Assessment of tinnitus: measurement of treatment outcomes.

There is a wide range of assessment techniques for tinnitus, but no consensus has developed concerning how best to measure either the presenting features of tinnitus or the effects of tinnitus treatments. Standardization of reliable and valid tinnitus measures would provide many advantages including improving the uniformity of diagnostic and screening criteria between clinics and facilitating comparison of treatment outcomes obtained at different sites. This chapter attempts to clarify issues involved in developing self-report questionnaires for the assessment of tinnitus. While the tinnitus questionnaires that are currently available provide valuable information on which to base diagnostic and screening decisions, they were not originally developed in such a way as to maximize their sensitivity to treatment-related changes in tinnitus. As a result, their construct validity for measuring treatment benefit has not received appropriate attention. In this paper, special emphasis is devoted to the use of effect sizes as an estimate of the ability of questionnaires (and their individual items) to measure changes associated with treatment. We discuss the criteria relevant to evaluating the effectiveness of a questionnaire for diagnostic purposes vs. for treatment-evaluation purposes, and we present a detailed illustration of how the various criteria have been applied in a recent questionnaire development effort.

Impact of 131I-SPECT/CT images obtained with an integrated system in the follow-up of patients with thyroid carcinoma.

PURPOSE: The purpose of the study was to determine the diagnostic impact of 131I-SPECT/CT imaging compared with conventional scintigraphic evaluation in the follow-up of patients with thyroid carcinoma. METHODS: Seventy-one patients with thyroid carcinoma underwent concurrent 131I-SPECT/CT, using an integrated imaging system, at various stages of their disease in order to evaluate foci of uptake detected on planar whole-body images. RESULTS: SPECT/CT imaging had an incremental diagnostic value in 57% (41/71) of patients. Uptake in the neck was evaluated in 61 patients, and SPECT/CT imaging in this region had an incremental diagnostic value in 27% of the whole patient population (19/71). Low-resolution integrated CT images allowed for the precise characterization of equivocal neck lesions on planar imaging in 14/17 patients and changed the assessment of the lesion location in five patients as compared with planar studies. Thirty-six patients underwent SPECT/CT for evaluation of foci of uptake distant from the neck. SPECT/CT imaging improved characterization of equivocal foci of uptake as definitely benign in 13% (9/71) of patients. Precise localization of malignant lesions to the skeleton was possible in 17% (12/71) and to the lungs versus the mediastinum in 6% (5/71) of patients. CONCLUSION: Integrated 131I-SPECT/CT was found to have an additional value over planar imaging in patients with thyroid cancer for correct characterization of equivocal tracer uptake seen on planar imaging as well as for precise localization of malignant lesions in the neck, chest, and skeleton. SPECT/CT optimized the localization of 131I uptake to lymph node metastases versus remnant thyroid tissue, to lung versus mediastinal metastases, and to the skeleton. It also had a further clinical impact on patient management by influencing referral for 131I treatment, tailoring of the administered radioiodine dose, and/or the addition of surgery or external radiation therapy when indicated.

Minimally invasive radioguided parathyroidectomy (MIRP).

The technique of parathyroidectomy has traditionally involved a bilateral exploration of the neck with the intent of visualizing 4 parathyroid glands and resecting pathologically enlarged glands. Parathyroid scanning using technetium-99m sestamibi has evolved and can now localize 80% to 90% of parathyroid adenomas. The technique of minimally invasive radioguided parathyroidectomy (MIRP) is a surgical option for most patients with primary hyperparathyroidism and a positive preoperative parathyroid scan. The technique makes use of a hand-held gamma probe that is used intraoperatively to guide the dissection in a highly directed manner with the procedure often performed under local anesthesia. The technique results in excellent cure rates while allowing most patients to leave the hospital within a few hours after the completion of the procedure. Current data also suggest the procedure can decrease hospital charges by approximately 50%. This technique may significantly change the management of primary hyperparathyroidism.

Sentinel lymph node detection and microstaging in vulvar carcinoma.

OBJECTIVE: To determine the efficacy of using complementary techniques for detecting sentinel lymph nodes (SLNs) in vulvar carcinoma and to evaluate the utility of microstaging techniques. STUDY DESIGN: Patients with invasive vulvar carcinoma underwent sentinel lymph node detection (SLND) using preoperative lymphoscintigraphy, intraoperative isosulfan blue dye injection and an intraoperative hand-held gamma-detecting probe. Eleven patients were included and a total of 16 groins evaluated. Sentinel nodes identified were excised, bisected and examined in surgical pathology using hematoxylin and eosin (H&E) staining. Pathologically negative SLNs were subjected to additional microstaging via serial sectioning and immunohistochemical staining for cytokeratin. Surgical management of the vulvar cancer and extent of inguinal-femoral lymphadenectomy were individualized based on clinicopathologic parameters, including depth of invasion, location of the tumor and patient performance status. RESULTS: Lymphoscintigraphy, dye and gamma-detector methods led to the total detection of 16, 19 and 17 SLNs, respectively. In two cases the isosulfan blue dye assisted in the isolation of an additional sentinel node over that of the gamma probe. Each method individually identified SLNs in 10/11 patients (91%). A total of 19 sentinel nodes were isolated. One SLN (5%) was positive for metastatic disease using H&E staining. Of the 18 negative SLNs, 2 (11%) had micrometastases (< 0.2 mm) upon serial sectioning and immunohistochemical staining. CONCLUSION: Combined-modality mapping enhances detection of SLNs in vulvar carcinoma. Histologic microstaging improves the detection of micrometastases within SLNs.

Positron emission tomography imaging in oncology.

The applications for FDG-PET imaging are rapidly growing and accepted in the field of oncology. FDG-PET imaging does not replace other imaging modalities, such as CT, but seems to be very helpful in specific situations where CT has known limitations, such as differentiation of benign from malignant indeterminate lesions on CT, differentiation of post-treatment changes versus recurrent tumor, differentiation of benign from malignant lymph nodes, and monitoring therapy. The biggest use of FDG-PET presently is in N and M staging of various body tumors. The addition of FDG-PET in the evaluation of oncologic patients in well-defined algorithms including a combination of imaging studies seems to be cost effective by accurately identifying patients who benefit from invasive procedures and saving unnecessary costly invasive procedures on patients who do not benefit from them. Although PET imaging may decrease the cost of health care by reducing the number of invasive procedures, implementation of clinical PET has been hindered by the high cost of the purchase, operation expenses, and maintenance of PET systems; the need for immediate access to a source of 18F (owing to the 110-minute half-life); and the limited reimbursement for clinical procedures by third-party payers. These combined factors have resulted in the development by manufacturers of hybrid gamma camera systems capable of performing positron imaging. These systems can be used to image conventional radiopharmaceuticals used in general nuclear medicine and positron-emitting radiopharmaceuticals. The performance of these camera-based PET systems has improved markedly over the past few years with the introduction of thicker NaI (T1) crystals, iterative reconstruction algorithms, and attenuation correction. These new developments in medical imaging instrumentation have contributed to the expansion of the number of cyclotrons, and have driven the concept of commercial FDG distribution centers.

Chronic tinnitus as phantom auditory pain.

OBJECTIVES: To investigate similarities between patients who experience chronic tinnitus or pain and to formulate treatment strategies that are likely to be effective for patients who experience phantom auditory pain. STUDY DESIGN: A total of 160 patients rated the severity and loudness of their tinnitus and completed the State-Trait Anxiety Inventory (STAI) and an abbreviated version of the Beck Depression Inventory (aBDI). Patients received counseling, audiometric testing, and matched the loudness of their tinnitus to sounds played through headphones. SETTING: A specialized tinnitus clinic within an urban medical center. RESULTS: Tinnitus severity was highly correlated with patients' degree of sleep disturbance, STAI, and aBDI scores. The self-rated (on a 1-to-10 scale)--but not the matched--loudness of tinnitus was correlated with tinnitus severity, sleep disturbance, STAI, and aBDI scores. CONCLUSIONS: The severity of chronic tinnitus is correlated with the severity of insomnia, anxiety, and depression. These relationships are the same for many patients with chronic pain. Treatment recommendations are discussed in reference to these results.

Value of iterative reconstruction, attenuation correction, and image fusion in the interpretation of FDG PET images with an integrated dual-head coincidence camera and X-ray-based attenuation maps.

PURPOSE: To compare lesion detectability on 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomographic (PET) images obtained with a dual-head coincidence (DHC) gamma camera equipped with an integrated x-ray tube-based transmission system (a) with images reconstructed with filtered back projection (FBP) and those reconstructed with an iterative reconstruction algorithm based on coincidence-ordered subsets expectation maximization (COSEM), (b) with images reconstructed without and with attenuation correction (AC), and (c) with images reconstructed without and with image fusion for anatomic mapping. MATERIALS AND METHODS: Thirty-five patients known or suspected to have malignancy underwent initial imaging with a dedicated positron emission tomography (PET) unit after injection of 10 mCi (370 MBq) of FDG. Transmission computed tomographic (CT) scans and FDG emission images were then obtained with the DHC camera. The proportion of lesions detected on the various sets of FDG DHC images was determined by using FDG PET as the standard of reference. Imaging findings were correlated with those from histologic examination and clinical follow-up, in consultation with the respective referring physicians. RESULTS: FDG PET depicted 78 lesions, 29 of which were equal to or less than 1.5 cm in diameter. FDG DHC depicted 52 of the 78 (67%), 59 of 78 (76%), and 61 of the 78 (78%) lesions, respectively, when image reconstruction was performed with FBP without AC, COSEM without AC, and both COSEM and AC. The detection rate of lesions 1.5 cm or smaller was better with COSEM and AC than with FBP (55% vs 34%, respectively). In addition, COSEM and AC allowed more confidence in the interpretation. None of these differences, however, were significant. Fusion of CT scans and FDG DHC images obtained with COSEM and AC allowed localization of lesions to the skeleton in three patients and to the liver versus adjacent bowel in three patients. Image fusion was especially helpful for localizing lesions in the neck in five patients. Anatomic mapping on fusion images was clinically relevant in 11 patients (31%). CONCLUSION: The COSEM reconstruction algorithm should replace FBP when available. Functional anatomic mapping improved lesion localization in one-third of the patients studied.

First branchial cleft cyst excision with electrophysiological facial nerve localization.

OBJECTIVE: To assess the safety and efficacy of surgical excision of selected first branchial cleft cysts using electrophysiological rather than anatomical location of the facial nerve. DESIGN: Retrospective review of consecutive surgical procedures by a single surgeon, using a consistent technique during a 9-year period. SETTING: Tertiary pediatric medical center. PATIENTS: Eleven children with first branchial cleft cysts. INTERVENTIONS: Selected first branchial cleft cysts were removed using a smaller surgical approach than that generally advocated. The facial nerve was localized using electrophysiological means rather than superficial parotidectomy and identification of the nerve trunk and branches. MAIN OUTCOME MEASURES: Successful removal of the lesion, avoidance of facial nerve injury, incidence of Fry syndrome, and cosmesis. RESULTS: Eleven patients underwent surgical excision of first branchial cleft cysts during a 9-year period. Ten lesions were removed without the need for anatomical localization of the facial nerve trunk. There was no facial weakness, recurrence of the lesions, or Fry syndrome during a follow-up of 6 months to 7 years. Cosmesis was superior. CONCLUSION: Electrophysiological location of the facial nerve may, in the appropriate setting, replace anatomical localization for first branchial cleft cysts that are (1) superior to the stylomastoid foramen and (2) not previously infected or surgically violated.

Effect of minimally invasive radioguided parathyroidectomy on efficacy, length of stay, and costs in the management of primary hyperparathyroidism.

OBJECTIVE: To compare the first 20 patients who underwent minimally invasive radioguided parathyroidectomies (MIRPs) performed at the authors' institution with 20 similar patients who underwent a more conventional surgical approach for primary hyperparathyroidism. SUMMARY BACKGROUND DATA: The technique of parathyroidectomy has traditionally involved a bilateral exploration of the neck with the intent of visualizing four parathyroid glands and resecting enlarged parathyroid glands. Parathyroid scanning using radioisotopes has evolved and now can localize adenomas in 80% to 90% of patients. MIRP combines parathyroid scanning with a hand-held intraoperative detector that guides the surgeon to the adenoma. METHODS: Forty patients with documented primary hyperparathyroidism who underwent surgery by a single surgeon between January 1998 and May 1999 were included in this study. Twenty of these patients underwent MIRP. The technique involved injecting 20 mCi technetium-99m sestamibi 2 hours before surgery and performing a parathyroid scan. If the scan was considered positive for a single adenoma, patients were taken to the operating room and given the choice of either general anesthesia or intravenous sedation with local anesthesia. Using an incision of 4 cm or less, the dissection down to the adenoma was guided by the Navigator miniature hand-held probe. An additional 20 patients who underwent more conventional bilateral or unilateral neck exploration were chosen to match the MIRP patient population. Both groups included four patients undergoing repeat surgery for persistent or recurrent primary hyperparathyroidism and one patient with multiple endocrine neoplasia type 1 syndrome. Patient demographics, preoperative calcium and parathyroid hormone levels, operative time, total time in the operating room, time in the recovery room, complications, hospital charges for the operating room, and total hospital charges were analyzed. RESULTS: There were no differences in patient demographics, presenting symptoms, or preoperative calcium level between patients undergoing the standard procedure versus MIRP. Operative time, total time in the operating room, operative charges, and total hospital charges were significantly reduced in the MIRP group. All 40 patients were cured of primary hyperparathyroidism. There were no recurrent laryngeal nerve injures in either group. The mean length of stay in the standard group was 1. 35 days; in the MIRP group, 65% of patients were discharged within 5 hours after surgery. CONCLUSIONS: The MIRP technique resulted in excellent cure rates for primary hyperparathyroidism while simultaneously decreasing operative time and hospital stays. These resulted in significant cost reductions without compromising patient safety. The technique may significantly change the management of primary hyperparathyroidism.

Endurance exercise training does not alter lipolytic or adipose tissue blood flow sensitivity to epinephrine.

We evaluated the relationship between lipolysis and adipose tissue blood flow (ATBF) in response to epinephrine and the effect of endurance exercise training on these responses. Five healthy untrained men underwent a four-stage incremental epinephrine infusion (0.00125, 0.005, 0.0125, and 0.025 microgram. kg fat free mass(-1). min(-1)) plus hormonal clamp before and after 16 wk of cycle ergometry exercise training. Whole body glycerol and free fatty acid (FFA) rates of appearance (R(a)) in plasma were determined by stable isotope methodology, and ATBF was assessed by (133)Xe clearance. After each training session, subjects were fed the approximate number of calories expended during exercise to prevent changes in body weight. Glycerol R(a), FFA R(a), and ATBF increased when plasma epinephrine concentration reached 0.8 nM, but at plasma epinephrine concentrations >1.6 nM ATBF plateaued, whereas lipolysis continued to increase. Exercise training increased peak oxygen uptake by 24 +/- 7% (2.9 +/- 0.2 vs. 3.6 +/- 0.1 l/min; P < 0. 05) but did not alter body weight [70.5 +/- 3.8 vs. 72.0 +/- 3.8 kg; P = nonsignificant (NS)] or percent body fat (18.4 +/- 1.6 vs. 17.8 +/- 1.9%; P = NS). Lipolytic and ATBF responses to epinephrine were also the same before and after training. We conclude that the lipolytic and ATBF responses to epinephrine are coordinated when plasma epinephrine concentration is

The use of beta, gamma-methyleneadenosine 5'-triphosphate to determine ATP competition in a scintillation proximity kinase assay.

A novel method for characterizing the kinetics of protein kinase inhibitors is described. This method uses glycogen synthase kinase beta as the model protein kinase and looks at the shift in IC50 of inhibitors using the nonhydrolyzable ATP analog, beta, gamma-methyleneadenosine 5'-triphosphate, also known as AMP-PCP. Due to its inability to be hydrolyzed, AMP-PCP is being used to characterize known glycogen synthase kinase inhibitors by determining the shift in IC50 at concentrations above its calculated Ki of 490 microM. The assay format for the detection of inhibition is a scintillation proximity assay which is robust and reproducible at very low levels of [gamma-33P]ATP. The use of AMP-PCP coupled with the use of the scintillation proximity assay allows this characterization of inhibition without increasing [gamma-33P]ATP and without significantly diluting the overall assay signal. We have used this method in kinetic analyses to demonstrate that we can detect a significant shift in IC50 with the known ATP competitive inhibitors, staurosporine, Ro 31-8220, and olomoucine. The IC50 for glycogen synthase peptide and lithium chloride, which has been reported to be uncompetitive, remains unchanged.

Tinnitus severity, loudness, and depression.

Answers to questionnaires filled out by 436 patients who visited our tinnitus clinic were analyzed. Patients were asked to report the presence or absence of depression and to rate the loudness and severity of their tinnitus. Responses to questions about tinnitus loudness and severity from 121 patients who reported current depression were compared with responses from 285 patients who reported no history of depression. There was no significant difference in reported loudness of tinnitus between patients with and without depression. However, patients with current depression scored significantly higher than patients without depression on all 12 questions relating to tinnitus severity. We conclude that depression and tinnitus severity are linked in some patients. Treatment of depression with medications and psychotherapy is likely to reduce tinnitus severity for many of these patients.

FDG PET and dual-head gamma camera positron coincidence detection imaging of suspected malignancies and brain disorders.

UNLABELLED: The purpose of the study was to compare the diagnostic accuracy of fluorodeoxyglucose (FDG) images obtained with a dual-head coincidence gamma camera (DHC) with those obtained with a dedicated PET in a series of 26 patients. METHODS: Nineteen patients with known or suspected malignancies and 7 patients with neurological disorders underwent PET imaging after injection of approximately 10 mCi of FDG. Whole-body imaging was performed on 19 patients and brain imaging on 7 patients. DHC images were then acquired for 30 min over the region of interest using a dual-head gamma camera equipped with 3/8-in.-thick NaI(TI) crystals and parallel slit-hole collimators. The images were reconstructed in the normal mode, using photopeak/photopeak, photopeak/Compton and Compton/photopeak coincidence events. RESULTS: Although the spatial resolutions of PET with a dedicated PET scanner and of DHC are in the same range, the lesion detectability remains superior with PET (4 mm for PET versus 13.5 mm for DHC in phantom experiments) with a contrast ratio of 5:1. This is most probably attributable to the higher sensitivity of PET (2238 coincidences/min/microCi for PET versus 89 coincidences/min/microCi for DHC). The pattern of uptake and interpretation for brain imaging was similar on both PET and DHC images in all patients. In the 19 oncology patients, 38 lesions ranging from 0.7 to 5 cm were detected by PET. DHC imaging detected 28 (73%) of these lesions. Among the 10 lesions not seen with DHC, 5 were less than 1.2 cm, 2 were located centrally within the liver and suffered from marked attenuation effects and 3 were adjacent to regions with high physiological activity. The nondetectability of some lesions with DHC compared with PET can be explained by several factors: (a) start of imaging time (mean+/-SD: 73+/-16 min for PET versus 115+/-68 min for DHC, leading to FDG decay to 6.75 mCi for PET and 5.2 mCi for DHC); (b) limited efficiency of a 3/8-inch-thick Nal(TI) crystal to detect 18F photons; (c) suboptimal two-dimensional reconstruction algorithm; and (d) absence of soft-tissue attenuation correction for centrally located lesions. CONCLUSION: FDG DHC imaging is a promising technique for oncological and brain imaging.

Fluorine-18-fluorodeoxyglucose cardiac imaging using a modified scintillation camera.

Conventional 201TI and hexakis 2-methoxy-2-isobutyl isonitrile studies are less accurate as compared to FDG PET in the prediction of functional recovery after revascularization in patients with injured but viable myocardium. The introduction of a dual-head variable-angle-geometry scintillation camera equipped with thicker crystals (5/8 in.) and high-resolution, ultrahigh-energy collimators capable of 511 keV imaging has permitted FDG SPECT to provide information equivalent to that of PET for the detection of injured but viable myocardium in patients with chronic ischemic heart disease. The development of standardized glucose-loading protocols, including glucose-insulin-potassium infusion and the potential use of nicotinic acid derivatives, has simplified the method of obtaining consistently good-to-excellent quality FDG SPECT cardiac studies. FDG SPECT may become the modality of choice for evaluating injured but viable myocardium because of enhanced availability of FDG, logistics, patient convenience, accuracy and cost-effectiveness compared to PET.

Plasma glucose levels are reduced in rats and mice treated with an inhibitor of glucose-6-phosphate translocase.

The activity of glucose-6-phosphatase (G-6-Pase) in isolated rat microsomes was inhibited by a new selective inhibitor of the multi-subunit G-6-Pase system, 1-[2-(4-chloro-phenyl)-cyclopropylmethoxy]-3,4-dihydroxy-5-(3-imid azo[4,5-b]pyridin-1-yl-3-phenyl-acryloyloxy)-cyclohexanecarboxylic acid (compound A) with a 50% inhibitory concentration (IC50) of approximately 10 nmol/l. Compound A (500 nmol/l) inhibited the uptake of [14C]glucose-6-phosphate (G-6-P) into intact isolated rat microsomes, confirming that this agent blocks G-6-P translocation, as suggested by previous studies using intact and permeabilized microsomes. The inhibition of microsomal G-6-P transport by compound A was associated with inhibition of the rate of glucose output from rat hepatocytes incubated in the presence of 25 nmol/l glucagon (IC50 approximately 320 nmol/l.) Compound A (1 micromol/l) also inhibited the basal rate of glucose production by rat hepatocytes by 47%. Intraperitoneal administration of compound A to fasted mice lowered circulating plasma glucose concentrations dose-dependently at doses as low as 1 mg/kg. This effect was comparatively short-lived; glucose lowering was maximal at 30 min after dosing with 100 mg/kg compound A (-71%) and declined thereafter, being reversed within 3 h. A similar time course of glycemic response was observed in fasted rats; glucose lowering was maximal 30 min after dosing with 100 mg/kg compound A (-36%) and declined until the effect was fully reversed by 3 h postdose. In rats subjected to compound A treatment, liver glycogen content was increased. G-6-P and lactate levels were maximally elevated 30 min after dosing and declined thereafter. Cumulatively, these results suggest that the mechanism of glucose lowering by compound A was via inhibition of G-6-Pase activity, mediated through inhibition of the T1 subunit of the microsomal G-6-Pase enzyme system. Drug levels measured over the same time course as that used to assess in vivo efficacy peaked within 30 min of administration, then declined, which is consistent with the transient changes in plasma glucose and liver metabolites.

Evaluation of benign vs malignant hepatic lesions with positron emission tomography.

BACKGROUND: In most malignant cells, the relatively low level of glucose-6-phosphatase leads to accumulation and trapping of [18F]fluorodeoxyglucose (FDG) intracellularly, allowing the visualization of increased uptake compared with normal cells. OBJECTIVES: To assess the value of FDG positron emission tomography (PET) to differentiate benign from malignant hepatic lesions and to determine in which types of hepatic tumors PET can help evaluate stage, monitor response to therapy, and detect recurrence. DESIGN: Prospective blinded-comparison clinical cohort study. SETTING: Tertiary care university hospital and clinic. PATIENTS: One hundred ten consecutive referred patients with hepatic lesions 1 cm or larger on screening computed tomographic (CT) images who were seen for evaluation and potential resection underwent PET imaging. There were 60 men and 50 women with a mean (+/-SD) age of 59 +/- 14 years. Follow-up was 100%. INTERVENTIONS: A PET scan using static imaging was performed on all patients. The PET scan imaging and biopsy, surgery, or both were performed, providing pathological samples within 2 months of PET imaging. All PET images were correlated with CT scan to localize the lesion. However, PET investigators were unaware of any previous interpretation of the CT scan. MAIN OUTCOME MEASURES: Visual interpretation, lesion-to-normal liver background (L/B) ratio of radioactivity, and standard uptake value (SUV) were correlated with pathological diagnosis. RESULTS: All (100%) liver metastases from adenocarcinoma and sarcoma primaries in 66 patients and all cholangiocarcinomas in 8 patients had increased uptake values, L/B ratios greater than 2, and an SUV greater than 3.5. Hepatocellular carcinoma had increased FDG uptake in 16 of 23 patients and poor uptake in 7 patients. All benign hepatic lesions (n = 23), including adenoma and fibronodular hyperplasia, had poor uptake, an L/B ratio of less than 2, and an SUV less than 3.5, except for 1 of 3 abscesses that had definite uptake. CONCLUSIONS: The PET technique using FDG static imaging was useful to differentiate malignant from benign lesions in the liver. Limitations include false-positive results in a minority of abscesses and false-negative results in a minority of hepatocellular carcinoma. The PET technique was useful in tumor staging and detection of recurrence, as well as monitoring response to therapy for all adenocarcinomas and sarcomas and most hepatocellular carcinomas. Therefore, pretherapy PET imaging is recommended to help assess new hepatic lesions.

Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo.

An inhibitor of human liver glycogen phosphorylase a (HLGPa) has been identified and characterized in vitro and in vivo. This substance, [R-(R*, S*)]-5-chloro-N-[3-(dimethylamino)-2-hydroxy-3-oxo-1-(phenylmethyl)pr opyl]-1H-indole-2-carboxamide (CP-91149), inhibited HLGPa with an IC50 of 0.13 microM in the presence of 7.5 mM glucose. CP-91149 resembles caffeine, a known allosteric phosphorylase inhibitor, in that it is 5- to 10-fold less potent in the absence of glucose. Further analysis, however, suggests that CP-91149 and caffeine are kinetically distinct. Functionally, CP-91149 inhibited glucagon-stimulated glycogenolysis in isolated rat hepatocytes (P < 0.05 at 10-100 microM) and in primary human hepatocytes (2.1 microM IC50). In vivo, oral administration of CP-91149 to diabetic ob/ob mice at 25-50 mg/kg resulted in rapid (3 h) glucose lowering by 100-120 mg/dl (P < 0.001) without producing hypoglycemia. Further, CP-91149 treatment did not lower glucose levels in normoglycemic, nondiabetic mice. In ob/ob mice pretreated with 14C-glucose to label liver glycogen, CP-91149 administration reduced 14C-glycogen breakdown, confirming that glucose lowering resulted from inhibition of glycogenolysis in vivo. These findings support the use of CP-91149 in investigating glycogenolytic versus gluconeogenic flux in hepatic glucose production, and they demonstrate that glycogenolysis inhibitors may be useful in the treatment of type 2 diabetes.