A randomized trial of a representational intervention for cancer pain: Does targeting the dyad make a difference?

Objective: To determine the efficacy in overcoming attitudinal barriers to reporting cancer pain and using analgesics of an educational intervention presented to patients accompanied by a significant other (SO) as compared with patients alone. Design: Patient–SO pairs (N = 161) were randomized to the dyad condition (patient and SO received the intervention), solo condition (patient received the intervention), or care as usual. Dyad and solo conditions received the intervention at baseline (T1) and 2 and 4 weeks later. Main Outcome Measures: Patients' and SOs' attitudes about analgesic use and patients' pain outcomes (pain severity, pain relief, interference with life, negative mood, and global quality of life [QOL]) at T1, 5 weeks later (T2), and 9 weeks later (T3). Results: Completers' analyses revealed no significant differences between groups at T2. At T3, patients in the dyad and the solo groups showed greater decreases in attitudinal barriers as compared with controls. T1–T3 changes in patients' barriers mediated between the dyad and solo interventions and pain severity, pain relief, pain interference, negative mood, and global QOL. Conclusion: The intervention was no more efficacious when it was presented to dyads than to patients alone. Conditions under which SOs should be included in interventions need to be determined. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Survival in stage T2-T3A bladder cancer treated with radical cystectomy

OBJECTIVE: The optimal treatment for patients with localized muscle-infiltrating urothelial carcinoma (Jewett stage B or T2-T3a of the TNM classification, UICC 1992) continues to be a controversy. The present study analyzed the survival rate in patients with stage T2-T3a bladder cancer who had been treated by radical cystectomy. METHODS: The records of 50 patients with T2-T3a NO tumor, submitted to pelvic lymphadenectomy and radical cystoprostatectomy, were reviewed to determine the prognosis in this group of patients. Seventeen patients (34%) received three courses of systemic chemotherapy (CMV) prior to cystectomy. RESULTS: The overall 5-year survival rate was 73%; 76% for those with T2 (n = 30) and 67% for those with T3a (n = 20) (log-rank, p = 0.27). No statistically significant differences were observed for age (less than or over 65 years), tumor growth pattern (papillary or flat), tumor size (less or greater than 5 cms) or treatment (with or without induction CMV). However, patients with G1-2 tumor had a better survival rate (94% at 5 years) than those with G3 tumor (51%), a difference with statistical significance (log-rank, p = 0.047). The Cox regression analysis showed no independent variable of prognostic significance. CONCLUSION: Muscle-infiltrating urothelial carcinoma is highly curable by radical surgery. Some authors believe it is unnecessary to distinguish T2-T3a lesions; therefore a critical review of the TNM classification appears to be warranted. We are unable to distinguish patients with a better prognosis that might benefit from less aggressive therapeutic options. Similarly, the therapeutic benefits of induction chemotherapy prior to cystectomy in patients with stage T2-T3a tumor could not be demonstrated.     

Abnormalities in oxygenation, coagulation, and fibrinolysis in colonic blood of horses with experimentally induced strangulation obstruction

OBJECTIVE: To measure arterial and venous blood gas, coagulation, and fibrinolysis variables in blood from isolated segments of control and ischemic large colons for the purpose of identifying variables for rapid, indirect assessment of colonic mucosal injury. DESIGN: Variables were determined at specific intervals during the 4-hour study (3 hours of ischemia and 1 hour of reperfusion). ANIMALS: Seven clinically normal horses between 2 and 15 years old. PROCEDURES: Horses underwent laparotomy and occlusion of the lumen and vasculature of the mid-portion of the pelvic flexure of the large colon. During ischemia of 1 randomly-chosen colonic segment, variables were measured to determine colonic mucosal damage and were compared with histologic scores of colonic biopsy specimens. RESULTS: Significant (P < 0.05) differences from control values were observed over time for venous pH, PCO2, PO2, oxygen saturation, oxygen content, arteriovenous oxygen difference, and lactate and glucose concentrations. Mean histologic scores of biopsy specimens obtained from ischemic colons were significantly (P < 0.05) greater (indicating greater damage) than those from control colons, and increased significantly (P < 0.05) with duration of ischemia. CONCLUSIONS: Venous lactate, oxygen saturation, and PO2 values were the most significant predictors of the severity of histologic damage within the ischemic colons (R2 = 0.661). CLINICAL RELEVANCE: Venous blood gas and lactate values in the large colon are good predictors of the amount of intestinal damage incurred during 3 hours of ischemia, and may be clinically useful for the rapid determination of colonic viability.     

Influence of anesthetic technique in postoperative analgesia in thoracic surgery

OBJECTIVE: To compare the intensity of postoperative pain after thoracotomy with 2 anesthetic techniques: 1) thoracic epidural block with bupivacaine administered before surgery (combined anesthesia with isoflurane) and 2) conventional balanced anesthesia with isoflurane and endovenous fentanyl. PATIENTS AND METHODS: Thirty patients scheduled for thoracotomy by lateral incision (T5-T6) were randomly divided into 2 groups of 15. Group A received 8 ml of 0.5% bupivacaine with adrenalin 1:200.000 30 min before start of surgery while group B received 8 ml saline solution through an epidural catheter inserted to T4-T8. Combined anesthesia (4 ml 0.5% bupivacaine through an epidural catheter 150 min after the first dose and isoflurane in 100% oxygen) was used in group A. Group B received balanced anesthesia with endovenous fentanyl 2.5 micrograms/kg and isoflurane in 100% oxygen. The difference in pain intensity during postoperative recovery was assessed by way of the following variables: number of boluses administered by epidural patient-controlled analgesia (bupivacaine 0.0625% and fentanyl 6 micrograms/ml); score on a visual analog scale of 10 at baseline and at 1, 3, 7, 11, 19 and 43 hours after surgery; and need for additional analgesia (diclofenac) during the 43 hours of study. Arterial gases were measured during the preoperative period and at 1, 3, 7, 19 and 43 hours after surgery. RESULTS: No significant differences in pain intensity measured on the visual analog scale, by the number of boluses per patients or by need for additional analgesia were found between the 2 groups. The total number of boluses administered and additional analgesic requirements were greater in the group receiving bupivacaine, although the difference was not significant (p = 0.095 and p = 0.056, respectively). Nor were there significant differences in pH and PaCO2 levels for the 2 groups. CONCLUSIONS: Analgesic efficacy after thoracotomy was similar for our 2 groups receiving either combined anesthesia (epidural bupivacaine at 0.5% and isoflurane) or balanced anesthesia with isoflurane and endovenous fentanyl.     

Phospholipase C isozymes in the human brain and their changes in Alzheimer''s disease

OBJECTIVE: We compared the efficacy of bladder training, pelvic muscle exercise with biofeedback-assisted instruction, and combination therapy, on urinary incontinence in women. The primary hypothesis was that combination therapy would be the most effective in reducing incontinent episodes. STUDY DESIGN: A randomized clinical trial with three treatment groups was conducted in gynecologic practices at two university medical centers. Two hundred and four women diagnosed with genuine stress incontinence (n = 145) and/or detrusor instability (n = 59) received a 12-week intervention program (6 weekly office visits and 6 weeks of mail/telephone contact) with immediate and 3-month follow-up. Outcome variables included number of incontinent episodes, quality of life, perceived improvement, and satisfaction. Data analyses consisted of analysis of covariance using baseline values as covariates and chi2 tests. RESULTS: The combination therapy group had significantly fewer incontinent episodes, better quality of life, and greater treatment satisfaction immediately after treatment. No differences among groups were observed 3 months later. Women with genuine stress incontinence had greater improvement in life impact, and those with detrusor instability had less symptom distress at the immediate follow-up; otherwise, no differences were noted by diagnosis, incontinence severity, or treatment site. CONCLUSIONS: Combination therapy had the greatest immediate efficacy in the management of female urinary incontinence regardless of urodynamic diagnosis. However, each of the 3 interventions had similar effects 3 months after treatment. Results suggest that the specific treatment may not be as important as having a structured intervention program with education, counseling, and frequent patient contact.     

Socioeconomic disparities in pain: The role of economic hardship and daily financial worry.

Objective: Socioeconomic disparities in pain may be attributable to both greater frequency in stressful financial events as well as greater vulnerability to economic hardship for those at the lower end of the socioeconomic spectrum. This study investigated the effects of economic hardship and daily financial worry on daily pain among women with a chronic musculoskeletal condition. Design: The sample consisted of 250 women with osteoarthritis (N = 105), fibromyalgia (N = 46), or both (N = 99). During an initial assessment, participants' chronic pain diagnosis, level of economic hardship, and demographic information were ascertained. For a period of 30 days, daily diary assessments recorded daily financial worries and daily pain severity. Hypotheses were tested using multilevel modeling for repeated measures in SAS PROC MIXED. Main Outcome Measure: Daily pain severity. Results: Conditions of economic hardship and daily ratings of financial worry both had significant detrimental effects on daily pain. Participants with greater levels of economic hardship reported greater pain severity in response to daily financial worries than their counterparts with little or no economic hardship. Further, participants in the sample who were not employed and who reported higher levels of economic hardship exhibited the most pain reactivity in response to daily financial worries. Conclusion: Economic hardship was associated not only with greater exposure to daily financial worries but also with greater vulnerability to pain on days when daily financial worries were experienced. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Observations on the zinc protoporphyrin/heme ratio in whole blood

The aim of this study was to examine whether severity of preoperative pain intensity is related to postoperative pain and morphine consumption. Sixty consecutive patients scheduled for total hip surgery during intrathecal anesthesia were studied. Preoperative visual analog scale (VAS) scores and analgesic intake was assessed 1 day before surgery. Three groups of patients were identified: those with mild pain (n = 12, VAS score 0-4), moderate pain (n = 18, VAS score 4-7), and severe pain (n = 28, VAS score 7-10). Postoperative pain scores were recorded in the first 24 h, as was the amount of morphine delivered by the patient-controlled analgesia pump. There were no differences among the groups in VAS scores at any time. Severe preoperative pain levels correlated with significantly greater postoperative morphine intake. The mean morphine intake during the first 24 h postoperatively was 19.2 mg in the mild pain group, 21.2 mg in the moderate pain group, and 29.5 mg in the severe pain group (P < 0.05 compared with both other groups). We conclude that patients with severe preoperative pain self-medicate to achieve postoperative pain scores equivalent to those of patients with mild and moderate pain and require a greater postoperative morphine intake for adequate analgesia than patients with mild or moderate preoperative pain. IMPLICATIONS: In this study, we showed that severity of preoperative pain intensity relates to postoperative pain levels and morphine consumption. Patients scheduled for total hip surgery with severe preoperative pain require more postoperative morphine in the first 24 h.     

Formal education and back-related disability. In search of an explanation

STUDY DESIGN: The present study is a 2-year prospective study with repeated measurements. OBJECTIVES: To examine the association of education with back-related disability along with four sets of variables that might explain this relationship: clinical, behavioral, and environmental factors; occupational variables; health care use; and interactions between stressful events and coping strategies. SUMMARY OF BACKGROUND DATA: Although education has been found to be associated with back-related disability in previous reports, this relationship remains to be explained. Examination of this association may yield a better understanding of the causes and natural history of disability resulting from back pain. METHODS: Subjects were 1213 enrollees of a Health Maintenance Organization (HMO) who consulted a primary care physician for back pain in 1989-1990, completed a baseline telephone interview, and had a follow-up evaluation after 1 and 2 years, using a modified version of the Roland-Morris Scale to measure disability. RESULTS: Subjects who completed 13 years or more of schooling had less disability and a greater decline in their disability over time than those who completed less schooling. Occupational characteristics and somatization were among the strongest explanatory factors. Cigarette smoking contributed to the explanation of the cross-sectional association. CONCLUSIONS: Education is associated cross-sectionally and longitudinally with disability resulting from back pain. A wide range of variables may mediate the education-back-related disability association, including a propensity to report diffuse physical symptoms (somatization), lifestyle (e.g., cigarette smoking), and occupational factors.     

Associations and Predictors of Posttraumatic Stress Levels According to Person-Related, Disability-Related, and Trauma-Related Variables Among Individuals With Spinal Cord Injuries.

Objective: To examine the associations and predictors of posttraumatic stress among individuals with spinal cord injuries (SCI) in the framework of a Person x Disability x Traumatic Event model. Design: An exploratory study involving analyses of variance, correlations, and a hierarchical multiple regression of a cross-sectional sample. Participants: Three hundred twelve individuals with SCI using a veteran or a civilian SCI clinic. Main Outcome Measures: Purdue Posttraumatic Stress Disorder--Revised scale (PPTSD-R). Results: Four out of all the examined variables had significant regression coefficients: spiritual-religious coping, pain level, severity of SCI, and number of traumatic events. Severity of SCI was a significant predictor, but data suggested that severity of SCI had a curvilinear association with both total posttraumatic stress levels and hyperarousal scores. Conclusion: Treatment of an individual's pain may reduce posttraumatic stress symptoms. Clinicians also can evaluate for previous trauma unrelated to the onset of the SCI and can intervene with the goal of reducing the impact of previous trauma on the individual's present emotional state and reactions to SCI. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A randomized double blind trial of verbal NSAID education compared to verbal and written education

OBJECTIVE: We performed a double blind randomized controlled trial to investigate whether patients taking nonsteroidal antiinflammatory drugs (NSAID) knew more about these drugs at followup depending on whether they were randomized to receiving or not receiving an NSAID information sheet. The patients were unaware they were in a study. METHODS: All patients received verbal education on the side effects of NSAID that was standardized and always given by the same rheumatologist. Thirty patients randomly received an NSAID information sheet and 26 patients did not. At next clinic followup, after reading a letter of explanation about the study and signing a consent form, patients completed a questionnaire asking about their knowledge of NSAID. RESULTS: Outcome variables assessed within the questionnaire included whether NSAID : (1) can decrease inflammation; (2) help with pain; (3) cause stomach upset and bleeding in the bowels. None of these variables were statistically significant. The only variable that was statistically significantly different between the groups was their report of whether they had received an information sheet about NSAID (p<0.00004). A greater proportion of patients who received the NSAID information sheet correctly reported they had received one compared to those who had not received one and who said they had not received one (85% in the former group, 70% in the latter group). The group who received the NSAID information sheet were more apt to say that NSAID can help with their pain (odds ratio 6.1, p<0.05). Education level was positively correlated with knowledge (p<0.04). However, level of education explained only 11% of the variance in overall knowledge scores (r=0.34) among all patients. CONCLUSION: An information sheet may not add educational value over verbal information by a physician in a clinic setting.     

Antitumor effect of positively charged resin in the hamster cheek pouch model

This paper presents the results of a detailed study of the pain epidemiology and health related quality of life (HRQL) in 150 chronic non-malignant pain patients consecutively referred to a Danish multidisciplinary pain center. Mean pain severity was 71.6 (SD = 18.5) on the VAS scale. Forty-two percent reported poor quality of sleep. HRQL was evaluated with the Medical Outcome Study-Short Form (SF-36), the Hospital Anxiety and Depression scale (HAD) and the Psychological General Well-Being Scale (PGWB). Compared with the normal population (NP) both SF-36 scores and PGWB scores were significantly reduced (P < 0.001) indicating that physical, psychological and social well-being were severely reduced. On the HAD scale 58% were found to have a depressive or anxiety disorder. Statistically significant but modest correlations were found between pain severity and HRQL. Psychological and social well-being was closely correlated. Sixty-three percent of the referred patients had neurogenic pain conditions. Of these, only 25% were treated with antidepressants or anticonvulsants at referral. Seventy-three percent were treated with opioids at referral. Mean opioid consumption was 64 mg of morphine per day (range 1-280 mg). Compared with the NP the chronic pain patients had used the health care system five times more often in the years prior to referral (P < 0.001). The study confirms the severe multidimensional impact of chronic pain and demonstrates that HRQL of chronic non-malignant pain patients is among the lowest observed for any medical condition.     

High dose combination radiotherapy for the treatment of localized prostate cancer

PURPOSE: We evaluate the efficacy of high dose combination radiotherapy for the treatment of localized prostate cancer. MATERIALS AND METHODS: A total of 212 patients with localized prostate cancer (T1-T3) were treated with transperineal radioactive seed implantation followed by 45 Gy. external beam radiation therapy. Patients with Gleason scores of 2-5 were treated with 125iodine at a minimum peripheral dose of 120 Gy., while 103palladium at a minimum peripheral dose of 90 Gy. was used for those with Gleason scores of 7-10. Patients with Gleason 6 diploid tumors were treated with 125iodine and those with aneuploid tumors were treated with 103palladium. Biochemical failure was defined as inability to achieve a prostate specific antigen nadir value of 0.5 ng./ml. or less. No patient was treated with androgen deprivation therapy. RESULTS: The 212 patients have a minimum of 24 months of followup (mean 33 months). Prostate specific antigen 0.5 ng./ml. or less was reached by 72% of the patients (152 of 212) and positive biopsies were detected in 13.9% (20 of 144). Using life table survivorship analysis the probability of initial biochemical success at 5 years was 91% (95% confidence interval, 83 to 97). The probability of subsequent failure following an initial success was 11% (95% confidence interval, 6 to 20) at 24 months. The complications of combination therapy included proctitis in 21.4% (47 of 212 men), impotence in 38% (38 of 100), urinary retention in 1.5%, incontinence in 2.8%, rectoprostate fistula in 2.4%, rectal wall breakdown in 0.5% and urethral stricture in 0.5%. Six patients (2.8%) required colostomy and urinary diversion. CONCLUSIONS: Short-term responses to high dose combination radiotherapy for localized prostate cancer are promising. The morbidity is acceptable. Further long-term followup is warranted to assess this treatment.     

Effects of supportive-expressive group therapy on pain in women with metastatic breast cancer.

Objective: To examine whether a group intervention including hypnosis can reduce cancer pain and trait hypnotizability would moderate these effects. Design: This randomized clinical trial examined the effects of group therapy with hypnosis (supportive-expressive group therapy) plus education compared to an education-only control condition on pain over 12 months among 124 women with metastatic breast cancer. Main Outcome Measures: Pain and suffering, frequency of pain, and degree of constant pain were assessed at baseline and 4-month intervals. Those in the treatment group also reported on their experiences using the hypnosis exercises. Results: Intention-to-treat analyses indicated that the intervention resulted in significantly less increase in the intensity of pain and suffering over time, compared to the education-only group, but had no significant effects on the frequency of pain episodes or amount of constant pain, and there was no interaction of the intervention with hypnotizability. Within the intervention group, highly hypnotizable participants, compared to those less hypnotizable, reported greater benefits from hypnosis, employed self-hypnosis more often outside of group, and used it to manage other symptoms in addition to pain. Conclusion: These results augment the growing literature supporting the use of hypnosis as an adjunctive treatment for medical patients experiencing pain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prediction of Educational Outcome After Pediatric Traumatic Brain Injury.

Objective: Evaluation of the predictive value of neuropsychological test scores with respect to special education placement following pediatric traumatic brain injury (TBI). Study Design: Longitudinal follow-up and hierarchical logistic regression analyses. Setting: Regional rehabilitation center. Participants: Consecutive series of referrals, including 58 children with TBI and no confounding premorbid histories or other complicating factors. Main Outcome Measures: Special education placement at, respectively, 12 and 24 months postinjury. Results: Children who obtained a composite T score of less than 45 on the California Verbal Learning Test--Children's Version during initial postinjury neuropsychological assessment were 8-13 times more likely to be placed in special education 12-24 months later compared with children who obtained higher scores. Conclusions: Neuropsychological test scores are not only sensitive to acute injury severity but also explain a substantial proportion of the variance in educational outcome after pediatric TBI, above and beyond that accounted for by demographic and medical variables. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The examination of myofascial face pain and its relationship to psychological distress among women.

In this study, 110 female myofascial face pain patients were assessed monthly for 10 months on measures of pain, distress, and stressful life events. D. A. Kenny and A. J. Zautra's (1995) structural equation model for examining the separate trait, state, and error components of the variables was used to analyze the data. Both pain and distress had sizable trait variance, and the trait components were correlated. The 2 variables also showed sizable state variance, and the states of pain covaried with states of distress. A significant time-lagged relationship between the 2 variables was found: Increases in distress led to elevations in pain 1 mo later. Stressful life events arising from major social roles were also associated with greater distress, but not pain. Illness events unrelated to the pain syndrome were associated with both pain and distress. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Residential segregation and disparities in health-related quality of life among Black and White cancer survivors.

Objective: Studies of health-related quality of life (HRQOL) among Black and White cancer survivors have been based on small convenience samples and yielded inconsistent results. We examined Black–White disparities in survivors' HRQOL with a population-based sample, and tested the hypothesis that area-level segregation accounts for those disparities. Design: A sample of survivors of 10 types of cancer was drawn from 11 U.S. state cancer registries and surveyed 12–15 months after diagnosis. The current sample consisted of 5195 survivors (415 Black, 4780 White) who resided in 584 counties. Main Outcome Measures: SF-36 General Health subscale scores were used as the measure of HRQOL. Results: Bivariate results revealed that Black survivors had significantly poorer HRQOL than did White survivors. Multilevel regression including individual-level (gender, age, marital status, education, cancer type, stage at diagnosis, cancer progression, comorbidities, race/ethnicity) and area-level (county segregation and poverty) variables found that HRQOL was poorer among survivors who resided in high-Black-segregated counties, whereas race/ethnicity was no longer significant. Conclusion: These findings indicate that Black–White disparities in HRQOL among cancer survivors might be a function, not of race/ethnicity, but of area-level variables associated with race/ethnicity. The strong role of segregation highlights the need for interventions to target Black-segregated areas. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Spatial distribution of insecticide resistance in Caribbean populations of Aedes aegypti and its significance

In a cross-sectional study 142 male and 139 female workers participated in a self-report questionnaire and a clinical examination. The aim of this study was to use the cervico-thoracic ratio (CTR), a clinical method for measuring segmental mobility between C7 and T5, to evaluate the influence of segmental mobility in neck-shoulder pain and different subjectively experienced symptoms. The study showed that reduced relative mobility at levels C7-T1 and T1-T2 significantly predicted neck-shoulder pain and the symptom weakness in the hands. The strongest relationship between segmental mobility and symptoms was found among subjects classified as having an inverse C7-T1 function, defined as equal or less mobility in motion segment C7-T1 compared to T1-T2. Reduced mobility explained 14% of neck-shoulder pain and 15% of weakness in the hands. It is suggested that deviation from synchronous distribution of mobility between motion segments C7-T1 and T1-T2 might be a factor provoking joint mechano receptors.     

Effects of work overload and burnout on cholesterol and triglycerides levels: The moderating efffects of emotional reactivity among male and female employees.

The effects of objective and subjective overload, and of physical and emotional burnout, on cholesterol and triglycerides levels were studied in a quasiprospective design. The possible moderating effects of emotional reactivity on these relationships were also investigated. The study's hypotheses were tested separately for male and female employees. Time I (T1) data were collected from 665 healthy employees (30% women) while they were undergoing periodic health examinations in a health-screening center Time 2 (T2) measures of cholesterol and triglycerides were collected 2 to 3 years after T1. The hypotheses were tested by regressing each T2 criterion on its T1 level; the control variables of age, obesity, diet, alcohol consumption, and smoking; and the other predictors. For female employees, the T2-T1 changes in the serum lipids were positively predicted by emotional burnout, as expected, but negatively predicted by physical fatigue. For male employees, both types of T1 burnout were positive predictors of the T2-T1 change in total cholesterol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The influence of preferred coping style and cognitive strategy on laboratory-induced pain.

Objective: To evaluate the effects of matching an individual's coping style (low, mixed, or high monitoring) to an appropriate cognitive strategy (distraction or sensation monitoring) to improve pain management. Design: This study used a split-plot factorial design in a laboratory setting. Main Outcome Measures: Main outcomes were pain threshold, pain tolerance, pain intensity, pain affect, and anxiety. Results: The results of the 2 × 3 × 3 (Experimental Condition × Coping Style × Trial) analysis of variance (ANOVA) interaction were significant for pain threshold scores, F(4, 178) = 2.95, p     

Structure-function relationship of the inhibition of the 3,5,3'-triiodothyronine binding to the alpha1- and beta1-thyroid hormone receptor by amiodarone analogs

Desethylamiodarone (DEA), the major metabolite of the potent antiarrhythmic drug amiodarone (A), acts as a competitive inhibitor of T3, binding to the alpha1-thyroid hormone receptor (alpha1-T3R), but as a noncompetitive inhibitor with respect to the beta1-T3R. To gain insight into the structure- function relationship of the interaction between A metabolites and T3Rs, we investigated the effects of several A analogs on T3 binding to the alpha1-T3R and beta1-T3R in vitro. The analogs tested were: 1) compounds obtained by deethylation of A, DEA, and desdiethylamiodarone (DDEA); 2) compounds obtained by deiodination of A, monoiodoamiodarone and desdiiodoamiodarone (DDIA); and 3) benzofuran derivatives with various iodination grades, 2-butyl-3-(4-hydroxy-3,5-diiodo-benzoyl)benzofuran (L3373, two iodine atoms), L6424 (L3373 with one iodine atom), and L3372 (L3373, no iodine atoms). IC50, values of inhibition of T3 binding to alpha1-T3R and beta1-T3R, respectively, were as follows (mean +/- SD, expressed x 10(-5) M): DEA, 4.7 +/- 0.9 and 2.7 +/- 1.4 (P < 0.001); DDEA, 3.7 +/- 0.9 and 1.9 +/- 0.3 (P < 0.001); monoiodoamiodarone, more than 20 and more than 20; DDIA, 16.2 +/- 5.6 and 9.1 +/- 2.1 (P < 0.01); L3373, 3.8 +/- 1.0 and 3.6 +/- 0.5 (P = NS); L6424, 11.3 +/- 5.7 and 10 +/- 2.0 (P = NS); and L3372, no inhibition. Scatchard analyses in the presence of DDEA, DDIA, and L3373 demonstrated a dose-dependent decrease in Ka, but no change in the maximum binding capacity (MBC) of T3 binding to alpha1-T3R. Langmuir plots clearly indicated competitive inhibition of T3 binding to alpha1-T3R by DDEA, DDIA, and L3373. In contrast, these three analogs acted differently with respect to the beta1-T3R. DDEA and DDIA decreased both Ka and MBC in Scatchard plots using beta1-T3R, demonstrating noncompetitive inhibition. L3373 decreased dose-dependently Ka, but not MBC, values of T3 binding to the beta1-T3R and clearly acted as a competitive inhibitor. Ki plots indicated that DDEA, DDIA, and L3373 do not interfere significantly with occupied T3Rs. KI (inhibition constant for the unoccupied receptor) plots demonstrated increasing inhibition of the T3 binding to unoccupied receptors with increasing analog concentrations. In summary, 1) removal of one or two ethyl groups of A results in compounds with strong but almost equal potency of inhibiting T3R binding, whereas removal of one or two iodine atoms of A has a lower potency in this respect. The strong inhibitory potency of the benzofuran derivative L3373 (equalling that of the deethylated compounds) is lost upon deiodination. 2) All tested A analogs acted as competitive inhibitors to the alpha1-T3R. The behavior to the beta1-T3R was different; deethylation or deiodination of A resulted in noncompetitive inhibition, whereas L3373 was a competitive inhibitor. The potency of deethylated and deiodinated compounds (but not of the benzofuran derivatives) for inhibiting T3 binding was twice as high for the beta1-T3R as for the alpha1-T3R. 3) All tested A analogs preferentially interfere with T3 binding to unoccupied receptors. The implications of these findings for the structure-activity relationship are the following: 1) the size of the diethyl-substituted nitrogen group and of the two bulky iodine atoms in the A molecule hamper the binding of A at the T3 binding site of T3Rs; and 2) differences in the hormone-binding domain of alpha1- and beta1-T3Rs are likely to account for the competitive or noncompetitive nature of inhibition of T3 binding by A analogs.