In vivo pathway of thermal hyperalgesia by intrathecal administration of alpha,beta-methylene ATP in mouse spinal cord: involvement of the glutamate-NMDA receptor system.

1. The aim of the present study is to characterize the role of the P2X receptor in spinal nociceptive processing in vivo. We investigated the mechanisms of the P2X receptor agonist alpha,beta-methylene ATP (alpha,betameATP)-induced modulation of acute nociceptive signalling in mouse spinal cord. 2. Intrathecal administration of alpha,betameATP produced a significant and dose-dependent thermal hyperalgesic response. This response was completely blocked by intrathecal pretreatment with the non-selective P2 receptor antagonist, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonate (PPADS) and the selective P2X1, P2X3 and P2X2-3 receptor antagonist, 2',3'-O-(2,4,6-trinitrophenyl)adenosine 5'-triphosphate (TNP-ATP). Pretreatment with alpha,betameATP 15, 30 and 60 min prior to administration of a second dose of alpha,betameATP diminished the alpha,betameATP-induced thermal hyperalgesia. 3. A potent agonist for the P2X1 receptor, beta,gamma-methylene-L-ATP, did not show the hyperalgesic response, indicating that the P2X1 receptor is not involved in the spinal nociceptive pathway. 4. In fura-2 experiments using mouse dorsal root ganglion (DRG) neurons, alpha,betameATP (100 microM) increased intracellular Ca2+ ([Ca2+]i). This was not produced by a second application of alpha,betameATP. The same DRG neurons also showed a marked [Ca2+]i increase in response to capsaicin (3 microM). 5. Intrathecal pretreatment with the Ca2+-dependent exocytosis inhibitor, botulinum neurotoxin B, abolished the thermal hyperalgesia by alpha,betameATP. Furthermore, thermal hyperalgesia was significantly inhibited by the N-methyl-D-aspartate (NMDA) receptor antagonists, 2-amino-5-phosphonopentanoate (APV), dizocilpine and ifenprodil. 6. These findings suggest that alpha,betameATP-induced thermal hyperalgesia may be mediated by the spinal P2X3 receptor subtype that causes unresponsiveness by repetitive agonist applications, and that alpha,betameATP (perhaps through P2X3 receptors) may evoke spinal glutamate release which, in turn, leads to the generation of thermal hyperalgesia via activation of NMDA receptors.     

Characterization of endogenous serotonin-mediated regulation of dopamine release in the rat prefrontal cortex.

Endogenous serotonin (5-hydroxytryptamine, 5-HT)-mediated regulation of dopamine release in the rat prefrontal cortex was pharmacologically characterized using in vivo microdialysis. To increase synaptic 5-HT availability, a selective 5-HT uptake inhibitor fluoxetine was applied via the dialysis probe. Local perfusion of fluoxetine (30 and 100 microM) increased dopamine levels in a concentration-dependent manner. The fluoxetine (100 microM)-induced increases in dopamine release were abolished by pretreatment with the 5-HT(1B/1D) receptor antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5- methyl-1,2,4-oxadiazol-3-yl)-[1,1-biphenyl]-4-carboxamide] ) (10 and 100 microM). The facilitation of dopamine release was also prevented by selective inactivation of the mRNA encoding 5-HT(6) receptors using antisense oligonucleotides techniques. These findings suggest that not only 5-HT(1B) receptors but also 5-HT(6) receptors are associated with the endogenous 5-HT-mediated facilitation of dopamine release. In other words, 5-HT(6) receptors may play, in part, a significant role in the functional interaction between the dopaminergic and serotonergic neuronal system in the rat prefrontal cortex.     

A phase I trial of the pharmacokinetics, toxicity, and activity of KNI-272, an inhibitor of HIV-1 protease, in patients with AIDS or symptomatic HIV infection.

The pharmacokinetics, toxicity, and activity of KNI-272, a transition state inhibitor of HIV-1 protease, was assessed in a phase I trial. After an initial phase in which the pharmacokinetics were assessed, 37 patients with AIDS or symptomatic HIV infection and 100-400 CD4 cells/mm3 were entered in an escalating dose study. KNI-272 was administered four times daily for up to 12 weeks. Oral bioavailability ranged from 22 to 55% and was not appreciably different in the fasting and post-prandial state. The dose limiting toxicity was hepatic transaminase elevation; this could be reduced by escalating the dose over 4 weeks. When administered this way, the maximum tolerated oral dose was 40 mg/kg per day. At the highest two tolerated doses (26.4 and 40 mg/kg per day), there was some evidence of an anti-HIV effect with median decreases of 0.2-0.3 log10 copies/ml plasma HIV RNA; these decreases persisted through 7-8 weeks of treatment. There was an upward trend in the CD4 count at the 40 mg/kg per day dose but not at other doses. Additional studies focused on approaches to improve the therapeutic index of KNI-272 may be warranted.     

Growth suppression of low HER-2/neu-expressing breast cancer cell line MDA-MB-435 by tyrosine kinase inhibitor emodin

The tyrosine kinase inhibitor emodin (3-methyl-1,6,8-tridroxyanthaquinone) is known to preferentially suppress the growth of the HER-2/neu-overexpressing breast cancer cell line. In this study, emodin effectively suppressed growth of MDA-MB-435, a breast cancer cell line with low HER-2/neu expression. Since emodin is a tyrosine kinase inhibitor, we questioned whether another tyrosine kinase might play a role in the tumorigenicity of MDA-MB-435. By Western blotting with anti-phosphotyrosine antibody, we detected a 72-kDa protein which is uniquely phosphorylated on tyrosine in MDA-MB-435. The level of phosphotyrosine in the 72-kDa protein was significantly reduced by treatment with emodin. This suggests that a strong tyrosine kinase may reside in MDA-MB-435 and the 72-kDa protein serves as a substrate for the tyrosine kinase.     

Antihypertensive effect of E-643, a new alpha-adrenergic blocking agent

Summary To determine whether E-643, a new -blocking agent, would reduce the blood pressure, regardless of the posture, a 1 mg dose was given 3 times daily for 7 consecutive days, to 8 male and 7 female inpatients, aged 37–73 years, with essential hypertension. Blood pressure and pulse rate were measured daily in the supine, sitting and standing positions. Before and after the treatment with E-643, plasma levels of noradrenaline, adrenaline, dopamine--hydroxylase, renin and aldosterone were determined, samples being obtained with the subjects recumbent and after standing upright for 60 min. A significant reduction in the systolic and diastolic blood pressures was evident in the supine (172±31/100±12 151±28/89±14 mmHg), sitting (158±22/101±11 138±28/89±15 mmHg) and standing (153±32/103±21 129±31/89±20 mmHg) positions. The reduction in blood pressure remained unchanged throughout the period of administration of E-643. Pulse rate was not affected when the subjects were supine (67±10 69±10 beats/min), but was increased in the sitting (68±10 73±9 beats/min) and standing (73±10 81±11 beats/min) positions. The increased pulse rate tended to decline during continued administration of E-643. Treatment with E-643 produced no significant change in plasma levels of adrenaline, noradrenaline, dopamine--hydroxylase, renin and aldosterone. The antihypertensive effect of treatment was more prominent in the patients with higher levels of plasma catecholamines and dopamine--hydroxylase, and was less prominent in those with higher plasma renin and aldosterone. Two patients had temporary bouts of dizziness and visual disturbances, but there were no subjective complaints during treatment.     

Surgical-management of carcinoma of the middle and distal bile-duct

Forty patients underwent surgical resection for cancer of the middle and distal bile duct. Nineteen patients underwent a curative resection with 3- and 5-year survival rates of 63% and 48%, respectively. None of the patients who underwent a palliative resection survived two years. The factor most strongly associated with recurrence was the presence of tumor in the surgical margin. Recurrence was frequent in patients with disease in the middle portion of the bile duct who underwent extrahepatic biliary resection with choledochojejunostomy, while lower bile duct cancer was associated with peri-aortic or retroperitoneal recurrence. Pancreatoduodenectomy, with combined resection of the portal vein in middle bile duct cancer, regional lymphadenectomy, including peri-aortic lymph nodes and nerve plexus is required for curative resection of middle and distal biliary carcinoma beyond the early noninvasive stage.     

Perception of odor quality by Free Image-Association Test]

A method was devised for evaluating odor quality. Subjects were requested to freely describe the images elicited by smelling odors. This test was named the "Free Image-Association Test (FIT)". The test was applied for 20 flavors of various foods, five odors from the standards of T&T olfactometer (Japanese standard olfactory test), butter of yak milk, and incense from Lamaism temples. The words for expressing imagery were analyzed by multidimensional scaling and cluster analysis. Seven clusters of odors were obtained. The feature of these clusters were quite similar to that of primary odors which have been suggested by previous studies. However, the clustering of odors can not be explained on the basis of the primary-odor theory, but the information processing theory originally proposed by Miller (1956). These results support the usefulness of the Free Image-Association Test for investigating odor perception based on the images associated with odors.     

MR and CT in the evaluation of sarcoid myopathy

Sarcoid myopathy is a relatively rare extrapulmonary complication of sarcoidosis. We evaluated the diagnostic utility of MR at 1.5 T in four patients with sarcoid myopathy of the lower extremities established by biopsy. Two of the patients were of the "atrophic type" and two of the "nodular type." The findings on MR were compared with the findings on CT, gallium scanning, and electromyography. Only MR was positive in all cases. The T2-weighted scans (spin echo 2,000/80) revealed two distinctly different patterns of abnormality (i.e., discrete foci of high signal intensity lesions in the patients with the nodular type of sarcoid myopathy and atrophic muscle of high signal intensity in the patients with the atrophic type). Due to its ability to provide objective findings of the extent and distribution of muscle involvement, MR should prove useful in the detection, diagnosis, and monitoring of sarcoid myopathy.     

A case of Morgagni's hernia: availability of CT scan, ultrasonography, and trans-abdominal surgical approach

A 60-year-old obese woman was admitted to our hospital to receive surgical treatment for "slow-growing mediastinal lipoma". With the non-invasive examination such as CT scan and ultrasonography, she was revealed as Morgagni's hernia containing a greater omentum. With a trans-abdominal approach, we could take a good surgical field for the bilateral foramina of Morgagni. Several discussions were described for availability of CT scan, ultrasonography and a trans-abdominal approach.     

A case of reflux nephropathy associated with pheochromocytoma]

A 26-year-old female patient complicated with reflux nephropathy and pheochromocytoma is reported. We could not find either intrinsic or extrinsic factor of urinary tract obstruction. The open bilateral renal biopsy was performed at the time of resection of the tumor. The renal biopsy specimen demonstrated minor glomerular change, severe tubular "thyroid-like" appearance and cast formation in the obvious reflux side. Otherwise focal glomerular sclerosis (FGS) lesion was found in less reflux side. In reflux nephropathy, FGS lesion is reported as main cause of progression, but mechanism of FGS lesion is unknown. This case which has both vesicoureteral reflux the high plasma nor-epinephrine concentration was considered to be important to emphasize circulative factor in the pathogenesis of FGS like lesion.