The air-stable complex Pd(η(3)-allyl)(DTBNpP)Cl (DTBNpP = di(tert-butyl)neopentylphosphine) serves as a highly efficient precatalyst for the arylation of amines and enolates using aryl bromides and chlorides under mild conditions with yields ranging from 74% to 98%. Amination reactions of aryl bromides were carried out using 1-2 mol % Pd(η(3)-allyl)(DTBNpP)Cl at 23-50 °C without the need to exclude oxygen or moisture. The C-N coupling of the aryl chlorides occurred at relatively lower temperature (80-100 °C) and catalyst loading (1 mol %) using the Pd(η(3)-allyl)(DTBNpP)Cl precatalyst than the catalyst generated in situ from DTBNpP and Pd(2)(dba)(3) (100-140 °C, 2-5 mol % Pd). Other Pd(DTBNpP)(2)-based complexes, (Pd(DTBNpP)(2) and Pd(DTBNpP)(2)Cl(2)) were ineffective precatalysts under identical conditions for the amination reactions. Both Pd(DTBNpP)(2) and Pd(DTBNpP)(2)Cl(2) precatalysts gave nearly quantitative conversions to the product in the α-arylation of propiophenone with p-chlorotoluene and p-bromoanisole at a substrate/catalyst loading of 100/1. At lower substrate/catalyst loading (1000/1), the conversions were lower but comparable to that of Pd(t-Bu(3)P)(2). In many cases, the tri-tert-butylphosphine (TTBP) based Pd(I) dimer, [Pd(μ-Br)(TTBP)](2), stood out to be the most reactive catalyst under identical conditions for the enolate arylation. Interestingly, the air-stable Pd(I) dimer, Pd(2)(DTBNpP)(2)(μ-Cl)(μ-allyl), was less active in comparison to [Pd(μ-Br)(TTBP)](2) and Pd(η(3)-allyl)(DTBNpP)Cl. The X-ray crystal structures of Pd(η(3)-allyl)(DTBNpP)Cl, Pd(DTBNpP)(2)Cl(2), Pd(DTBNpP)(2), and Pd(2)(DTBNpP)(2)(μ-Cl)(μ-allyl) are reported in this paper along with initial studies on the catalyst activation of the Pd(η(3)-allyl)(DTBNpP)Cl precatalyst.
Surgical procedures for dystonia and tremor have evolved over the past few decades, and our understanding of risk, benefit, and predictive factors has increased substantially in that time. Deep brain stimulation (DBS) is the most utilized surgical treatment for dystonia and tremor, though lesioning remains an effective option in appropriate patients. Dystonic syndromes that have shown a substantial reduction in severity secondary to DBS are isolated dystonia, including generalized, cervical, and segmental, as well as acquired dystonia such as tardive dystonia. Essential tremor is quite amenable to DBS, though the response of other forms of postural and kinetic tremor is not nearly as robust or consistent based on available evidence. Regarding targeting, DBS lead placement in the globus pallidus internus has shown marked efficacy in dystonia reduction. The subthalamic nucleus is an emerging target, and increasing evidence suggests that this may be a viable target in dystonia as well. The ventralis intermedius nucleus of the thalamus is the preferred target for essential tremor, though targeting the subthalamic zone/caudal zona incerta has shown promise and may emerge as another option in essential tremor and possibly other tremor disorders. In the carefully selected patient, DBS and lesioning procedures are relatively safe and effective for the management of dystonia and tremor.
Despite substantial experience with deep brain stimulation for movement disorders and recent interest in electrode targeting under general anesthesia, little is known about whether awake macrostimulation during electrode targeting predicts postoperative side effects from stimulation. We hypothesized that intraoperative awake macrostimulation with the newly implanted DBS lead predicts dose-limiting side effects during device activation in clinic. We reviewed 384 electrode implants for movement disorders, characterized the presence or absence of stimulus amplitude thresholds for dose-limiting DBS side effects during surgery, and measured their predictive value for side effects during device activation in clinic with odds ratios ±95% confidence intervals. We also estimated associations between voltage thresholds for side effects within participants. Intraoperative clinical response to macrostimulation led to adjustments in DBS electrode position during surgery in 37.5% of cases (31.0% adjustment of lead depth, 18.2% new trajectory, or 11.7% both). Within and across targets and disease states, dose-limiting stimulation side effects from the final electrode position in surgery predict postoperative side effects, and side effect thresholds in clinic occur at lower stimulus amplitudes versus those encountered in surgery. In conclusion, awake clinical testing during DBS targeting impacts surgical decision-making and predicts dose-limiting side effects during subsequent device activation.
The cost of prescription drugs in the United States is rising like never before and has led to an inflection point where clinicians must consider the potential financial damage to the patient and to society related to the more expensive drugs available. Many of the highest-priced drugs are approved as orphan drugs, a legally defined status providing additional benefits to pharmaceutical companies that is intended to incentivize therapeutic development for rare diseases. The Orphan Drug Act has been a great success since it was enacted in 1983, resulting in the development of many innovative, life-changing, and even lifesaving drugs; however, high drug prices place patients at risk for personal bankruptcy, prescription abandonment, and higher rates of hospitalization. These negative consequences have become more widespread and severe because some companies exploit pricing via the market exclusivity granted to them under the provisions of the Orphan Drug Act. As more and more companies develop these drugs, the cost to society increases as does the capacity to tolerate unjustified prices. The societal effects of drug pricing must be considered through the prism of opportunity costs; that is, what benefit is lost by choosing to spend on one thing instead of another. Clinical- and economic-based analyses from independent groups such as the Institute for Clinical and Economic Review can help physicians understand the value of drugs (ie, the benefits relative to cost). When prescribing a high-priced medication, clinicians should discuss the drug’s value and the associated opportunity cost with patients and have an open discussion about patients’ ability to financially tolerate the treatment.
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