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[This corrects the article DOI: 10.7759/cureus.39335.].
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Importance: Multimodal generative artificial intelligence (AI) methodologies have the potential to optimize emergency department care by producing draft radiology reports from input images. Objective: To evaluate the accuracy and quality of AI-generated chest radiograph interpretations in the emergency department setting. Design, Setting, and Participants: This was a retrospective diagnostic study of 500 randomly sampled emergency department encounters at a tertiary care institution including chest radiographs interpreted by both a teleradiology service and on-site attending radiologist from January 2022 to January 2023. An AI interpretation was generated for each radiograph. The 3 radiograph interpretations were each rated in duplicate by 6 emergency department physicians using a 5-point Likert scale. Main Outcomes and Measures: The primary outcome was any difference in Likert scores between radiologist, AI, and teleradiology reports, using a cumulative link mixed model. Secondary analyses compared the probability of each report type containing no clinically significant discrepancy with further stratification by finding presence, using a logistic mixed-effects model. Physician comments on discrepancies were recorded. Results: A total of 500 ED studies were included from 500 unique patients with a mean (SD) age of 53.3 (21.6) years; 282 patients (56.4%) were female. There was a significant association of report type with ratings, with post hoc tests revealing significantly greater scores for AI (mean [SE] score, 3.22 [0.34]; P < .001) and radiologist (mean [SE] score, 3.34 [0.34]; P < .001) reports compared with teleradiology (mean [SE] score, 2.74 [0.34]) reports. AI and radiologist reports were not significantly different. On secondary analysis, there was no difference in the probability of no clinically significant discrepancy between the 3 report types. Further stratification of reports by presence of cardiomegaly, pulmonary edema, pleural effusion, infiltrate, pneumothorax, and support devices also yielded no difference in the probability of containing no clinically significant discrepancy between the report types. Conclusions and Relevance: In a representative sample of emergency department chest radiographs, results suggest that the generative AI model produced reports of similar clinical accuracy and textual quality to radiologist reports while providing higher textual quality than teleradiologist reports. Implementation of the model in the clinical workflow could enable timely alerts to life-threatening pathology while aiding imaging interpretation and documentation.
Subject(s)
Artificial Intelligence , Emergency Medical Services , Humans , Female , Middle Aged , Male , Retrospective Studies , Emergency Service, Hospital , RadiologistsABSTRACT
BACKGROUND: Retriage is the emergency transfer of severely injured patients from nontrauma and lower-level trauma centers to higher-level trauma centers. We identified the barriers to retriage at sending centers in a single health system. METHODS: We conducted a failure modes effects and criticality analysis at 4 nontrauma centers and 5 lower-level trauma centers in a single health system. Clinicians from each center described the steps in the trauma assessment and retriage process to create a process map. We used standardized scoring to characterize each failure based on frequency, impact on retriage, and prevention safeguards. We ranked each failure using the scores to calculate a risk priority number. RESULTS: We identified 26 steps and 93 failures. The highest-risk failure was refusal by higher-level trauma centers (receiving hospitals) to accept a patient. The most critical failures in the retriage process based on total risk, frequency, and safeguard scores were (1) refusal from a receiving higher-level trauma center to accept a patient (risk priority number = 191), (2) delay in a sending center's consultant examination of a patient in the emergency department (risk priority number = 177), and (3) delay in receiving hospital's consultant calling back (risk priority number = 177). CONCLUSION: We identified (1) addressing obstacles to determining clinical indications for retriage and (2) identifying receiving level I trauma centers who would accept the patient as opportunities to increase timely retriage. Establishing clear clinical indications for retriage that sending and receiving hospitals agree on represents an opportunity for intervention that could improve the retriage of injured patients.
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Trauma Centers , Humans , IllinoisABSTRACT
PURPOSE: To analyze the impact of the coronavirus disease (COVID) pandemic on emergency department (ED) computed tomography (CT) utilization. METHODS: A retrospective observational study was conducted assessing seven hospitals' ED imaging volumes between Jan. 6, 2019, and Feb. 27, 2021. Weekly CT utilization is reported as CTs ordered per 100 ED visits. Utilization was ascertained in aggregate and by body area. Interrupted time series analysis was performed to assess significance of utilization change. Prespecified sensitivity analysis was performed for influenza-like or COVID-like illness (ILI/CLI). RESULTS: Weekly ED CT utilization increased from 35.9 CTs per 100 visits (95% confidence interval [95% CI] 35.8-36.1) to 41.8 per 100 visits (95% CI 41.7-42.0) in pre- and post-pandemic periods. Weekly ED CT chest utilization increased immediately following the pandemic declaration (+ 0.52 chest CTs per 100 ED visits, 95% CI 0.01-1.03, p < 0.05) and compared to pre-pandemic period (+ 0.02 per 100 ED visits, 95% CI 0.02-0.05, p < 0.02). For both CT abdomen/pelvis and CT head, there was neither an immediate effect (+ 0.34 CT-AP per 100 ED visits, 95% CI - 0.74 to 1.44, p = 0.89; - 0.42 CT-H per 100 ED visits, 95% CI - 1.53 to 0.70, p = 0.46) nor a change in weekly CT utilization (+ 0.03 CT-AP per 100 ED visits, 95% CI - 0.01 to 0.05, p = 0.09; + 0.03 CT-H per 100 ED visits, 95% CI - 0.01 to 0.06, p = 0.10). CONCLUSION: These data may help formulate future strategies for resource utilization and imaging operations as we envision a future with COVID and other federal mandates affecting imaging utilization and appropriateness.
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COVID-19 , Pandemics , Emergency Service, Hospital , Head , Humans , Retrospective Studies , Tomography, X-Ray ComputedABSTRACT
BACKGROUND: COPD exacerbations lead to excessive health care utilization, morbidity, and mortality. The Ottawa COPD Risk Scale (OCRS) was developed to predict short-term serious adverse events (SAEs) among patients in the emergency department (ED) with COPD exacerbations. We assessed the utility of the OCRS, its component elements, and other clinical variables for ED disposition decisions in a United States population. METHODS: We compared the OCRS and other factors in predicting SAEs among a retrospective cohort of ED patients with COPD exacerbations. We followed subjects for 30 d, and the primary outcome, SAE, was defined as any death, admission to monitored unit, intubation, noninvasive ventilation, major procedure, myocardial infarction, or revisit with hospital admission. RESULTS: A total of 246 subjects (median 61-y old, 46% male, total admission rate to ward 52%) were included, with 46 (18.7%) experiencing SAEs. Median OCRS scores did not differ significantly between those with and without an SAE (difference: 0 [interquartile range 0-1)]. The OCRS predicted SAEs poorly (Hosmer-Lemeshow goodness of fit [H-L GOF] P ≤ .001, area under the receiver operating characteristic [ROC] curve 0.519). Three variables were significantly related to SAEs in our final model (H-L GOF P = .14, area under the ROC curve 0.808): Charlson comorbidity index (odds ratio [OR] 1.3 [1.1-1.5] per 1-point increase); triage venous PCO2 (OR 1.7 [1.2-2.4] per 10 mm Hg increase); and hospitalization within previous year (OR 9.1 [3.3-24.8]). CONCLUSIONS: The OCRS did not reliably predict SAEs in our population. We found 3 risk factors that were significantly associated with 30-d SAE in our United States ED population: triage [Formula: see text] level, Charlson comorbidity index, and hospitalization within the previous year. Further studies are needed to develop generalizable decision tools to improve safety and resource utilization for this patient population.
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Hospitalization , Pulmonary Disease, Chronic Obstructive , Humans , Male , Female , Retrospective Studies , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/epidemiology , Emergency Service, HospitalABSTRACT
Emergency department (ED) utilization changed notably during the coronavirus disease 2019 (COVID-19) pandemic in the United States. The purpose of the study was to gain a more thorough understanding of ED patient experience during the early stages of the COVID-19 pandemic. This study used the consensual qualitative approach to analyze open-ended responses from post-ED patient experience surveys from February through July 2020. Comments were included in the analysis if they pertained to care during the pandemic (eg, mentioned "the virus," "masks," "PPE"). A total of 242 COVID-specific comments from 192 unique patients were analyzed (median age 49 years; 69% female). Six themes were identified: visually observed changes, experiences of process changes, expressions of understanding or appreciation, sense of security, COVID-19 disease-specific comments, and "classic" satisfaction comments that align with previous literature on patient experience. The COVID-19 pandemic has challenged health care systems across the world in unique and unprecedented ways. This study identified six themes that better elucidate ED patient experience during an unprecedented public health crisis.
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The COVID-19 pandemic has placed significant strain on emergency departments (EDs) that were not designed to care for many patients who may be highly contagious. This report outlines how a busy urban ED was adapted to prepare for COVID-19 via 3 primary interventions: (1) creating an open-air care space in the ambulance bay to cohort, triage, and rapidly test patients with suspected COVID-19, (2) quickly constructing temporary doors on all open treatment rooms, and (3) adapting and expanding the waiting room. This description serves as a model by which other EDs can repurpose their own care spaces to help ensure safety of their patients and health care workers.
Subject(s)
COVID-19 , Emergency Service, Hospital/organization & administration , COVID-19/epidemiology , Chicago/epidemiology , Emergency Service, Hospital/statistics & numerical data , Facilities and Services Utilization , Hospitalization/statistics & numerical data , Humans , Length of Stay , Pandemics , Retrospective Studies , SARS-CoV-2 , Time-to-TreatmentABSTRACT
BACKGROUND: Chronic obstructive pulmonary disease exacerbations (eCOPD) can be life-threatening and costly. Emergency department (ED) observation units (ED-Obs) offer short-term care to safely reduce preventable hospitalizations. Accurately identifying eCOPD patients who can be discharged safely will improve outcomes. OBJECTIVES: The objective were to: I) evaluate utility of conventional clinical variables as predictors of safe discharge and II) assess utility of serial resting Borg score and novel Dyspnea Assessment Score (DAS) for identifying eCOPD patients who can be safely discharged from ED-Obs. METHODS: This study was carried out in a 680-bed tertiary, academic hospital with >700 annual eCOPD ED encounters and a 16-bed ED-Obs. A two-phase study of eCOPD patients admitted to ED-Obs was performed. Objective I was a retrospective study including all eCOPD admits from April 2016 to May 2017. Predictor variables (demographics, COPD severity, comorbid conditions, exacerbation severity, clinical care in ED) and outcome variables (ED-Obs disposition, ED revisits) were obtained through electronic medical records. Safe discharge was defined as home disposition from ED-Obs without 7-day revisit. A stepwise regression was performed for predictors of safe discharge. Objective II was a prospective observation study for change in every 4-hour serial resting Borg score and DAS as identifiers of safe discharge. Comparative and receiver operating characteristic (ROC) analyses were performed. A p-value of <0.05 was considered significant. RESULTS: In Objective I, 171 patients with age, FEV1 %, and body mass index of 59.8 (±9.5) years, 35 (±24)%, and 28.8 (±8) m2 /kg were included. After ED-Obs treatment 78 (45.6%) were hospitalized and 93 (54.4%) were discharged home, of whom 11 (6.4%) had 7-day ED revisit. Safe discharge occurred in 82 (48%). None of the predictor variables correlated with safe discharge. In Objective II, of 38 patients included, 20 (52.6%) had safe discharge. Among others, 16 (42%) were hospitalized and two (5.2%) had 7-day ED revisit. The admission Borg scores and DASs were similar in both groups. The predisposition Borg score was significantly lower in patients with safe discharge (2.75 vs. 5.28, p < 0.001) and had the highest area under curve on ROC (0.77) for safe discharge. DAS was not significantly different between groups. CONCLUSIONS: Routine clinical variables do not identify eCOPD patients who can be safely discharged from ED-Obs. Change in resting Borg score during the course of ED-Obs treatment safely identifies patients for discharge. Prospective, external validation is needed to incorporate serial Borg scores in ED-Obs disposition decision for improved safety.
Subject(s)
Clinical Observation Units , Emergency Service, Hospital , Pulmonary Disease, Chronic Obstructive , Aged , Humans , Middle Aged , Patient Discharge , Prospective Studies , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/therapy , Retrospective StudiesABSTRACT
BACKGROUND: COPD exacerbations lead to accelerated decline in lung function, poor quality of life, and increased mortality and cost. Emergency department (ED) observation units provide short-term care to reduce hospitalizations and cost. Strategies to improve outcomes in ED observation units following COPD exacerbations are needed. We sought to reduce 30-d ED revisits for COPD exacerbations managed in ED observation units through implementation of a COPD care bundle. The study setting was an 800-bed, academic, safety-net hospital with 700 annual ED encounters for COPD exacerbations. Among those discharged from ED observation unit, the 30-d all-cause ED revisit rate (ie, the outcome measure) was 49% (baseline period: August 2014 through September 2016). METHODS: All patients admitted to the ED observation unit with COPD exacerbations were included. A multidisciplinary team implemented the COPD bundle using iterative plan-do-study-act cycles with a goal adherence of 90% (process measure). The bundle, adopted from our inpatient program, was developed using care-delivery failures and unmet subject needs. It included 5 components: appropriate inhaler regimen, 30-d inhaler supply, education on devices available after discharge, standardized discharge instructions, and a scheduled 15-d appointment. We used statistical process-control charts for process and outcome measures. To compare subject characteristics and process features, we sampled consecutive patients from the baseline (n = 50) and postbundle (n = 83) period over 5-month and 7-month intervals, respectively. Comparisons were made using t tests and chi-square tests with P < .05 significance. RESULTS: During baseline and postbundle periods, 410 and 165 subjects were admitted to the ED observation unit, respectively. After iterative plan-do-study-act cycles, bundle adherence reached 90% in 6 months, and the 30-d ED revisit rate declined from 49% to 30% (P = .003) with a system shift on statistical process-control charts. There was no difference in hospitalization rate from ED observation unit (45% vs 51%, P = .16). Subject characteristics were similar in the baseline and postbundle periods. CONCLUSIONS: Reliable adherence to a COPD care bundle reduced 30-d ED revisits among those treated in the ED observation unit.
Subject(s)
Clinical Observation Units/statistics & numerical data , Hospitalization/statistics & numerical data , Patient Care Bundles/statistics & numerical data , Patient Readmission/statistics & numerical data , Pulmonary Disease, Chronic Obstructive/therapy , Aged , Clinical Protocols , Emergency Service, Hospital/statistics & numerical data , Female , Humans , Male , Middle Aged , Patient Discharge/statistics & numerical dataABSTRACT
B-type natriuretic peptide (BNP) is used widely to exclude heart failure (HF) in patients with dyspnea. However, most studies of BNP have focused on diagnosing HF with reduced ejection fraction (EF). The aim of this study was to test the hypothesis that a normal BNP level (≤100 pg/ml) is relatively common in HF with preserved EF (HFpEF), a heterogenous disorder commonly associated with obesity. A total of 159 consecutive patients enrolled in the Northwestern University HFpEF Program were prospectively studied. All subjects had symptomatic HF with EF >50% and elevated pulmonary capillary wedge pressure. BNP was tested at baseline in all subjects. Clinical characteristics, echocardiographic parameters, invasive hemodynamics, and outcomes were compared among patients with HFpEF with normal (≤100 pg/ml) versus elevated (>100 pg/ml) BNP. Of the 159 patients with HFpEF, 46 (29%) had BNP ≤100 pg/ml. Subjects with normal BNP were younger, were more often women, had higher rates of obesity and higher body mass index, and less commonly had chronic kidney disease and atrial fibrillation. EFs and pulmonary capillary wedge pressures were similar in the normal and elevated BNP groups (62 ± 7% vs 61 ± 7%, p = 0.67, and 25 ± 8 vs 27 ± 9 mm Hg, p = 0.42, respectively). Elevated BNP was associated with enlarged left atrial volume, worse diastolic function, abnormal right ventricular structure and function, and worse outcomes (e.g., adjusted hazard ratio for HF hospitalization 4.0, 95% confidence interval 1.6 to 9.7, p = 0.003). In conclusion, normal BNP levels were present in 29% of symptomatic outpatients with HFpEF who had elevated pulmonary capillary wedge pressures, and although BNP is useful as a prognostic marker in HFpEF, normal BNP does not exclude the outpatient diagnosis of HFpEF.
Subject(s)
Heart Failure/physiopathology , Natriuretic Peptide, Brain/blood , Stroke Volume , Aged , Echocardiography , Female , Follow-Up Studies , Heart Failure/blood , Hemodynamics , Humans , Logistic Models , Male , Middle Aged , Prevalence , Prospective StudiesABSTRACT
BACKGROUND: The application of indirect reduction techniques has improved fracture-healing and reduced the need for bone-grafting compared with the outcomes of older, direct reduction techniques. We investigated the results of such indirect reduction techniques for the treatment of periprosthetic femoral shaft fractures. METHODS: Fifty consecutive patients with a femoral shaft fracture about a stable intramedullary implant (a Vancouver Type-B1 fracture) were treated with a protocol that included open reduction with use of indirect reduction techniques and internal fixation with a single lateral plate without structural allografting or other bone-grafting. Four patients died in the early postoperative period, and five had inadequate follow-up. The remaining forty-one patients (average age, seventy-two years) were evaluated clinically and radiographically at an average of twenty-four months. RESULTS: All fractures healed in satisfactory alignment at an average of twelve weeks (range, seven to twenty-three weeks) after the index procedure. One patient had one fractured cable and two others had one fractured screw, but all of the fractures healed without evidence of implant loosening or malalignment. There was one deep infection in the perioperative period. Thirty of the forty-one patients returned to their baseline ambulatory status. CONCLUSIONS: The results of this study support the use of indirect open reduction and internal fixation with a single extraperiosteal lateral plate, without the use of allograft struts, for the treatment of a femoral shaft fracture about a stable intramedullary implant.
Subject(s)
Arthroplasty, Replacement, Hip/adverse effects , Femoral Fractures/surgery , Fracture Fixation, Internal/methods , Postoperative Complications , Adult , Aged , Aged, 80 and over , Bone Plates , Bone Transplantation , Female , Femoral Fractures/etiology , Fracture Fixation, Internal/instrumentation , Hip Prosthesis , Humans , Male , Middle Aged , Treatment OutcomeABSTRACT
OBJECTIVE: New locked plate devices offer theoretical advantages for the treatment of supracondylar femur fractures associated with a total knee arthroplasty (TKA). These devices also can be inserted with relative ease by using minimally invasive techniques, provide a fixed angle construct, and improve fixation in osteoporotic bone. The purpose of this study was to evaluate the results and complications of treating periprosthetic supracondylar femur fractures above a TKA with a locked plate designed for the distal femur. DESIGN: Prospective, consecutive case series. SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: Twenty-two consecutive adult patients with 24 (2 bilateral) supracondylar femur fractures (OTA 33A) above a well-fixed non-stemmed TKA were treated with the Locking Condylar Plate. One patient who died before fracture healing and 1 who was lost to follow-up were excluded from analysis. All remaining patients (5 males, 15 females, average age, 73 (range, 50-95) years) were available for follow-up at an average of 15 (range, 6-45) months. According to the OTA classification, there were three 33A1, eight 33A2, and eleven 33A3 fractures. All fractures were closed. Indirect reduction methods without bone graft were used in all cases. RESULTS: Nineteen of 22 fractures healed after the index procedure (86%). All 3 patients with healing complications were insulin-dependent patients with diabetes who also were obese (body mass index >30). Two developed infected nonunions and 1 an aseptic nonunion. Postoperative alignment was satisfactory (within 5 degrees ) for 20 of 22 fractures. Fracture of screws in the proximal fragment occurred in 4 patients. In 3 of these cases, there was progressive coronal plane deformity. There was no change in alignment in any other patient. Fifteen of 17 patients who healed returned to their baseline ambulatory status, with 5 requiring additional ambulatory support compared with baseline. CONCLUSIONS: Fixation of periprosthetic supracondylar femur fractures with a locking plate provided satisfactory results in nondiabetic patients. Diabetic patients seem to be at high risk for healing complications and infection.
Subject(s)
Arthroplasty, Replacement, Knee , Bone Plates , Femoral Fractures/surgery , Aged , Aged, 80 and over , Arthroplasty, Replacement, Knee/adverse effects , Diabetes Mellitus , Equipment Failure , Female , Femoral Fractures/etiology , Fractures, Ununited/epidemiology , Humans , Male , Middle Aged , Minimally Invasive Surgical Procedures , Prospective Studies , Recovery of FunctionABSTRACT
BACKGROUND: The application of indirect reduction techniques has improved fracture-healing and reduced the need for bone-grafting compared with the outcomes of older, direct reduction techniques. We investigated the results of such indirect reduction techniques for the treatment of periprosthetic femoral shaft fractures. METHODS: Fifty consecutive patients with a femoral shaft fracture about a stable intramedullary implant (a Vancouver Type-B1 fracture) were treated with a protocol that included open reduction with use of indirect reduction techniques and internal fixation with a single lateral plate without structural allografting or other bone-grafting. Four patients died in the early postoperative period, and five had inadequate follow-up. The remaining forty-one patients (average age, seventy-two years) were evaluated clinically and radiographically at an average of twenty-four months. RESULTS: All fractures healed in satisfactory alignment at an average of twelve weeks (range, seven to twenty-three weeks) after the index procedure. One patient had one fractured cable and two others had one fractured screw, but all of the fractures healed without evidence of implant loosening or malalignment. There was one deep infection in the perioperative period. Thirty of the forty-one patients returned to their baseline ambulatory status. CONCLUSIONS: The results of this study support the use of indirect open reduction and internal fixation with a single extraperiosteal lateral plate, without the use of allograft struts, for the treatment of a femoral shaft fracture about a stable intramedullary implant. LEVEL OF EVIDENCE: Therapeutic Level IV.
Subject(s)
Arthroplasty, Replacement, Hip/adverse effects , Femoral Fractures/surgery , Fracture Fixation, Internal/methods , Postoperative Complications , Adult , Aged , Aged, 80 and over , Bone Plates , Bone Transplantation , Female , Femoral Fractures/etiology , Fracture Fixation, Internal/instrumentation , Hip Prosthesis , Humans , Male , Middle Aged , Treatment OutcomeABSTRACT
The effects of a series of 102 bisphosphonates on the inhibition of growth of Entamoeba histolytica and Plasmodium falciparum in vitro have been determined, and selected compounds were further investigated for their in vivo activity. Forty-seven compounds tested were active (IC(50) < 200 microM) versus E. histolytica growth in vitro. The most active compounds (IC(50) approximately 4-9 microM) were nitrogen-containing bisphosphonates with relatively large aromatic side chains. Simple n-alkyl-1-hydroxy-1,1-bisphosphonates, known inhibitors of the enzyme farnesylpyrophosphate (FPP) synthase, were also active, with optimal activity being found with C9-C10 side chains. However, numerous other nitrogen-containing bisphosphonates known to be potent FPP synthase inhibitors, such as risedronate or pamidronate, had little or no activity. Several pyridine-derived bisphosphonates were quite active (IC(50) approximately 10-20 microM), and this activity was shown to correlate with the basicity of the aromatic group, with activity decreasing with increasing pK(a) values. The activities of all compounds were tested versus a human nasopharyngeal carcinoma (KB) cell line to enable an estimate of the therapeutic index (TI). Five bisphosphonates were selected and then screened for their ability to delay the development of amebic liver abscess formation in an E. histolytica infected hamster model. Two compounds were found to decrease liver abscess formation at 10 mg/kg ip with little or no effect on normal liver mass. With P. falciparum, 35 compounds had IC(50) values <200 microM in an in vitro assay. The most active compounds were also simple n-alkyl-1-hydroxy-1,1-bisphosphonates, having IC(50) values around 1 microM. Five compounds were again selected for in vivo investigation in a Plasmodium berghei ANKA BALB/c mouse suppressive test. The most active compound, a C9 n-alkyl side chain containing bisphosphonate, caused an 80% reduction in parasitemia with no overt toxicity. Taken together, these results show that bisphosphonates appear to be useful lead compounds for the development of novel antiamebic and antimalarial drugs.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Diphosphonates/chemical synthesis , Entamoeba histolytica/drug effects , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Cell Line , Cricetinae , Diphosphonates/chemistry , Diphosphonates/pharmacology , Entamoebiasis/drug therapy , Humans , In Vitro Techniques , Liver Abscess/drug therapy , Liver Abscess/parasitology , Malaria/drug therapy , Mice , Mice, Inbred BALB C , Structure-Activity RelationshipABSTRACT
We report the inhibition of a human recombinant geranylgeranyl diphosphate synthase (GGPPSase) by 23 bisphosphonates and six azaprenyl diphosphates. The IC50 values range from 140 nM to 690 microM. None of the nitrogen-containing bisphosphonates that inhibit farnesyl diphosphate synthase were effective in inhibiting the GGPPSase enzyme. Using three-dimensional quantitative structure-activity relationship/comparative molecular field analysis (CoMFA) methods, we find a good correlation between experimental and predicted activity: R2 = 0.938, R(cv)2 = 0.900, R(bs)2 = 0.938, and F-test = 86.8. To test the predictive utility of the CoMFA approach, we used three training sets of 25 compounds each to generate models to predict three test sets of three compounds. The rms pIC50 error for the nine predictions was 0.39. We also investigated the pharmacophore of these GGPPSase inhibitors using the Catalyst method. The results demonstrated that Catalyst predicted the pIC50 values for the nine test set compounds with an rms error of 0.28 (R2 between experimental and predicted activity of 0.948).