Study of the analgesic effect of lanepitant in patients with osteoarthritis pain.

OBJECTIVE: Lanepitant selectively blocks substance P binding to the neurokinin-1 receptor, preventing neurogenic inflammation and pain transmission. Substance P is present in synovial fluid and in excess in cerebral spinal fluid. We investigated the effect of lanepitant on pain caused by osteoarthritis to evaluate the role of neurokinin-1 blockade. METHODS: Outpatients (n = 214) with moderate to severe lower-limb osteoarthritis pain were treated for 3 weeks in a parallel, randomized double-blind study with initial doses of 20, 60, 200, or 600 mg lanepitant, 375 mg naproxen, or placebo, followed by 10, 30, 100, or 300 mg lanepitant twice a day, 375 mg naproxen twice a day, or placebo twice a day in the multiple-dose period. Pain intensity, pain relief, patient global impression, and adjunctive analgesic use were compared across treatments. Safety was evaluated with adverse events, vital signs, and laboratory assessments. RESULTS: There was no statistically significant difference in efficacy or safety across treatments for the initial dose assessment. After 1 week of therapy, naproxen was statistically significantly (P < .05) better than placebo and lanepitant in reducing average pain. During the second and third weeks of therapy, patients receiving naproxen continued to have statistically significantly (P < .05) less pain than those receiving placebo or lanepitant despite using significantly less adjunctive analgesic medication. There were no statistically significant differences in rates of discontinuation across treatments. Lanepitant treatment was associated with diarrhea, whereas naproxen treatment was associated with gastric discomfort. There were no clinically relevant changes in vital signs or laboratory analytes for any of the treatments. CONCLUSION: Lanepitant was ineffective in relieving osteoarthritis pain, possibly because neurokinin-1 binding of substance P does not play a significant role in osteoarthritis pain or because lanepitant fails to adequately penetrate the blood-brain barrier to affect central pain perception.

Hepatic cirrhosis and hepatitis: MR imaging enhanced with superparamagnetic iron oxide.

Superparamagnetic iron oxide was applied as a reticuloendothelial contrast agent in the diagnosis of cirrhosis and hepatitis in seven patients. Three patients had compensated cirrhosis, and four had active hepatitis. T1- and T2-weighted spin-echo magnetic resonance images were obtained before and 1 hour after the administration of iron oxide. Eight patients without diffuse liver disease served as a control group. Normal liver tissue showed a 75% +/- 9% reduction in signal intensity after the administration of iron oxide, and the liver appeared homogeneously hypointense. Cirrhotic liver tissue showed a smaller response (P less than .05) to iron oxide, with a 52% +/- 13% reduction in liver signal intensity. Inhomogeneous structures could be observed in enhanced images and are thought to represent fibrous bands or regenerating nodules. Liver tissue with active hepatitis showed a markedly reduced response to iron oxide (11% +/- 2%) (P less than .05), and the parenchyma appeared homogeneous. The authors conclude that the uptake of iron oxide particles is inhomogeneously altered in cirrhosis because of structural changes and homogeneously decreased in hepatitis because of functional changes of hepatic parenchyma.

Characterization of skeletal muscles by MR imaging and relaxation times.

Magnetic resonance (MR) images of three major flight muscles of chicks were obtained with surface coils using a 0.3 Tesla whole body imaging system (FONAR Beta 3000). The two fast muscles, pectoralis major (PM) and posterior latissimus dorsi (PLD), and a slow muscle, anterior latissimus dorsi (ALD), were identified in the axial, coronal, and sagittal images. The signal intensity (SI) of each muscle was electronically measured and its ratio to the background noise (S/N) was determined. Although visually the three muscles showed intermediate SI, the slow and fast muscles could be differentiated on the basis of their S/N values. These values were invariably higher in the slow muscles than in the fast muscles. To understand these differences, the muscles were excised and their mono- and multiexponential MR relaxation times (T1 and T2) were determined at 30 MHz. Multiexponential analysis enhanced the differences between the muscle types. With the sole exception of short T2, all relaxation components of the slow muscles were significantly longer than those of the fast muscles. These results suggest that elevation in the S/N, T1 and T2 values of muscles may not necessarily indicate a pathologic event, but may reflect the preponderance of slow fibers.

MR imaging in neurocysticercosis: a study of 56 cases.

We reviewed the MR findings in 56 patients with neurocysticercosis (NCC). MR findings were correlated with other neuroradiologic findings in 40 cases, with histopathologic studies in 15 surgically treated patients, and with autopsy findings in one case. Active NCC was characterized by the presence of a cyst in the brain parenchyma (53%) or in an intraventricular subependymal (22%) or subarachnoid (10%) location. The cysticercus appeared as a vesicle with a high-intensity signal nodule that corresponded to the scolex. Cyst mobility was observed in two intraventricular cases. Periventricular edema and ependymitis appeared as high-intensity signal on T2 sequences. Inactive NCC (15%) was characterized by calcifications (signal void on T1 and T2 sequences), aqueductal stenosis, and tissue thickness in the basal meninges. Degenerative cysticercus appeared on MR as an irregular vesicle without a scolex. Active NCC was better detected with MR than with CT (85% vs 21%), whereas inactive forms were observed better with CT (23% vs 14%). We conclude that MR is sensitive in the diagnosis of active NCC and may be useful in evaluating the degenerative changes in the parasite that occur as a result of natural degeneration, host response, or medical therapy.

The diagnosis of splenic lymphoma by MR imaging: value of superparamagnetic iron oxide.

This study was designed to evaluate superparamagnetic iron oxide (AMI-25) as a contrast agent for MR to distinguish normal spleens from those diffusely infiltrated by lymphoma. As diffuse splenic involvement lacks visible tumor-tissue boundaries, signal-intensity measurements of spleens were used as a diagnostic criterion in 33 patients (lymphoma, n = 8; benign splenomegaly, n = 5; normal subjects, n = 20). Unenhanced MR images were insensitive (four of eight patients) and nonspecific (20 of 25 patients) in the diagnosis of lymphoma. After injection of superparamagnetic iron oxide (40 mumol Fe/kg), lymphomatous spleens showed a significantly higher signal intensity (p less than .05) than did normal spleens or spleens enlarged by benign disease (hepatic cirrhosis, n = 4; spherocytosis, n = 1). Changes in splenic MR signal intensity unambiguously identified eight of eight lymphomatous spleens and 25 of 25 normal or enlarged spleens that did not contain lymphoma. Phagocytosis of superparamagnetic iron oxide in lymphomatous spleens is reduced because of diffuse displacement of splenic macrophages by lymphoma cells and/or by immunologic suppression of macrophage activity. Our results suggest that superparamagnetic iron oxide (AMI-25) can improve the accuracy of MR imaging in the diagnosis of splenic lymphoma. With further development, this noninvasive technique may reduce the need for diagnostic splenectomy in lymphoma patients.

Superparamagnetic iron oxide: enhanced detection of focal splenic tumors with MR imaging.

Superparamagnetic iron oxide (AMI-25), a reticuloendothelial cell-specific contrast agent for magnetic resonance (MR) imaging, was evaluated for its ability to permit detection of splenic metastases in 18 patients. Superparamagnetic iron oxide, at a dose of 30 mumol of iron per kilogram, decreased the signal intensity of spleen from 19.5 +/- 4.8 to 3.1 +/- 2.2 (spin-echo sequence, repetition time msec/echo time msec = 1,500/42; P less than .05), without changing the signal intensity of tumor. As a result, the tumor-spleen contrast-to-noise ratio increased from 0.2 (tumor isointense relative to spleen) to 18.0 (tumor hyperintense relative to spleen). As a consequence of increased contrast, splenic tumors were detected in four of 18 patients (45 individual lesions; P less than .05), whereas nonenhanced MR imaging permitted detection of splenic lesions in only two of 18 patients (four individual lesions). Maximum tumor-spleen contrast was achieved within 60 minutes after intravenous administration. These initial clinical results indicate that MR imaging with superparamagnetic iron oxide may offer improved accuracy in the diagnosis of splenic tumors.

Pituitary gland growth during normal pregnancy: an in vivo study using magnetic resonance imaging.

PURPOSE: Autopsy studies have shown that pregnancy results in physiologic pituitary enlargement. We used magnetic resonance imaging (MRI) to corroborate those findings in vivo. PATIENTS AND METHODS: Based on gestational age, 32 normal primigravid patients were divided into three groups: Group I (n = 10), less than 12 gestational weeks; Group II (n = 11), 13 to 26 gestational weeks; and Group III (n = 11), 27 gestational weeks or more. The pituitary dimensions and volumes in these groups were compared with those in 20 healthy nulliparous women (control group). RESULTS: MRI measurements showed a significant increase in pituitary volume in Groups I, II, and III when compared with the control group (p less than 0.001). Furthermore, there was an increase in pituitary volume between Groups I and II and between Groups II and III, although the former was not statistically significant (p greater than 0.05). At the end of pregnancy, the hypophysis had increased 2.6 mm in vertical, anteroposterior, and transversal dimensions, with an overall increase of 136 percent when compared with that of the control group. CONCLUSION: Baseline measurements of the normal enlargement of the pituitary gland that occurs during pregnancy could prove useful when evaluating pregnant patients with suspected pituitary tumors or lymphocytic hypophysitis.

Superparamagnetic iron oxide: clinical application as a contrast agent for MR imaging of the liver.

Superparamagnetic iron oxide (ferrite) particles were evaluated as a contrast agent for magnetic resonance (MR) imaging. In this pilot study, doses ranging from 10 to 50 mumol/kg were administered intravenously to 15 patients. Ferrite-enhanced images of the liver obtained with standard pulse sequence techniques significantly increased the number of hepatic lesions detected (P less than .01) and reduced the threshold size for detection to 3 mm (P less than .01). The improved clinical performance of ferrite-enhanced images correlated with significant increases in measured contrast-to-noise ratios (P less than .01). Degradation of superparamagnetic activity and/or clearance of ferrite from the liver was demonstrated as early as 12 hours after injection, suggesting that the lack of chronic toxicity observed in animal studies may be reproduced in humans. These initial clinical results appear to confirm extensive preclinical data indicating that ferrite administered at a dose of 20 mumol/kg has the potential to significantly improve the performance of abdominal MR imaging.

Amebic liver abscess: diagnosis and treatment evaluation with MR imaging.

Magnetic resonance images were obtained before and after treatment in 17 patients with 29 amebic liver abscesses. Pretreatment T1-weighted images showed a sharply circumscribed, heterogeneous, low-signal-intensity mass, devoid of normal hepatic tissue and corresponding to the abscess cavity as measured sonographically. T2-weighted images showed the abscess cavity as a hyperintense region and also showed a larger region of hyperintensity extending from the cavity margins to the liver surface, corresponding to edematous but morphologically normal liver tissue. After treatment, the abscess cavity became homogeneously hypointense on T1-weighted images, corresponding to liquefaction of the abscess center. With successful treatment, concentric rings corresponding to (a) an inner margin of inflamed granulation tissue, (b) bands of type I collagen, and (c) the outer margin of atrophic and/or mildly inflamed liver tissue became prominent on T1- and T2-weighted images. T2-weighted images showed rapid resolution of the perifocal hepatic edema.

Enhanced T1 differentiation between normal and dystrophic muscles.

Proton spin-lattice relaxation times (T1) of pectoralis major muscles from normal (Line 412) and homozygous dystrophic (Line 413) chicks was measured by FONAR QED 80 at 1.69 MHz. The T1 values of dystrophic muscles (216.8 +/- 17.3 ms) was two-fold higher than those of normal muscles (110.2 +/- 8.1 msec). When these values were compared with the T1 values obtained at high frequencies (20 MHz and 32 MHz), the T1 differentiation between normal and dystrophic muscles was considerably enhanced at 1.69 MHz. Based on these results, we suggest that the high resolution of T1 obtained at low frequency (1.69 MHz) could be effectively used to detect the degenerative processes in muscles by the NMR techniques.

Nuclear magnetic resonance in bipolar affective disorders.

Nuclear magnetic resonance produced by a FONAR QED 80 whole-body scanner with measurement in vivo of T1 proton relaxation time was used in 20 patients with the clinical diagnosis of bipolar affective disorder. Diagnoses were based on Research Diagnostic Criteria, Diagnostic Statistical Manual III code 296.66, and on Schedule for Affective Disorders and Schizophrenia. Proton T1 relaxation times were measured in all patients and in 18 normal controls before and after lithium carbonate treatment. Normal values of T1 in frontal and temporal lobes were 210 +/- 10 msec. All but three patients had prelithium T1 values higher than the controls (264 +/- 8.8 msec). After lithium therapy of 900 mg/day for 10 days, serum lithium levels were in the therapeutic range of 0.5-1.5 mEq/L, and patient T1 values were near normal levels (208 +/- 8.0 msec). One patient with a prelithium level within normal range proved to have cyclothymic disorder and not bipolar affective disorder; two patients did not complete the study. This study shows a statistically significant difference (p less than 0.01) in the behavior of hydrogen protons in bipolar affective disorder, which has not previously been reported in medical literature.

T1 relaxation times in vivo of human normal pelvic tissues and gynecologic malignancies.

The spin-lattice relaxation time (T1) of the water protons of intrapelvic tissues was determined in vivo in women using an NMR imager. T1's of squamous cell carcinoma of the cervix are significantly longer than those of the normal cervix. A similar trend occurs in carcinomas of the endometrium and ovary. The results suggest that direct determination of T1 in vivo may be useful in the diagnosis and management of gynecologic malignancies.

In vivo NMR imaging and T1 measurements of water protons in the human brain.

Nuclear magnetic resonance (NMR) proton density images of the human brain have been made by the FONAR method. Spin-lattice relaxation times, T1, of water hydrogen protons have been determined at random positions within frontal and temporal regions of the human brain. The primary purpose of this ongoing research is to accumulate a large data base of normal T1 values for water protons in normal human brain tissue. Our experience to date includes 31 measurements on 18 volunteer subjects, and the mean value +/- standard deviation is 215 +/- 42 msec. In addition, two metastatic lesions of the brain were studied and found to have T1 values longer than those for normal brain tissue.