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1.
Plast Reconstr Surg Glob Open ; 12(3): e5636, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38435460

ABSTRACT

Intraoperative anaphylaxis can be life threatening. Anaphylaxis to gelatin-based topical hemostatic agents is an underrecognized hypersensitivity. To date, only 21 cases of intraoperative anaphylaxis have been reported for gelatin-based hemostatic agents. In this article, we report the case of a 10-year-old male patient who sustained anaphylaxis after the use of Gelfoam during harvest of a bone graft. Rapid diagnosis and treatment of intraoperative anaphylaxis is imperative to prevent adverse outcomes. Referral to an allergist for identification of the allergen and appropriate notation in the medical record are paramount to avoid future anaphylactic events. Surgeons should avoid gelatin-based hemostatic agents, such as Gelfoam, in patients with reported intolerance of gelatin-based foods and medicines.

2.
Plast Reconstr Surg Glob Open ; 12(3): e5663, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38463706

ABSTRACT

The differential diagnosis of large congenital scalp defects includes aplasia cutis and encephalocele, among others. Treatment includes conservative management with dressings or operative management with dermal substitutes, skin grafting, local flaps, and free flaps. This case report discusses the technical considerations and reconstructive strategies for repair of a meningocele in a newborn with a large 5.5-cm scalp defect. The key strategies include preemptive cerebrospinal fluid (CSF) diversion with external ventricular drain to reduce the risk of CSF leak and mitigate wound-healing complications; careful identification and avoidance of key anatomic structures, such as the superior sagittal sinus, as anatomy may be significantly distorted due to the presence of a meningocele and after CSF diversion; and careful, thoughtful design of the local scalp flaps to maximize blood supply and to avoid tension on the final reconstruction.

3.
Wound Repair Regen ; 31(5): 641-646, 2023.
Article in English | MEDLINE | ID: mdl-37583305

ABSTRACT

In this study, we sought to clarify the patient traits and comorbidities that are associated with pressure injury recurrence following pressure injury reconstruction. An insurance claims database, PearlDiver, was used to conduct a retrospective cohort study. The two cohorts included patients who underwent pressure injury reconstruction without recurrence and patients who experienced recurrence with subsequent reconstruction. Multiple logistic regression analysis was used to identify risk factors for recurrence after reconstruction. Recurrence was associated with hypoalbuminemia (p < 0.05), paraplegia (p < 0.05), and osteomyelitis (p < 0.05). In patients with osteomyelitis, primary closure was associated with recurrence (p < 0.05) while flap reconstruction was not (p > 0.05). Osteomyelitis was not associated with recurrence after flap reconstruction. Prior to reconstruction, patients with osteomyelitis and hypoalbuminemia should have their nutrition and infection optimised.


Subject(s)
Hypoalbuminemia , Osteomyelitis , Pressure Ulcer , Humans , Pressure Ulcer/etiology , Retrospective Studies , Hypoalbuminemia/epidemiology , Hypoalbuminemia/complications , Wound Healing , Recurrence , Risk Factors , Osteomyelitis/epidemiology , Osteomyelitis/complications
4.
Plast Reconstr Surg Glob Open ; 11(7): e5121, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37465288

ABSTRACT

Radial artery occlusion leading to hand ischemia is a serious problem that may require prompt surgical intervention. Due to the rarity of these events, consensus on the most effective surgical approach has not yet been reached. There is even scarce literature on appropriate management of symptomatic radial occlusion in patients with a congenital variation in hand vasculature. We report on a case of a 38-year-old woman with radial artery occlusion who underwent a successful distal radial artery bypass to the deep palmar arch due to a diminutive ulnar artery and the absence of a superficial palmar arch. Radial artery bypass to the deep palmar arch using a reversed vein graft is a viable treatment option for preventing further digital ischemia or necrosis in patients with a compromised vasculature of the hand.

5.
J Plast Reconstr Aesthet Surg ; 85: 127-133, 2023 10.
Article in English | MEDLINE | ID: mdl-37482026

ABSTRACT

BACKGROUND: Cannabis is the third most used controlled substance in the world. Despite its widespread use, minimal research investigates cannabis usage in patients undergoing facial fracture surgeries. This study aimed to evaluate patterns of postoperative complications related to cannabis and tobacco usage after mandible fracture surgeries. MATERIALS AND METHODS: PearlDiver™, a commercially available healthcare database, was used to identify patients endorsing the use of cannabis, tobacco, or both who underwent mandible fracture surgeries for cross-sectional analysis. The study population was categorized into groups using the Classification of Diseases, 9th revision (ICD-9), ICD-10, and Current Procedural Terminology (CPT) codes. A chi-square analysis was performed to assess the influence of cannabis and tobacco use on postoperative complications. RESULTS: A total of 8288 patients met the inclusion criteria, with 72 patients with cannabis-only usage, 914 patients with cannabis and tobacco usage, 3236 patients with tobacco-only usage, and 4066 in the control group. For patients using only cannabis, there was not an increased risk of developing postoperative complications compared with the control population. Patients with concurrent cannabis and tobacco usage and those with tobacco-only usage had an increased risk of surgical site infection, facial nonunion, facial abscess, debridement, and malocclusion after surgical repair of mandibular facial fracture. CONCLUSION: Patients with tobacco-only as well as cannabis and tobacco usage had an increased risk of all postoperative complications, except malocclusion, compared with cannabis-only. Based on the results of this study, it is recommended that healthcare providers consider a patient's history of tobacco use when planning and performing surgical treatment for traumatic mandible fractures.


Subject(s)
Cannabis , Malocclusion , Mandibular Fractures , Skull Fractures , Humans , Cross-Sectional Studies , Retrospective Studies , Mandibular Fractures/epidemiology , Mandibular Fractures/etiology , Mandibular Fractures/surgery , Mandible , Postoperative Complications/epidemiology , Postoperative Complications/etiology
6.
Plast Reconstr Surg Glob Open ; 11(6): e5063, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37313482

ABSTRACT

Dupuytren disease is associated with inflammation and myofibroblast overgrowth, as is stenosing tenosynovitis (trigger finger). Both are linked with fibroblast proliferation, but a potential associative link between the diseases is unknown. The purpose of this study was to evaluate the progression of trigger finger following treatment for Dupuytren contracture in a large database. Methods: A commercial database encompassing 53 million patients was utilized from January 1, 2010 to March 31, 2020. The study cohort included patients diagnosed with either Dupuytren disease or trigger finger utilizing International Classification Codes 9 and 10. Terminology codes were used to identify common Dupuytren procedures, as well as trigger finger release. Logistic regression analysis was used to define independent risk factors for developing trigger finger. Results: A total of 593,606 patients were diagnosed with trigger finger. Of these patients, 15,416 (2.6%) were diagnosed with trigger finger after diagnosis of Dupuytren disease, whereas 2603 (0.4%) patients were diagnosed with trigger finger after treatment of Dupuytren contracture. Independent risk factors for trigger finger included age 65 years or older (OR 1.00, P < 0.05), diabetes (OR 1.12, P < 0.05) and obesity (OR 1.20, P < 0.005). Patients who received collagenase clostridium histolyticum treatment (OR 0.34, P < 0.005) for Dupuytren contracture were significantly less likely to develop trigger finger. Conclusions: Dupuytren contracture is associated with inflammation and subsequent trigger finger development at a higher rate than the background population frequency. Collagenase clostridium histolyticum injection may lead to a decreased risk of trigger finger requiring surgical intervention in patients with risk factors.

7.
Aesthet Surg J ; 43(10): NP763-NP770, 2023 09 14.
Article in English | MEDLINE | ID: mdl-37071801

ABSTRACT

BACKGROUND: Macromastia is associated with increased opioid consumption, which could potentially be the initial exposure for patients with an opioid use disorder amid an escalating opioid crisis in the United States. OBJECTIVES: The purpose of this study was to evaluate outpatient cost of care and opioid consumption in patients with macromastia and compare those who underwent reduction mammaplasty vs those who did not have surgery. METHODS: PearlDiver, a database encompassing a national cohort of private payers with 153 million unique patients, was queried. The study cohort included patients diagnosed with macromastia who did or did not undergo reduction mammaplasty utilizing both ICD-9 and ICD-10 and CPT codes. Outpatient cost of care and morphine milligram equivalents (MME) were calculated up to 5 years postoperatively for both cohorts. RESULTS: At 1 to 3 years postoperatively, there was no statistically significant difference in outpatient cost of care between cohorts. At every follow-up thereafter, outpatient cost of care was higher among macromastia patients who did not undergo reduction mammaplasty, with cohort differences of US$240.68 and US$349.90 at 4 years and 5 years, respectively (P < .05). MME consumption was greater in patients who underwent reduction mammaplasty up to 30 days postoperatively (P < .01). Beyond that, there was no significant difference in MME consumption between cohorts. However, patients who did not undergo surgery had opioid consumption levels above 50 MME/day until 3 years after diagnosis of macromastia. CONCLUSIONS: Patients with macromastia who undergo reduction mammaplasty have lower outpatient care costs than patients who do not undergo reduction mammaplasty, with safer long-term opioid consumption in alignment with current Centers for Disease Control and Prevention guidelines.


Subject(s)
Analgesics, Opioid , Mammaplasty , Female , Humans , United States/epidemiology , Analgesics, Opioid/therapeutic use , Outpatients , Pain, Postoperative/drug therapy , Pain, Postoperative/etiology
8.
J Hand Surg Glob Online ; 4(3): 123-127, 2022 May.
Article in English | MEDLINE | ID: mdl-35601524

ABSTRACT

Purpose: Infection after distal radius fracture fixation can be a devastating complication, leading to potential hardware removal, prolonged antibiotic courses, multiple office visits, and increased costs. This study aimed to identify potential risk factors for infectious complications after distal radius fracture fixation and assess the impacts on cost. Methods: This study used the PearlDiver national database, encompassing 53 million unique patients from January 1, 2010, to March 31, 2020. The cohort included patients undergoing distal radius fracture fixation. The endpoint was postoperative infection within 180 days of fixation. Two-sample t test was used to compare rates of infection between open and percutaneous fracture fixation techniques. A propensity-matched cohort was created using patient age, gender, and open fracture. Logistic regression analyses defined independent risk factors for developing a postoperative infection among all patients and within the matched cohorts. A Mann-Whitney U test was used to compare costs of care with and without infection. Results: The database included 87,169 patients who underwent distal radius fracture fixation. Postoperative infections were identified in 781 patients (0.9%). There was a significant difference in rates of postoperative infection with percutaneous fixation (1.3%) versus open fixation (0.8%). Logistic regression analysis identified male gender, open fracture, lung disease, chronic kidney disease, diabetes, hypertension, liver disease, obesity, and tobacco to be independent risk factors for developing a postoperative infection. Logistic regression analysis of the propensity-matched cohorts identified tobacco use as a significant risk factor. The average cost of care for patients undergoing fracture fixation without an infection was $6,383, versus $23,355 for those with an infection, which was significantly different. Conclusions: Multiple risk factors for postoperative infection were identified. Cost is significantly increased after postoperative infection, by almost 4-fold. Attempts to correct or optimize modifiable risk factors may lead to substantial cost savings, and potentially decreased rates of infection. Type of study/level of evidence: Prognostic III.

9.
ACS Med Chem Lett ; 11(6): 1175-1184, 2020 Jun 11.
Article in English | MEDLINE | ID: mdl-32550998

ABSTRACT

Two novel compounds were identified as Naa50 binders/inhibitors using DNA-encoded technology screening. Biophysical and biochemical data as well as cocrystal structures were obtained for both compounds (3a and 4a) to understand their mechanism of action. These data were also used to rationalize the binding affinity differences observed between the two compounds and a MLGP peptide-containing substrate. Cellular target engagement experiments further confirm the Naa50 binding of 4a and demonstrate its selectivity toward related enzymes (Naa10 and Naa60). Additional analogs of inhibitor 4a were also evaluated to study the binding mode observed in the cocrystal structures.

10.
J Behav Med ; 43(2): 185-197, 2020 04.
Article in English | MEDLINE | ID: mdl-31512105

ABSTRACT

Patient perceptions of the causes of preoperative symptoms, expected impact of surgery on symptoms and anticipated timeline of recovery are likely to affect the risk of readmission following elective surgical procedures. However, these perceptions have not been studied. A qualitative study was designed to explore these perceptions, using the common-sense model of self-regulation (CSM) as the conceptual framework. CSM is grounded in illness representations, describing how patients make sense of changes in physical well-being (e.g. symptoms) and develop and assess management plans. It also establishes a broader framework for examining patients' a priori expectations and timelines for outcomes based on comparisons to prior experiences and underlying self-prototypes, or "Self as Anchor". A convenience sample of 14 patients aged 56-81 who underwent elective surgery was recruited. Semi-structured interviews informed by the CSM were completed on the day of discharge. Content analysis with deductive coding was used, and emerging themes were fit to components of the CSM, including the five domains of Illness Representations-identity, cause, timeline, control, and consequences. Two additional themes, outlook (toward the health care system, providers and recovery efforts), and motivation (external or internal for recovering), relate to self-prototypes, expectations for outcomes, and search for coherence. Misattribution of symptoms, unrealistic expectations for outcomes (e.g. expecting complete resolution of symptoms unrelated to the surgical procedure) and timelines for recovery (unrealistically short), and the (baseline) "normal healthy self" as distinct from the (temporarily) "sick self" were recurrent themes. Findings suggest that patient perceptions and the actual recovery process may be misaligned. The results underscore the importance of assessing patients' perceptions and expectations, actively engaging patients in their own healthcare, and providing adequate support during the transition to home.


Subject(s)
Elective Surgical Procedures/psychology , Motivation , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Patient Discharge , Qualitative Research
11.
Plast Reconstr Surg Glob Open ; 7(1): e2088, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30859045

ABSTRACT

BACKGROUND: Both stenosing tenosynovitis and Dupuytren's contracture are common conditions encountered in hand surgery. Connections between 2 diseases have been suggested in literature. The purpose of this study was to examine whether there's an association between the 2 processes. METHODS: A retrospective chart review was performed to include all patients seen by a single surgeon between 2014 and 2017 with the diagnosis of either trigger finger or Dupuytren's contracture in the same hand. Patients' demographics, medical history, social and surgical histories are recorded. Univariate and multivariate analysis were conducted. RESULTS: A cohort of 238 patients was identified. One hundred ninety-two patients were diagnosed with trigger finger. Eighty-nine patients were diagnosed with Dupuytren's contracture. Forty-three patients carried both diagnoses. Median age was 61.6 (56-72). Half were male (50.4%) and 66.8% reported current alcohol intake. Other factors include history of former or current tobacco use (52.9%), diabetes (23.9%), and manual labor (31.1%). In the univariate model, trigger finger, sex, and age were significantly associated with the diagnosis of Dupuytren's contracture, and Dupuytren's contracture and sex were significantly associated with the trigger finger diagnosis. Diabetes, manual labor, use of alcohol and tobacco were not significant. In the multivariate model, age and trigger finger were significantly associated with Dupuytren's contracture. CONCLUSIONS: Significant association between stenosing tenosynovitis and Dupuytren's contracture was identified in our patient cohort. Patients with stenosing tenosynovitis may be at an increased risk of developing Dupuytren's contracture or vice versa.

12.
Plast Reconstr Surg Glob Open ; 7(12): e2600, 2019 Dec.
Article in English | MEDLINE | ID: mdl-32537317

ABSTRACT

Adherence of pulp tissue to the underlying distal phalanx is required for fundamental actions including grip, proprioception, and fine motor skills. Disruption of the fibrous septa causes sliding between the distal phalanx and overlying soft tissues, hindering basic hand function. The authors present a novel surgical technique in which the fibrous pulp septa are resuspended to the distal phalanx with bone anchors and sclerosing agents after a closed degloving injury.

13.
J Am Geriatr Soc ; 66(12): 2243-2248, 2018 12.
Article in English | MEDLINE | ID: mdl-30246863

ABSTRACT

Improving quality and delivery of care for people with Alzheimer disease and related dementias (ADRD) requires a comprehensive research agenda that encompasses the entire care continuum. Logistical and ethical challenges of informed consent for research participation of persons with ADRD include determination of capacity to consent, surrogate consent when capacity to consent is compromised, timely identification of the legally authorized representative (LAR) providing surrogate consent, and balancing residual autonomy with surrogate consent. Short stays; limited access to patients, caregivers, and LARs; and fluctuating influences of acute illness on capacity determination compound these challenges in the acute care setting. To address these challenges, we worked with the University of Wisconsin Health Sciences Institutional Review Board to develop a procedural framework for obtaining informed consent from hospitalized individuals with ADRD and their caregivers to participate in a minimal risk care intervention. The framework is specially designed for minimal risk situations in which rapid enrollment is a necessity and uses rapid identification of surrogates to consent for patients who lack legal capacity to make medical decisions, indicated by an activated healthcare power of attorney, and individualized formal assent procedures for patients who lack capacity to consent. These methods were proven effective in facilitating hospital-based recruitment in an ongoing randomized controlled trial and provide a basis for increasing access to acute care clinical research for persons with ADRD. Bolstering research participation through more easily used consent procedures during acute illness is critical to fostering improvements in the delivery of high-quality care to persons with ADRD. J Am Geriatr Soc 66:2243-2248, 2018.


Subject(s)
Dementia , Health Services Research , Hospitals , Informed Consent/legislation & jurisprudence , Caregivers/legislation & jurisprudence , Decision Making , Humans , Inpatients , Legal Guardians
14.
Gerontologist ; 58(3): 521-529, 2018 05 08.
Article in English | MEDLINE | ID: mdl-29746689

ABSTRACT

Background: Twenty-five percentage of patients who are transferred from hospital settings to skilled nursing facilities (SNFs) are rehospitalized within 30 days. One significant factor in poorly executed transitions is the discharge process used by hospital providers. Objective: The objective of this study was to examine how health care providers in hospitals transition care from hospital to SNF, what actions they took based on their understanding of transitioning care, and what conditions influence provider behavior. Design: Qualitative study using grounded dimensional analysis. Participants: Purposive sample of 64 hospital providers (15 physicians, 31 registered nurses, 8 health unit coordinators, 6 case managers, 4 hospital administrators) from 3 hospitals in Wisconsin. Approach: Open, axial, and selective coding and constant comparative analysis was used to identify variability and complexity across transitional care practices and model construction to explain transitions from hospital to SNF. Key Results: Participants described their health care systems as being Integrated or Fragmented. The goal of transition in Integrated Systems was to create a patient-centered approach by soliciting feedback from other disciplines, being accountable for care provided, and bridging care after discharge. In contrast, the goal in Fragmented Systems was to move patients out quickly, resulting in providers working within silos with little thought as to whether or not the next setting could provide for patient care needs. In Fragmented Systems, providers achieved their goal by rushing to complete the discharge plan, ending care at discharge, and limiting access to information postdischarge. Conclusions: Whether a hospital system is Integrated or Fragmented impacts the transitional care process. Future research should address system level contextual factors when designing interventions to improve transitional care.


Subject(s)
Delivery of Health Care/organization & administration , Hospitals , Patient Readmission , Patient Transfer/organization & administration , Skilled Nursing Facilities , Grounded Theory , Humans , Nurses , Patient Discharge , Physicians , Qualitative Research , Wisconsin
16.
PLoS Pathog ; 13(5): e1006081, 2017 May.
Article in English | MEDLINE | ID: mdl-28520808

ABSTRACT

Interactions between early developing Schistosoma mansoni larval stages and the hemolymph of its snail intermediate host represent the first molecular encounter with the snail's immune system. To gain a more comprehensive understanding of this early parasite-host interaction, biotinylated sporocyst tegumental membrane (Mem) proteins and larval transformation proteins (LTP) were affixed to streptavidin-agarose beads and used as affinity matrices to enrich for larval-reactive plasma proteins from susceptible (NMRI) and resistant (BS-90) strains of the snail Biomphalaria glabrata. Nano-LC/MS-MS proteomic analyses of isolated plasma proteins revealed a diverse array of 94 immune-and nonimmune-related plasma proteins. Included among the immune-related subset were pattern recognition receptors (lectins, LPS-binding protein, thioester-containing proteins-TEPs), stress proteins (HSP60 and 70), adhesion proteins (dermatopontins), metalloproteases (A Disintegrin And Metalloproteinase (ADAM), ADAM-related Zn proteinases), cytotoxins (biomphalysin) and a Ca2+-binding protein (neo-calmodulin). Variable immunoglobulin and lectin domain (VIgL) gene family members, including fibrinogen-related proteins (FREPs), galectin-related proteins (GREPs) and C-type lectin-related proteins (CREPs), were the most prevalent of larval-reactive immune lectins present in plasma. FREPs were highly represented, although only a subset of FREP subfamilies (FREP 2, 3 and 12) were identified, suggesting potential selectivity in the repertoire of plasma lectins recognizing larval glycoconjugates. Other larval-binding FREP-like and CREP-like proteins possessing a C-terminal fibrinogen-related domain (FReD) or C-type lectin binding domain, respectively, and an Ig-fold domain also were identified as predicted proteins from the B. glabrata genome, although incomplete sequence data precluded their placement into specific FREP/CREP subfamilies. Similarly, a group of FReD-containing proteins (angiopoeitin-4, ficolin-2) that lacked N-terminal Ig-fold(s) were identified as a distinct group of FREP-like proteins, separate from the VIgL lectin family. Finally, differential appearance of GREPs in BS-90 plasma eluates, and others proteins exclusively found in eluates of the NMRI strain, suggested snail strain differences in the expression of select larval-reactive immune proteins. This hypothesis was supported by the finding that differential gene expression of the GREP in BS-90 and ADAM in NMRI snail strains generally correlated with their patterns of protein expression. In summary, this study is the first to provide a global comparative proteomic analysis of constitutively expressed plasma proteins from susceptible and resistant B. glabrata strains capable of binding early-expressed larval S. mansoni proteins. Identified proteins, especially those exhibiting differential expression, may play a role in determining immune compatibility in this snail host-parasite system. A complete listing of raw peptide data are available via ProteomeXchange using identifier PXD004942.


Subject(s)
Biomphalaria/metabolism , Blood Proteins/metabolism , Helminth Proteins/metabolism , Host-Parasite Interactions , Proteomics , Schistosoma mansoni/physiology , Amino Acid Sequence , Animals , Bacterial Proteins , Biomphalaria/immunology , Biomphalaria/parasitology , Hemolymph/metabolism , Larva , Protein Interaction Mapping , Schistosoma mansoni/immunology , Schistosoma mansoni/metabolism , Sepharose/analogs & derivatives , Sequence Alignment
18.
Res Social Adm Pharm ; 12(4): 548-58, 2016.
Article in English | MEDLINE | ID: mdl-26781670

ABSTRACT

BACKGROUND: No methodological standards are available for researchers and clinicians to examine medication discrepancies between health care settings. Systematic methods of examining medication discrepancies will allow researchers and clinicians to better understand factors driving medication discrepancies, to better measure effects of medication reconciliation interventions, and to compare findings across studies. OBJECTIVE: This article proposes a four-phase approach for systematically collecting medication data and measuring medication discrepancies between a hospital and community pharmacies. Methodologic considerations related to studying medication discrepancies in health services research are also discussed. METHODS: A multi-disciplinary study team developed a four-phase systematic approach to improve quality of data and study rigor: 1) operationalization of a medication discrepancy, 2) acquiring medication data, 3) abstraction of medication data and creation of dataset, and 4) measuring and reporting medication discrepancies. RESULTS: Using this phase-based approach, the study team successfully identified and reported medication discrepancies between a hospital and community pharmacies at the patient, medication, and community pharmacy units of analyses. CONCLUSIONS: Systematically measuring medication discrepancies that occur in the care transitions process is a critical step as researchers, clinicians, and other stakeholders work to improve health care quality and patient outcomes. This article detailed how a phase-based approach can be used in research to examine medication discrepancies as well as address the complexity of collecting medication data and analyzing medication discrepancies. Such methods should be considered when developing, conducting, and reporting research on medication discrepancies.


Subject(s)
Continuity of Patient Care , Data Collection/methods , Medication Errors/prevention & control , Medication Reconciliation/methods , Community Pharmacy Services/organization & administration , Humans , Interdisciplinary Communication , Pharmacy Service, Hospital/organization & administration , Quality of Health Care
19.
J Med Chem ; 54(9): 3368-85, 2011 May 12.
Article in English | MEDLINE | ID: mdl-21438541

ABSTRACT

A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.


Subject(s)
Antineoplastic Agents/chemical synthesis , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Binding, Competitive , Biological Availability , Blood Proteins/metabolism , Cell Line, Tumor , Cell Membrane Permeability , Drug Screening Assays, Antitumor , Drug Stability , Female , Humans , Hydrophobic and Hydrophilic Interactions , In Vitro Techniques , Male , Melanoma/drug therapy , Melanoma/pathology , Mice , Mice, Nude , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Protein Binding , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Transplantation, Heterologous
20.
Cancer Lett ; 300(1): 30-9, 2011 01 01.
Article in English | MEDLINE | ID: mdl-20926183

ABSTRACT

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Authors. Following an investigation by Pfizer, Figures 2, 5B and 5C appear to be duplications and hence the conclusions in the manuscript cannot be verified. The Authors apologize for this inconvenience.


Subject(s)
Antineoplastic Agents/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Melanoma/drug therapy , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Melanoma/pathology , Mice , Mutation , Phosphorylation , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins c-akt/metabolism
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