycoconjugates to a cellular microarray, with the goal of miniaturizing cell based assaysfor the high throughput study of glycomaterials
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Cancer Regulation Through Splice Modulation
RNA splicing plays a central role in cell regulation, development, and disease progression, but the complexity of this macromolecular assembly process has left RNA splicing underexplored in cancer. In recent years, it has become clear that alternative RNA splicing becomes mis-regulated in and plays a role in the progression of a wide range of cancers. Therefore, drugs that regulate RNA splicing could serve as powerful therapeutics for cancer. Splice modulators (SPLMs) are a class of chemotherapeutics that regulate aberrant splicing profiles in tumors, thereby inducing tumor cell apoptosis. SPLMs interfere with the overused splicing machinery that cancer cells become dependent upon for expansion, thereby limiting the tumorâs ability to produce proteins necessary for growth and survival. Understanding the relationship between splicing and cancer progression will allow for expansion of our therapeutic arsenal in tackling cancer.In my graduate studies, I evaluated splice modulator regulation of the cell cycle genes Aurora kinase (AURK) and Polo-like kinase 1 (PLK-1). Next, I leveraged the SPLM FD- 895âs regulation of the cell cycle to develop a splicing-based combination therapy capable of targeting a wide range of tumor types. This co-dosing approach relied on use of the splice modulator FD-895 to reduce cell cycle RNA, followed by treatment with a cell cycle protein inhibitor to further reduce cell cycle protein expression. This combination therapy was found to be effective against a range of tumor types, including cervical, ovarian, and colorectal tumor cell lines, indicating that this approach has wide therapeutic applications. These studies suggest the potential to engage small molecule SPLM pretreatment as a therapeutic tool to edit the levels of therapeutically targeted proteins by mis-splicing their RNAs. SPLM combination therapy may be particularly useful for enhancing clinical agents that suffer from off-target effects or dose-limiting toxicity and could therefore allow for previously abandoned lead molecules (therapeutics) to re-enter the clinic.
Next, I synthesized analogs of the splice modulator FD-895 to investigate structure- activity relationships (SARs) for this class of compound. Structural differences from one SPLM to another lead to significant changes in splicing activity based on SPLM orientation within the spliceosome binding pocket. Therefore, although most SPLMs affect the splicing of the same category of genes, each SPLM affects the splicing of individual genes to a different extent. Through these efforts, we have been able to synthesize splice modulators like 17S-FD-895 with enhanced stability compared to their parent natural products [Villa 2013]
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