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1.
Proc (Bayl Univ Med Cent) ; 36(6): 706-715, 2023.
Article in English | MEDLINE | ID: mdl-37829209

ABSTRACT

Background: Opioids are a mainstay for acute pain management, but their side effects can adversely impact patient recovery. Multimodal analgesia (MMA) is recommended for treatment of postoperative pain and has been incorporated in enhanced recovery after surgery (ERAS) protocols. The objective of this quality improvement study was to implement an MMA care pathway as part of an ERAS program for colorectal surgery and to measure the effect of this intervention on patient outcomes and costs. Methods: This pre-post study included 856 adult inpatients who underwent an elective colorectal surgery at three hospitals within an integrated healthcare system. The impact of ERAS program implementation on opioid prescribing practices, outcomes, and costs was examined after adjusting for clinical and demographic confounders. Results: Improvements were seen in MMA compliance (34.0% vs 65.5%, P < 0.0001) and ERAS compliance (50.4% vs 57.6%, P < 0.0001). Reductions in mean days on opioids (4.2 vs 3.2), daily (51.6 vs 33.4 mg) and total (228.8 vs 112.7 mg) morphine milligram equivalents given during hospitalization, and risk-adjusted length of stay (4.3 vs 3.6 days, P < 0.05) were also observed. Conclusions: Implementing ERAS programs that include MMA care pathways as standard of care may result in more judicious use of opioids and reduce patient recovery time.

2.
BMJ Open ; 11(11): e051663, 2021 11 24.
Article in English | MEDLINE | ID: mdl-34819283

ABSTRACT

OBJECTIVES: Opioid-induced respiratory depression (OIRD) and oversedation are rare but potentially devastating adverse events in hospitalised patients. We investigated which features predict an individual patient's risk of OIRD or oversedation; and developed a risk stratification tool that can be used to aid point-of-care clinical decision-making. DESIGN: Retrospective observational study. SETTING: Twelve acute care hospitals in a large not-for-profit integrated delivery system. PARTICIPANTS: All inpatients ≥18 years admitted between 1 July 2016 and 30 June 2018 who received an opioid during their stay (163 190 unique hospitalisations). MAIN OUTCOME MEASURES: The primary outcome was occurrence of sedation or respiratory depression severe enough that emergent reversal with naloxone was required, as determined from medical record review; if naloxone reversal was unsuccessful or if there was no evidence of hypoxic encephalopathy or death due to oversedation, it was not considered an oversedation event. RESULTS: Age, sex, body mass index, chronic obstructive pulmonary disease, concurrent sedating medication, renal insufficiency, liver insufficiency, opioid naïvety, sleep apnoea and surgery were significantly associated with risk of oversedation. The strongest predictor was concurrent administration of another sedating medication (adjusted HR, 95% CI=3.88, 2.48 to 6.06); the most common such medications were benzodiazepines (29%), antidepressants (22%) and gamma-aminobutyric acid analogue (14.7%). The c-statistic for the final model was 0.755. The 24-point Oversedation Risk Criteria (ORC) score developed from the model stratifies patients as high (>20%, ≥21 points), moderate (11%-20%, 10-20 points) and low risk (≤10%, <10 points). CONCLUSIONS: The ORC risk score identifies patients at high risk for OIRD or oversedation from routinely collected data, enabling targeted monitoring for early detection and intervention. It can also be applied to preventive strategies-for example, clinical decision support offered when concurrent prescriptions for opioids and other sedating medications are entered that shows how the chosen combination impacts the patient's risk.


Subject(s)
Analgesics, Opioid , Respiratory Insufficiency , Analgesics, Opioid/adverse effects , Humans , Naloxone , Respiratory Insufficiency/chemically induced , Respiratory Insufficiency/epidemiology , Retrospective Studies , Risk Factors
3.
Dimens Crit Care Nurs ; 40(6): 333-344, 2021.
Article in English | MEDLINE | ID: mdl-34606224

ABSTRACT

BACKGROUND: The ABCDE (Awakening and Breathing Coordination, Delirium monitoring and management, and Early exercise/mobility) bundle has been associated with reductions in delirium incidence and improved patient outcomes but has not been widely adopted. OBJECTIVE: The objective of this study was to determine how to facilitate ABCDE bundle adoption by examining the impact of different implementation strategies on bundle adherence rates and assessing clinicians' perceptions of the bundle and implementation efforts. METHODS: This study examined the effect of 2 bundle implementation strategies on patient care in 8 adult intensive care units. The basic strategy included electronic health record (EHR) modification, whereas the enhanced strategy included EHR modification plus additional bundle training, clinical champions, and staff engagement. A total of 84 nurses, physicians, and therapists participated in interviews and a survey to assess bundle implementation. RESULTS: Respondents indicated bundle use resulted in "best care" through care standardization and coordination and improved patient outcomes. Intensive care units in both intervention groups had significant improvements in bundle adherence after implementation efforts, but intensive care units in the basic intervention group outperformed other sites after initiating their own implementation strategies. Successful implementation tactics included incorporating the bundle into multidisciplinary rounds and providing ongoing support, training, and routine auditing and feedback. DISCUSSION: The ABCDE bundle can improve quality of care and outcomes, and implementation can be accelerated through EHR tools, trainings, and performance feedback.


Subject(s)
Delirium , Adult , Critical Care , Humans , Intensive Care Units , Respiration, Artificial , Surveys and Questionnaires
4.
Hepatology ; 72(5): 1747-1757, 2020 11.
Article in English | MEDLINE | ID: mdl-32083761

ABSTRACT

BACKGROUND AND AIMS: Compared to other chronic diseases, patients with chronic liver disease (CLD) have significantly higher inpatient mortality; accurate models to predict inpatient mortality are lacking. Serum lactate (LA) may be elevated in patients with CLD due to both tissue hypoperfusion as well as decreased LA clearance. We hypothesized that a parsimonious model consisting of Model for End-Stage Liver Disease (MELD) and LA at admission may predict inpatient mortality in patients with CLD. APPROACH AND RESULTS: We examined all patients with CLD in two large and diverse health care systems in Texas (North Texas [NTX] and Central Texas [CTX]) between 2010 and 2015. We developed (n = 3,588) and validated (n = 1,804) a model containing MELD and LA measured at the time of hospitalization. We further validated the model in a second cohort of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 726). MELD-LA was an excellent predictor of inpatient mortality in development (concordance statistic [C-statistic] = 0.81, 95% confidence interval [CI] 0.79-0.82) and both validation cohorts (CTX cohort, C-statistic = 0.85, 95% CI 0.78-0.87; multicenter cohort C-statistic = 0.82, 95% CI 0.74-0.88). MELD-LA performed especially well in patients with specific cirrhosis diagnoses (C-statistic = 0.84, 95% CI 0.81-0.86) or sepsis (C-statistic = 0.80, 95% CI 0.78-0.82). For MELD score 25, inpatient mortality rates were 11.2% (LA = 1 mmol/L), 19.4% (LA = 3 mmol/L), 34.3% (LA = 5 mmol/L), and >50% (LA > 8 mmol/L). A linear increase (P < 0.01) was seen in MELD-LA and increasing number of organ failures. Overall, use of MELD-LA improved the risk prediction in 23.5% of patients compared to MELD alone. CONCLUSIONS: MELD-LA (bswh.md/meldla) is an early and objective predictor of inpatient mortality and may serve as a model for risk assessment and guide therapeutic options.


Subject(s)
End Stage Liver Disease/mortality , Hospital Mortality , Lactic Acid/blood , Liver Cirrhosis/mortality , Severity of Illness Index , Aged , Clinical Decision-Making , Decision Support Techniques , End Stage Liver Disease/blood , End Stage Liver Disease/diagnosis , End Stage Liver Disease/therapy , Female , Humans , Liver Cirrhosis/blood , Liver Cirrhosis/diagnosis , Liver Cirrhosis/therapy , Male , Middle Aged , Nomograms , Patient Admission/statistics & numerical data , Prospective Studies , Risk Assessment/methods , Risk Assessment/statistics & numerical data
5.
Gastroenterology ; 155(3): 719-729.e4, 2018 09.
Article in English | MEDLINE | ID: mdl-29802851

ABSTRACT

BACKGROUND & AIMS: Chronic liver disease (CLD) is a common and expensive condition, and studies of CLD-related hospitalizations have underestimated the true burden of disease. We analyzed data from a large, diverse health care system to compare time trends in CLD-related hospitalizations with those in congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD). METHODS: We collected data from a large health care system in Texas on hospitalizations related to CLD (n = 27,783), CHF (n = 60,415), and COPD (n = 34,199) from January 1, 2004 through December 31, 2013. We calculated annual hospitalization rates (per 100,000) and compared hospital course, inpatient mortality, ancillary services, and readmissions. RESULTS: Compared with patients with CHF (median age, 71 years) or COPD (median age, 69 years), patients with CLD were significantly younger (median age, 57 years) (P < .01 vs CHF and COPD). Higher proportions of patients with CLD were uninsured (11.7% vs 5.4% for CHF and 5.4% for COPD, P < .01) and Hispanic (17% for CLD vs 9.3% for CHF and 5.0% for COPD, P < .01). A lower proportion of patients with CLD had Medicare (41.5% vs 68.6% with CHF and 70.1% with COPD, P < .01). From 2004 through 2013, the rate of CLD-related hospitalization increased by 92% (from 1295/100,000 to 2490/100,000), compared with 6.7% for CHF (from 3843/100,000 to 4103/100,000) and 48.8% for COPD (from 1775/100,000 to 2642/100,000). During this time period, CLD-related hospitalizations covered by Medicare increased from 31.8% to 41.5%, whereas hospitalizations covered by Medicare did not change for CHF (remained at 70%) or COPD (remained at 70%). Patients with CLD had longer hospital stays (7.3 days vs 6.2 days for CHF and 5.9 days for COPD, P < .01). A higher proportion of patients with CLD died or were discharged to hospice (14.2% vs 11.5% of patients with CHF and 9.3% of patients with COPD, P < .01), and a smaller proportion had access to postacute care (13.2% vs 23.2% of patients with CHF and 27.4% of patients with COPD, P < .01). A higher proportion of patients with CLD were readmitted to the hospital within 30 days (25% vs 21.9% of patients with CHF and 20.6% with COPD, P < .01). CONCLUSIONS: Patients with CLD, compared with selected other chronic diseases, had increasing rates of hospitalization, longer hospital stays, more readmissions, and, despite these adverse outcomes, less access to postacute care. Disease management models for CLD are greatly needed to manage the anticipated increase in hospitalizations for CLD.


Subject(s)
Cost of Illness , End Stage Liver Disease/epidemiology , Heart Failure/epidemiology , Hospitalization/statistics & numerical data , Pulmonary Disease, Chronic Obstructive/epidemiology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , United States/epidemiology
6.
JAMA Surg ; 153(8): 757-763, 2018 08 01.
Article in English | MEDLINE | ID: mdl-29799927

ABSTRACT

Importance: Opioids are commonly used for pain control during and after invasive procedures. However, opioid-related adverse drug events (ORADEs) are common and have been associated with worse patient outcomes. Objectives: To examine the incidence of ORADEs in patients undergoing hospital-based surgical and endoscopic procedures and to evaluate the association of ORADEs with clinical and cost outcomes. Design, Setting, and Participants: In this retrospective study of clinical and administrative data, ORADEs were identified using International Classification of Diseases, Ninth Revision diagnosis codes for known adverse effects of opioids or by opioid antagonist use. Multivariable regression analysis was used to measure the association of ORADEs with outcomes after adjusting for potential confounding factors. The setting was 21 acute care hospitals in a large integrated health care delivery system. Participants were 135 379 patients (aged ≥18 years, admitted from January 1, 2013, to September 30, 2015) who underwent surgical and endoscopic procedures and were given opioids. Exposure: Opioid use, reported as morphine milligram equivalent doses. Main Outcomes and Measures: Opioid-related adverse drug events and their association with inpatient mortality, discharge to another care facility, length of stay, cost of hospitalization, and 30-day readmission. Results: Among 135 379 adult patients in this study (67.5% female), 14 386 (10.6%) experienced at least one ORADE. Patients with ORADEs were more likely to be older, of white race/ethnicity, and male and have more comorbidities. Patients with ORADEs received a higher total dose of opioids (median morphine milligram equivalent dose, 46.8 vs 30.0 mg; P < .001) and for a longer duration (median, 3.0 vs 2.0 days; P < .001). In adjusted analyses, ORADEs were associated with increased inpatient mortality (odds ratio [OR], 28.8; 95% CI, 24.0-34.5), greater likelihood of discharge to another care facility (OR, 2.9; 95% CI, 2.7-3.0), prolonged length of stay (OR, 3.1; 95% CI, 2.8-3.4), high cost of hospitalization (OR, 2.7; 95% CI, 2.4-3.0), and higher rate of 30-day readmission (OR, 1.3; 95% CI, 1.2-1.4). ORADEs were associated with a 2.9% increase in absolute mortality, an $8225 increase in cost for the index hospitalization, and a 1.6-day increase in length of stay for the index hospitalization. Conclusions and Relevance: Opioid-related adverse drug events were common among patients undergoing hospital-based invasive procedures and were associated with significantly worse clinical and cost outcomes. Hospital-acquired harm from ORADEs in the surgical patient population is an important opportunity for health systems to improve patient safety and reduce cost.


Subject(s)
Analgesics, Opioid/adverse effects , Delivery of Health Care, Integrated/methods , Drug-Related Side Effects and Adverse Reactions/epidemiology , Hospital Costs , Opioid-Related Disorders/epidemiology , Pain, Postoperative/drug therapy , Surgical Procedures, Operative/adverse effects , Analgesics, Opioid/therapeutic use , Drug-Related Side Effects and Adverse Reactions/economics , Female , Humans , Incidence , Male , Middle Aged , Opioid-Related Disorders/economics , Retrospective Studies , Risk Factors , United States/epidemiology
7.
Endocr Pract ; 24(6): 517-526, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29624099

ABSTRACT

OBJECTIVE: Understanding of acromegaly disease management is hampered in the U.S. by the lack of a national registry. We describe medical management in a population with confirmed acromegaly. METHODS: Inpatient and outpatient electronic health records (EHRs) were used to create a database of de-identified patients assigned the Acromegaly and Gigantism International Classification of Diseases, 9th revision (ICD-9) code and/or an appropriate pituitary procedure code at 1 of 4 regional hospital systems over a 6- to 11-year period. Information regarding demographics, medical history, labs, procedures, and medications was collected and supplemented with a chart review to validate the diagnosis of acromegaly. RESULTS: Of 367 patients with validated acromegaly, available records showed that during the years studied, pituitary surgery was performed on 31%, 4% received radiosurgery, and 22% were prescribed a drug indicated for acromegaly. Insulin-like growth factor-1 (IGF-1) levels were measured in 62% of patients, 83% of whom had at least 1 normal value. Coded comorbidities reflect those reported previously in patients with acromegaly, with the exception of esophageal reflux in 20% of patient records. Fewer data regarding acromegaly-specific medications and testing were available for patients aged 65 and older. CONCLUSION: AcroMEDIC is a U.S. multisite retrospective study of acromegaly that captured medical management in the majority of patients included in the cohort. Chart review highlighted the importance of verification of coded diagnoses. Most of the acromegaly-related comorbidities identified here are known to increase with age and obesity. Patients ≥65 appeared to have less active management/monitoring of their disease. Medical attention should be directed to this population to address evolving needs over time. ABBREVIATIONS: AcroMEDIC = Acromegaly Multisite Electronic Data Innovative Consortium; BMI = body mass index; CCI = Charlson Comorbidity Index; EHR = electronic health record; GH = growth hormone; GHRA = growth hormone receptor antagonist; ICD-9 = International Classification of Diseases, 9th revision; IGF-1 = insulin-like growth factor-1; SSA = somatostatin analogue.


Subject(s)
Acromegaly/therapy , Electronic Health Records , Rare Diseases/therapy , Acromegaly/blood , Acromegaly/diagnosis , Adult , Age Factors , Aged , Comorbidity , Female , Follow-Up Studies , Humans , Insulin-Like Growth Factor I/analysis , Male , Middle Aged , Rare Diseases/diagnosis
8.
EGEMS (Wash DC) ; 2(1): 1121, 2014.
Article in English | MEDLINE | ID: mdl-25848599

ABSTRACT

CONTEXT: Electronic health records (EHRs) have been promoted as a key driver of improved patient care and outcomes and as an essential component of learning health systems. However, to date, many EHRs are not optimized to support delivery of quality and safety initiatives, particularly in Intensive Care Units (ICUs). Delirium is a common and severe problem for ICU patients that may be prevented or mitigated through the use of evidence-based care processes (daily awakening and breathing trials, formal delirium screening, and early mobility-collectively known as the "ABCDE bundle"). This case study describes how an integrated health care delivery system modified its inpatient EHR to accelerate the implementation and evaluation of ABCDE bundle deployment as a safety and quality initiative. CASE DESCRIPTION: In order to facilitate uptake of the ABCDE bundle and measure delivery of the care processes within the bundle, we worked with clinical and technical experts to create structured data fields for documentation of bundle elements and to identify where these fields should be placed within the EHR to streamline staff workflow. We created an "ABCDE" tab in the existing patient viewer that allowed providers to easily identify which components of the bundle the patient had and had not received. We examined the percentage of ABCDE bundle elements captured in these structured data fields over time to track compliance with data entry procedures and to improve documentation of care processes. MAJOR THEMES: Modifying the EHR to support ABCDE bundle deployment was a complex and time-consuming process. We found that it was critical to gain buy-in from senior leadership on the importance of the ABCDE bundle to secure information technology (IT) resources, understand the different workflows of members of multidisciplinary care teams, and obtain continuous feedback from staff on the EHR revisions during the development cycle. We also observed that it was essential to provide ongoing training to staff on proper use of the new EHR documentation fields. Lastly, timely reporting on ABCDE bundle performance may be essential to improved practice adoption and documentation of care processes. CONCLUSION: The creation of learning health systems is contingent on an ability to modify EHRs to meet emerging care delivery and quality improvement needs. Although this study focuses on the prevention and mitigation of delirium in ICUs, our process for identifying key data elements and making modifications to the EHR, as well as the lessons learned from the IT components of this program, are generalizable to other health care settings and conditions.

9.
EGEMS (Wash DC) ; 2(1): 1126, 2014.
Article in English | MEDLINE | ID: mdl-25848600

ABSTRACT

CONTEXT: Collaborative networks support the goals of a learning health system by sharing, aggregating, and analyzing data to facilitate identification of best practices care across delivery organizations. This case study describes the infrastructure and process developed by an integrated health delivery system to successfully prepare and submit a complex data set to a large national collaborative network. CASE DESCRIPTION: We submitted four years of data for a diverse population of patients in specific clinical areas: diabetes, chronic heart failure, sepsis, and hip, knee, and spine. The most recent submission included 19 tables, more than 376,000 unique patients, and almost 5 million patient encounters. Data was extracted from multiple clinical and administrative systems. LESSONS LEARNED: We found that a structured process with documentation was key to maintaining communication, timelines, and quality in a large-scale data submission to a national collaborative network. The three key components of this process were the experienced project team, documentation, and communication. We used a formal QA and feedback process to track and review data. Overall, the data submission was resource intensive and required an incremental approach to data quality. CONCLUSION: Participation in collaborative networks can be time and resource intense, however it can serve as a catalyst to increase the technical data available to the learning health system.

10.
PLoS One ; 7(8): e40533, 2012.
Article in English | MEDLINE | ID: mdl-22879878

ABSTRACT

BACKGROUND: HIV transmitted drug resistance (TDR) is a public health concern because it has the potential to compromise antiretroviral therapy (ART) at the population level. In New York State, high prevalence of TDR in a local cohort and a multiclass resistant case cluster led to the development and implementation of a statewide resistance surveillance system. METHODOLOGY: We conducted a cross-sectional analysis of the 13,109 cases of HIV infection that were newly diagnosed and reported in New York State between 2006 and 2008, including 4,155 with HIV genotypes drawn within 3 months of initial diagnosis and electronically reported to the new resistance surveillance system. We assessed compliance with DHHS recommendations for genotypic resistance testing and estimated TDR among new HIV diagnoses. PRINCIPAL FINDINGS: Of 13,109 new HIV diagnoses, 9,785 (75%) had laboratory evidence of utilization of HIV-related medical care, and 4,155 (43%) had a genotype performed within 3 months of initial diagnosis. Of these, 11.2% (95% confidence interval [CI], 10.2%-12.1%) had any evidence of TDR. The proportion with mutations associated with any antiretroviral agent in the NNRTI, NRTI or PI class was 6.3% (5.5%-7.0%), 4.3% (3.6%-4.9%) and 2.9% (2.4%-3.4%), respectively. Multiclass resistance was observed in <1%. TDR did not increase significantly over time (p for trend = 0.204). Men who have sex with men were not more likely to have TDR than persons with heterosexual risk factor (OR 1.0 (0.77-1.30)). TDR to EFV+TDF+FTC and LPV/r+TDF+FTC regimens was 7.1% (6.3%-7.9%) and 1.4% (1.0%-1.8%), respectively. CONCLUSIONS/SIGNIFICANCE: TDR appears to be evenly distributed and stable among new HIV diagnoses in New York State; multiclass TDR is rare. Less than half of new diagnoses initiating care received a genotype per DHHS guidelines.


Subject(s)
Drug Resistance, Viral , HIV Infections/epidemiology , HIV Infections/transmission , Population Surveillance , Adolescent , Adult , Anti-Retroviral Agents/pharmacology , Anti-Retroviral Agents/therapeutic use , Child , Demography , Drug Resistance, Viral/drug effects , Drug Resistance, Viral/genetics , Female , Genotype , HIV Infections/diagnosis , HIV Infections/drug therapy , HIV-1/drug effects , HIV-1/genetics , Humans , Male , Middle Aged , Mutation/genetics , New York/epidemiology , Young Adult
11.
Paediatr Respir Rev ; 8(4): 292-8, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18005897

ABSTRACT

Rates of hospitalization for asthma and respiratory infectious disease in children were modeled as a function of residence: (1) in a zip code containing a hazardous waste site with persistent organic pollutants ('POPs'); (2) in a zip code with a waste site that did not contain POPs ('other'); or (3) in a zip code without any identified waste site ('clean'), as well as other demographic covariates. After adjustment, living in a zip code containing a POPs waste site significantly increased the frequency of hospitalization for asthma and infectious respiratory disease. Living in a zip code with an 'other' waste site also increased hospitalization frequencies for both diseases. The association was strongest for zip codes whose residents were in the lowest quartile of medium family income. This evidence supports the hypothesis that living near a hazardous waste site increases risk of respiratory disease in children.


Subject(s)
Asthma/epidemiology , Hazardous Waste/adverse effects , Housing , Respiratory Tract Infections/epidemiology , Child , Child, Preschool , Hospitalization/statistics & numerical data , Humans , Infant , New York City/epidemiology , Regression Analysis
12.
Environ Health Perspect ; 115(1): 75-9, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17366823

ABSTRACT

BACKGROUND: Epidemiologic studies suggest that there may be an association between environmental exposure to persistent organic pollutants (POPs) and diabetes. OBJECTIVE: The aim of this study was to test the hypothesis that residential proximity to POP-contaminated waste sites result in increased rates of hospitalization for diabetes. METHODS: We determined the number of hospitalized patients 25-74 years of age diagnosed with diabetes in New York State exclusive of New York City for the years 1993-2000. Descriptive statistics and negative binomial regression were used to compare diabetes hospitalization rates in individuals who resided in ZIP codes containing or abutting hazardous waste sites containing POPs ("POP" sites); ZIP codes containing hazardous waste sites but with wastes other than POPs ("other" sites); and ZIP codes without any identified hazardous waste sites ("clean" sites). RESULTS: Compared with the hospitalization rates for diabetes in clean sites, the rate ratios for diabetes discharges for people residing in POP sites and "other" sites, after adjustment for potential confounders were 1.23 [95% confidence interval (CI), 1.15-1.32] and 1.25 (95% CI, 1.16-1.34), respectively. In a subset of POP sites along the Hudson River, where there is higher income, less smoking, better diet, and more exercise, the rate ratio was 1.36 (95% CI, 1.26-1.47) compared to clean sites. CONCLUSIONS: After controlling for major confounders, we found a statistically significant increase in the rate of hospitalization for diabetes among the population residing in the ZIP codes containing toxic waste sites.


Subject(s)
Diabetes Mellitus/epidemiology , Hazardous Waste , Hospitalization/trends , Adult , Black or African American , Aged , Environmental Exposure , Female , Humans , Male , Middle Aged , New York , Residence Characteristics , Rivers , White People
13.
Mol Pharmacol ; 61(3): 477-85, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11854427

ABSTRACT

Prolonged exposure to cannabinoids results in tolerance in vivo and desensitization of cannabinoid receptors in vitro. We show here that cannabinoid-induced presynaptic inhibition of glutamatergic neurotransmission desensitized after prolonged exposure to the cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-napthalenyl)methanone monomethanesulfonate (Win55,212-2). Synaptic activity between hippocampal neurons in culture was determined from network-driven increases in intracellular Ca(2+) concentration ([Ca(2+)](i) spikes) and excitatory postsynaptic currents. Win55,212-2-induced (100 nM) inhibition partially desensitized after 2 h and completely desensitized after 18- to 24-h exposure. The desensitization could be overcome by higher concentrations of agonist as indicated by a parallel rightward shift of the concentration response curve from an EC(50) of 2.7 +/- 0.3 nM to 320 +/- 147 nM for inhibition of [Ca(2+)](i) spiking and from 43 +/- 17 nM to 4505 +/- 403 nM for inhibition of synaptic currents, suggesting that this phenomenon may underlie tolerance. Presynaptic expression of dominant negative G-protein-coupled-receptor kinase (GRK2-Lys220Arg) or beta-arrestin (319-418) reduced the desensitization produced by 18- to 24-h pretreatment with 100 nM, Win55,212-2 suggesting that desensitization followed the prototypical pathway for G-protein-coupled receptors. Prolonged treatment with Win55,212-2 produced a modest increase in the EC(50) for adenosine inhibition of synaptic transmission and pretreatment with cyclopentyladenosine produced a slight increase in the EC(50) for Win55,212-2, suggesting a reciprocal ability to produce heterologous desensitization. The long-term changes in synaptic function that accompany chronic cannabinoid exposure will be an important factor in evaluating the therapeutic potential of these drugs and will provide insight into the role of the endocannabinoid system.


Subject(s)
Cannabinoids/pharmacology , Drosophila Proteins , Neurons/drug effects , Receptors, Drug/metabolism , Synaptic Transmission/drug effects , Transforming Growth Factor alpha , Animals , Arrestins/metabolism , Benzoxazines , Calcium Channel Blockers/pharmacology , Cannabinoid Receptor Modulators , Cells, Cultured , Excitatory Amino Acid Antagonists/pharmacology , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/physiology , Insect Proteins/metabolism , Morpholines/pharmacology , Naphthalenes/pharmacology , Neurons/physiology , Rats , Receptor Cross-Talk , Receptors, Cannabinoid , Receptors, Glutamate/metabolism , Receptors, Purinergic P1/metabolism , Transforming Growth Factors/metabolism , beta-Arrestins
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