Regional blood flows and cardiac function changes induced by angiotensin II in conscious dogs

Hemodynamic properties of angiotensin (ANG) II 1, 5, 10 and 100 ng/kg i.v. and 10, 100 and 1000 ng/kg i.v.t. were assessed in conscious dogs. ANG II i.v. produced a dose-dependent pressor response (59 +/- 5-124 +/- 16 mmHg) and renal vasoconstriction (1.3 +/- 0.4-96 +/- 32 mmHg/ml/min). Ganglionic blockade (chlorisondamine 2 mg/kg i.v.) diminished mean arterial responses without altering peptide effects on renal circulation. At the highest dose, ANG II i.v. induced cardiac stimulation: increased heart rate (75 +/- 4-115 +/- 6 beats/min), cardiac output (2.0 +/- 0.1-2.4 +/- 0.2 l/min), dP/dt (2308 +/- 181-2773 +/- 173 mmHg/sec) and coronary blood flow (49 +/- 10-96 +/- 23 ml/min). Although with chlorisondamine cardiac response was more pronounced, subsequent beta blockade abolished it. Concomitantly, an isolated increase in plasma epinephrine was recorded (63 +/- 8-1505 +/- 354 pg/ml). A pressor response (59 +/- 8-89 +/- 13 mmHg) and renal vasoconstriction (1.1 +/- 0.1-2.2 +/- 0.5 mmHg/ml/min) were also produced by ANG II i.v.t. at the highest dose. These centrally mediated changes were prevented by chlorisondamine. Our study demonstrates 1) i.v. ANG II-mediated pressor responses are dependent on direct and indirect components, the relative contribution of each being dependent on the regional circulation; ANG II i.v. also produced a biphasic cardiac response--an initial centrally mediated depression and a secondary stimulation dependent on epinephrine via cardiac beta receptors and 2) i.v.t. ANG II-mediated pressor effects are essentially indirect. Finally, no evidence was found to support the role of vasopressin in ANG II effects.     

黄河流域11个地区51个干休所离退休干部认知障碍及老年痴呆危险因素分析

目的:调查兰州部队辖区黄河流域老年痴呆及认知障碍的患病率并分析其危险因素。方法:应用《长谷川智力量表》(22～30.5分为轻度异常,10.5～21.5分为痴呆前期,≤10分为痴呆期)和《临床记忆量表》(≤80分为异常),对黄河流域11个地区51个干休所16538人群中2944名60岁以上人员进行调查。采用挨家挨户一对一的的方法开展调查检测,只有2个量表评分均为异常才列为病例组,同时对一般情况、驻地海拔高度、家族遗传史、既往病史、生活习惯等5个方面30个危险因素进行调查,并应用SPSS10.0软件包将调查结果进行多元回归分析。结果:2944名受试者全部完成测试进入结果分析。①老年痴呆的患病率分别为痴呆0.71%,痴呆前期2.11%,轻度异常28.46%,总患病率为31.28%。②多元回归分析结果:脑萎缩(t=-6.304)、重大生活事件(t=-5.328)、高龄(t=-5.415)、无喝茶嗜好(t=-3.802)、脑梗死(t=-3.343)、女性(t=-2.604)、冠心病(t=2.496)、低文化程度(t=1.973)、职业(t=1.965)、高海拔地区(t=1.957)与老年痴呆相关(P均<0.05)。结论:①黄河流域老年痴呆及认知障碍发生与脑萎缩、重大生活事件、高龄、无喝茶嗜好、脑梗死、女性、冠心病、低文化程度、职业、高海拔地区等10种危险因素有关。②结果显示痴呆发病率较低,而痴呆前期及轻度异常发病率较高,所以应重视痴呆前期及轻度异常患者的干预治疗。     

Acamprosate (Aotal): could adverse effects upset the treatment of alcohol dependence?

Acamprosate, a stimulant of central inhibitory GABA neurotransmision and an antagonist of excitatory amino acids, is used in alcohol withdrawal and for the maintenance of abstinence. After identification of several cases of treatment discontinuation during alcohol abstinence because of acamprosate-induced adverse drug reactions (ADRs), a retrospective study was conducted in order to investigate and quantify acamprosate-induced ADRs. Up to July 2002, 472 patients were included for treatment of alcohol withdrawal: of these, 68% (n = 322) received acamprosate. At least one ADR occurred in 98 patients (30%). The mean age of the patients was 41.5 +/- 8.8 years (range: 24-65) and 70% were male. All ADRs were classified as 'non serious'. However, ADRs required a dose decrease in 61 cases or acamprosate discontinuation in 76 cases (62.2% and 77.5%, respectively, of patients with an ADR). We identified mainly gastrointestinal ADRs in 67 patients (mean delay before occurrence: 7.6 days), i.e. 20.8% of patients treated with acamprosate (corresponding to 68.3% of ADRs), with a positive rechallenge in five cases. Moreover, cutaneous ADRs (pruritus) occurred in 29 patients (mean delay before occurrence: 9.0 days), and required acamprosate withdrawal in 22 patients (75.9%) with a prior dose decrease in 18 of these patients (62.1%). Our results show that a dose decrease or withdrawal of acamprosate was necessary in 18.9% and 23.6%, respectively, of patients because of the occurrence of ADRs. The present study shows the important role of acamprosate-induced ADRs among the various causes for failure of alcohol abstinence.     

Application of biosafety principles in blood establishments

In light of increasing public and employee concern over potential infectious hazards associated with blood and other body fluids, several government agencies (the Food and Drug Administration, the Centers for Disease Control, the Occupational Safety and Health Administration, the Environmental Protection Agency, the Health Care Financing Administration and the National Heart, Lung and Blood Institute) cosponsored a Biosafety Workshop in April 1988. The objective of the workshop was to identify appropriate biosafety practices and standard control procedures to protect workers involved in the collection, storage, and transportation of human blood donations with the least possible disruption of the nation's blood supply. Speakers focused on human immunodeficiency virus (HIV) and hepatitis B virus (HBV); however, the safety principles discussed were considered equally applicable to other known (e.g., non-A, non-B hepatitis and human T-lymphotropic virus type I (HTLV-1) blood-transmitted infections. The resulting consensus included the need for blood establishments to develop and apply thoughtful biosafety programs to address staff training, accident prevention, HBV vaccination, handling spills, managing contaminated waste and transporting blood specimens. There was lack of agreement, however, on the usefulness of gloves during the phlebotomy of healthy blood donors.     

Establishing a phase I unit: organisation

Summary— The organisation of a phase I unit must take into account the safety, quality and scientific requirements of such studies. The clinical pharmacology unit demands a highly qualified staff, as well as intensive care equipment. The investigator, generally a clinical pharmacologist who coordinates the different tasks as a project leader, has often to initiate a fruitful collaboration with a specialised consultant staff in order to implement the studies.     

Fluoxetine in orthostatic hypotension of Parkinson's disease: A clinical and experimental pilot study

Summary— Recent clinical studies have reported a beneficial effect of fluoxetine, a serotonin reuptake inhibitor, in patients with severe refractory orthostatic hypotension. The present study was undertaken to investigate the effect of fluoxetine in orthostatic hypotension occurring during Parkinson's disease on both blood pressure values and number of clinical symptoms during orthostatic procedure evaluated using a validated clinical rating scale. In a pilot study performed in fourteen patients with idiopathic Parkinson's disease plus orthostatic hypotension, fluoxetine hydrochloride (20 mg orally daily during one month) significantly reduced the fall in systolic blood pressure [-33 ± 21 (SD) mmHg before fluoxetine vs -22 ± 19 mmHg after fluoxetine, P = 0.03] elicited by standing without modifying heart rate. The drug also significantly reduced the number of postural symptoms occurring during the orthostatic procedure [2.9 ± 1.5 (SD) before fluoxetine vs 1.2 ± 1.3 after fluoxetine, P = 0.006]. A similar pattern of response was obtained in an experimental model of neurogenic orthostatic hypotension obtained in chronically sino-aortic denervated dogs submitted to an 80° head-up tilt test procedure under chloralose anaesthesia. Fluoxetine did not change plasma noradrenaline levels. This pilot study suggests a slight but clinically significant effect of fluoxetine on both hemodynamic parameters and clinical symptoms in parkinsonian patients suffering from orthostatic hypotension.     

Short-term culture of acute myeloid leukemia blasts: analysis of acquired susceptibility to activated natural killer cells

Following a cryopreservation step, short-term cultures of circulating leukemic blasts from a patient with acute myeloid leukemia (AML) were performed. Because cultured tumor cells became susceptible to natural killer (NK) activity, in vitro alteration of the blasts was studied. Immediately after thawing, cell suspensions consisted of a relatively homogeneous population of undifferentiated blasts. In culture, tritiated thymidine uptake by the leukemic cells was low during the first 24 hours and then increased (X20) to a peak on day 7. The cell concentration started to increase on day 4. On day 8, less than 10% of the cultured cells still appeared as undifferentiated blasts, whereas up to 60% were granular and 30% to 40% had a monocytoid morphology. Prior to being cultured, the blasts were resistant to resting and IL2- activated natural killing. When the kinetics of in vitro acquired susceptibility were studied, it was found that maximum cytotoxicity against these leukemic cells was reached within 24 hours. Thus, the blasts had become NK-sensitive prior to increase in DNA synthesis, proliferation, and differentiation based on morphological and cytochemical criteria. In contrast, there was a positive correlation between acquired susceptibility and surface expression of an activation antigen, termed TNKtar. To dissect further the mechanisms of acquired susceptibility, a series of six NK clones representing four distinct phenotypes of NK active lymphocytes were tested against the leukemic cells. Immediately after thawing, blasts were essentially resistant to all clones, whereas they were strongly killed by 5 of 6 clones when cultured for 24 hours. Cold target inhibition assays indicated that resistance of fresh blasts was likely to be due to a binding defect. These results suggested that tumor cells became susceptible because they surface-expressed NK target structure(s) in the early phase of an activation process leading to their proliferation and/or differentiation. This hypothesis was substantiated for one clone, termed JT9, because the anti-TNKtar antibody blocked cytotoxicity of JT9 cells against the cultured blasts.