Droperidol inhibits tracheal contraction induced by serotonin,histamine or carbachol in guinea pigs

Purpose

Droperidol (D) is effective in the treatment of patients with status asthmaticus. It has been reported that D inhibits the bronchoconstriction induced by serotonin (5-HT) but not that by histamine (H) or acetylcholine. However, haloperidol, another butyrophenone, is known to interact with and inhibit calmodulin, an intracellular Ca⁺⁺-binding protein which is important in the contraction of smooth muscles. The present study was designed to investigate the effects of D on tracheal contractions induced by 5-HT, H or carbachol (C) and to determine the contribution of α-adrenoceptors to the relaxant effect of D in vitro.

Methods

Tracheas of female guinea pigs were cut spirally into strips and mounted in water-jacketed organ baths in Tyrode’s solution, aerated with a mixture of 95% O₂ and 5% CO₂ at 37°C. The changes in isometric tension induced by each spasmogen in the strips were measured with a transducer and a polygraph.

Results

We found that D inhibited the tracheal contractions induced by 5-HT, H or C in a concentration-dependent manner. At 1.25 × 10^?6 M D blocked the effect of 10^?4 M 5-HT by 44.1 ± 4.3% and at 2.5 × 10^?6 M by 63.8 ± 3.8%. Similarly, at 5.0 × 10^?6 M concentration, D blocked the effect of 10^?5 M H by 27.7 ± 5.3% and at 10^?5 M by 56.2 ± 2.6%. Furthermore, 5 ×10^?6 M of D reduced the contractions produced by 10^?7 M C by 37.1 ± 3.0% and 70^?5 M of D by 76.1 ± 3.2%. The inhibiting effect of D was strongest on contractions induced by 5-HT. Prazosin (70^?6 M) affected neither 5-HT-induced contractions nor the inhibition by D.

Conclusion

Our data indicate that D partially blocks the contractile responses not only to 5-HT, an effect which would be mediated through a blockade of the 5-HT receptors, but also to H or C, probably through inhibition of calmodulin. Our data support previous reports indicating that droperidol may be an important therapeutic agent in the treatment of patients with hyperreactive airways.     

Penetration of etoposide into human malignant brain tumors after intravenous and oral administration

Summary Penetration of etoposide into the cerebrospinal fluid, brain tumor, and brain tissue after intravenous administration was investigated in patients presenting with malignant brain tumors. A relatively low dose (55–65 mg/m²) was used to compare intravenous with oral administration. High-performance liquid chromatography with fluorescence detection was used to evaluate drug levels. Plasma and cerebrospinal fluid levels of etoposide after oral administration (50–150 mg/day) were also studied so as to determine the adequate oral dose for the treatment of malignant brain tumors. The peak plasma concentration after intravenous administration ranged from 7.01 to 10.47 g/ml, varying in proportion to the injected dose, whereas that after oral administration was lower, namely, 1.44–4.99 g/ml, and was unstable when the oral dose was 150 mg daily. The peak cerebrospinal fluid level following either intravenous or oral administration was much lower than the plasma concentration and was influenced by the peak plasma level and the sampling site. The etoposide concentration in cerebrospinal fluid taken from the subarachnoid space and ventricle of patients displaying no tumor invasion and of those presenting with meningeal carcinomatosis and in cerebrospinal fluid taken from the dead space after tumor resection was 0.7%±0.5%, 3.4%±1.0%, and 7.2% ± 8.5%, respectively, of the plasma concentration. Serial oral administration did not result in the accumulation of etoposide in cerebrospinal fluid. The tumor concentration (1.04–4.80 g/g) was 14.0%±2.9% of the plasma level after intravenous administration, was related to the injected dose, and was approximately twice the concentration detected in the brain tissue. Therefore, a relatively low dose of etoposide injected intravenously penetrates the brain tumor at an efficacious concentration. Our results indicate than an oral dose of 100 mg etoposide be given for malignant brain tumors, as limited penetration of the drug into the intracranial region was observed.     

A study of surface markers in non-Hodgkin's lymphoma by using anti-T and anti-B lymphocyte sera

Cell surface markers of 44 cases of non-Hodgkin's lymphoma (NHL) were studied with various surface markers, especially by using antihuman B lymphocyte serum (ABS), antihuman thymocyte serum (ATS-T), and antihuman peripheral T lymphocyte serum (ALS-T), which were rendered specific for human B lymphocytes, human thymocytes, and human peripheral T lymphocytes, respectively. An immunofluorescent study with ABS, ATS-T, and ALS-T enabled us to demonstrate the histologic localization of normal or neoplastic B and T cells in preserving the original structure of lymphoid organs or tumor tissues. The proportion of cell types in NHL was B cell type 59%, T1 (ATS-T reactive) type 7%, T2 (ALS-T reactive) type 23%, and Null (non T, non B) type 11%. The relationships among cell types, histologic findings, and clinical characteristics were also investigated. Patients with T1-NHL had mediastinal tumors, which were histologically classified into "Lymphoblastic lymphoma." These facts suggest that T1-NHL may have originated in the thymus. Patients with T2-NHL showed a high incidence of skin lesions. Median survival of ten patients with T1- and T2-NHL was seven months, which was much shorter than that of B- or Null-NHL.     

Psychological changes of Japan Self-Defense Forces personnel during selection and training for the peacekeeping mission in the Golan Heights

We sought to determine whether a selection process for deployment had a measurable effect on psychological symptoms by comparing scores on the Yatabe-Guilford Personality Index, the Manifest Anxiety Scale, and the 30-item version of the General Health Questionnaire between deployed and nondeployed mission candidates from the Japan Self-Defense Forces. The studies were undertaken in Japan during education and training for the United Nations peacekeeping mission in the Golan Heights. The participants included 80 candidates for deployment. Personnel who were not deployed had significantly higher measures of manifest anxiety and general psychological distress than deployed personnel, whereas deployed personnel showed more symptoms suggesting somatization. The selection process and training for deployment appear to have been stressful for all personnel, whether deployed or not.     

Aneurysms at nonbranching sites in the surpaclinoid portion of the internal carotid artery: internal carotid artery trunk aneurysms

OBJECTIVE: Aneurysms at nonbranching sites in the supraclinoid internal carotid artery (ICA), known as blood blister-like aneurysms or ICA anterior or dorsal wall aneurysms, are not well understood. To clarify this clinical entity, 7408 patients with subarachnoid hemorrhage who were treated during a 5-year period were analyzed. METHODS: Forty-eight patients had aneurysms that were intraoperatively confirmed to be located at a nonbranching site in the supraclinoid portion of the ICA. Neuroradiological and clinicopathological features and outcomes were studied. RESULTS: The aneurysms were divided into the "blister type," with a blood blister-like configuration and fragile walls, and the "saccular type," with a saccular configuration and a relatively firm neck, like ordinary berry aneurysms. The most frequent origin was the anteromedial wall for both types. ICA dissection was associated only with the blister type, and hypertension was more frequent with the blister type (P = 0.0978). The preoperative conditions of the patients were the same, but the outcomes for patients with blister-type aneurysms were worse, because of frequent intra- and postoperative aneurysmal bleeding. Saccular-type aneurysms were safely clipped. Treatment of blister-type aneurysms by clipping on wrapping material achieved good results, but ICA trapping (P = 0.0952), clipping (P = 0.0146), and wrapping (P = 0.0110) were associated with much worse results. CONCLUSION: Blister-type and saccular-type aneurysms have different shapes and wall characteristics. The saccular type can be treated by clipping, whereas the blister type requires clipping on wrapping material. ICA trunk aneurysms may be a better designation to express the diversity of these aneurysms, rather than ICA blood blister-like or anterior or dorsal wall aneurysms.     

Postoperative hyperperfusion syndrome in elderly patients with chronic subdural hematoma

BACKGROUND: Temporary acute agitated delirium is a frequent complication after surgery for chronic subdural hematoma (CSH) in elderly patients. To clarify the pathogenic mechanism underlying this complication, we measured cerebral blood flow before and after surgery in elderly patients with CSHs. METHODS: Twenty-seven patients aged 75 years or older with unilateral CSH underwent treatment involving a single burr hole craniostomy with continuous catheter drainage. Cerebral blood flow was measured using single photon emission computed tomography 1 day before surgery, and at 1 hour and 24 hours after surgery. Acute agitated delirium was diagnosed by the characteristic behavioral abnormality. RESULTS: SPECT imaging 1 hour after surgery demonstrated hyperperfusion in the cerebral cortex beneath the CSH in 14 patients (51.9%). Of these 14 patients, five showed acute agitated delirium a few hours after surgery that persisted for 10 to 12 hours. A hematoma was detected in the right hemisphere in all five patients. Hyperperfusion was significantly more intense in patients with acute agitated delirium both 1 hour and 24 hours after surgery than in patients (n = 9) without acute agitated delirium. Moreover, mean arterial blood pressure during the first postoperative hour was significantly higher in patients with acute agitated delirium. CONCLUSION: In elderly patients with CSH, intense and prolonged hyperperfusion after surgery induces temporary acute agitated delirium. This postoperative hyperperfusion syndrome is exacerbated by hypertension.     

Thrombin inhibitor ameliorates secondary damage in rat brain injury: suppression of inflammatory cells and vimentin-positive astrocytes

The effects of the thrombin inhibitor argatroban on the number of inflammatory cells and reactive astrocytes were investigated in a rat brain injury model. Gelatin sponge soaked with thrombin inhibitor (treatment group) or saline (control group) was placed in the brain defect to assess the infiltration of inflammatory cells by hematoxylin-eosin and immunohistochemical staining. Expression of polymorphonuclear leukocytes (PMNs) and monocyte/macrophage (Mo/Mo) cells, and vimentin (VIM)-positive astrocytes and glial fibrillary acidic protein (GFAP)-positive astrocytes were compared between groups. In the treatment group, infiltration of both PMNs and Mo/Mo cells, and the number of VIM-positive astrocytes were significantly reduced, but the number of GFAP-positive astrocytes was not different from the control group. Thrombin inhibitor suppresses the infiltration of inflammatory cells and excessive gliosis caused by VIM-positive astrocytes, but not expression of GFAP-positive astrocytes, suggesting minimization of secondary brain damage and promotion of the conditions required for neural regeneration.     

Relative preservation of peripheral lung function in smoking-related pulmonary emphysema: assessment with 99mTc-MAA perfusion and dynamic 133Xe SPET

In this study the cross-sectional functional differences between the central and peripheral lung in smokers with pulmonary emphysema were evaluated by lung perfusion and dynamic xenon-133 single-photon emission tomography (SPET). The subjects were 81 patients with a long-term smoking history and relatively advanced emphysema, 17 non-smoker patients with non-obstructive lung diseases and six healthy non-smokers. Regional lung functional difference between the peripheral and central lung was assessed in the upper, middle and lower lung zones by technetium-99m macroaggregated albumin SPET and dynamic 133Xe SPET. The distribution of emphysematous changes was assessed by density-mask computed tomography (CT) images which depicted abnormally low attenuation areas (LAAs) of less than -960 Hounsfield units. Two hundred and eighty-eight (59.2%) lung zones of 63 (77.7%) patients with pulmonary emphysema showed relative preservation of lung function in the peripheral lung, with a curvilinear band of normal perfusion (a stripe sign) and a significantly faster 133Xe half-clearance time (T(1/2)) than in central lung (P<0.0001). Of these lung zones, 256 (88.8%) showed central-dominant LAA distributions on density-mask CT images, but the remaining 32 zones did not show any regional preference in LAA distribution. Conversely, 117 (24.0%) lung zones of 19 (23.4%) patients showed periphery-dominant perfusion defects and LAA distributions, with significantly prolonged T(1/2) in the peripheral lung area (P<0.0001). The remaining 81 lung zones of the patients with pulmonary emphysema and all the lung zones of the healthy subjects and patients with non-obstructive lung diseases did not show a stripe sign, and no differences were observed in T(1/2) values and LAA distributions between the central and peripheral lung. Relative preservation of peripheral lung function seems to be a characteristic feature in smoking-related pulmonary emphysema, and may indicate a lower susceptibility of peripheral parenchyma to the development of this disease.     

Serine protease inhibitors prevent alcoholic liver injury]

The hepatotoxic effects of alcohol have been described in detail, but factors responsible for its hepatotoxicity have only partially characterized. It now appears that Kupffer cell derived TNF-alpha participates in several aspects of alcoholic liver injury. On the other hand, protease inhibitors have been used successfully for treatment of intractable diseases in which TNF-alpha is involved in the pathogenesis, including ulcerative colitis and Crohn's disease. Here, we will review new evidence for the proposal that serine protease inhibitors prevents alcoholic liver injury via mechanisms dependent on Kupffer cell derived TNF-alpha.     

Successful Treatment of Nephrotic Syndrome Due to Collapsing Focal Segmental Glomerulosclerosis Accompanied by Acute Interstitial Nephritis

A 39-year-old woman was hospitalized for nephrotic syndrome. Laboratory test results showed increased serum creatinine levels and urinary excretions of beta-2-microglobulin, and N-acetyl-beta-D-glucosaminidase. A renal biopsy revealed collapsing focal segmental glomerulosclerosis (FSGS) and acute interstitial nephritis. Despite treatment with pulse steroid followed by oral high-dose glucocorticoids and cyclosporines, heavy proteinuria persisted. After low-density lipoprotein apheresis (LDL-A) therapy was initiated, her proteinuria gradually decreased, leading to complete remission. A repeat renal biopsy after treatment revealed no collapsing glomeruli. Immediate LDL-A should be performed to treat cases of collapsing FSGS poorly responding to other treatments.