β 1- andβ 2-adrenoceptor binding and functional response in right and left atria of rat heart

Summary The properties of ₁- and ₂-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses to-adrenoceptor agonists were examined. [¹²⁵I](-)-pindolol (¹²⁵IPIN) bound saturably and specifically to a single class of high affinity sites in homogenates of both right and left atria. Thek ₁'s for association in right and left atria were 6.5×10⁹ l/mol-min and 2.3×10⁹ l/mol-min respectively, while thek _–1's for dissociation were 0.20 min^–1 and 0.17 min^–1. The kinetically determinedK _D's were 75 pmol/l in right and 30 pmol/l in left atria and were similar to the equilibriumK _D's determined from Scatchard analysis of saturation isotherms of specific¹²⁵IPIN binding. Inhibition of¹²⁵IPIN binding by-adrenoceptor antagonists was stereoselective and the order of potency was timolol > 1-propranolol > d-propranolol > sotalol. Inhibition by ₁- and ₂-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement by ₁-selective (practolol, atenolol and metoprolol) and ₂-selective (ICI 118,551) antagonists gave estimates of the proportion of ₁- and ₂-adrenoceptors present in rat atria. Right atria contained 67±4.2% ₂-adrenoceptors and 33±4.2% ₂-adrenoceptor, while left atria contained 67±2.8% ₁- and 33±2.8% ₂-adrenoceptors. Increases in the rate of spontaneously beating right atria and the force of electrically driven left atria caused by-adrenoceptor agonists were also measured. pA₂ values for non-subtype selective-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated withK _D values determined for specific¹²⁵IPIN binding. pA₂ values for ₁- and ₂-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the pK _D values of these drugs in binding to ₁-adrenoceptors, but not with the pK _D values in binding to ₂-adrenoceptors. Dose-response curves for stimulation of both rate and force by the ₂-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade of ₁-adrenoceptors with metoprolol than by selective blockade of ₂-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activating ₁-adrenoceptors. These results suggest that ₁- and ₂-adrenoceptors coexist in both left and right atria of rat heart in approximately a 21 ratio, however only ₁-adrenoceptors mediate the chronotropic and inotropic effects of-adrenoceptor agonists.Supported by a grant from the American Heart Association — Georgia Affiliate     

Yohimbine: a new street drug

Following the ingestion of an alleged aphrodisiac known as "yo-yo," a 16-year-old girl experienced an acute dissociative reaction accompanied by weakness, paresthesias, and incoordination. Subsequent symptoms included anxiety, headache, nausea, palpitations, and chest pain. Hypertension, tachycardia, tachypnea, diaphoresis, pallor, tremors, and an erythematous rash were noted on physical examination. Serum epinephrine and norepinephrine levels were found to be elevated. Symptoms resolved spontaneously but lasted approximately 36 hours. The ingested substance was identified as yohimbine. The pharmacology of yohimbine and the treatment of yohimbine poisoning are discussed.     

The effect of neuroleptic treatment and of high dosage diazepam therapy onβ-endorphin immunoreactivity in plasma of schizophrenic patients

Summary Synapsin I (Protein I), a neuron-specific phosphoprotein enriched in presynaptic nerve terminals, has been used as a quantitative marker for the density of nerve terminals in five brain regions (caudate nucleus, cingulate gyrus, hippocampus, mesencephalon and putamen) from patients who had suffered from Alzheimer disease/senile dementia of Alzheimer type (AD/ SDAT), from patients with multi-infarct dementia (MID), and from agematched controls. Samples were obtained at autopsy. Lower levels of Synapsin I were observed in the hippocampus of patients with AD/SDAT but not with MID. There were no significant differences in Synapsin I levels between patients and controls in any of the other four brain regions examined.     

Animal models and treatment of prostate cancer

Model systems for prostate cancer in rats have been developed and used for investigations on tumor biology and therapy. The "Pollard tumors" provide a combination of in vitro and in vivo attributes by which investigations can be directed at local tumor development and spontaneous metastasis. The evolution and early applications of this model system are reviewed, and the therapeutic benefits of delayed release of cyclophosphamide are presented.     

医疗用超硬质热塑性聚氨酯TPU的抗肿瘤药物溶剂耐受性研究

研究四种类型热塑性聚合物的6种常见医用输液接头材料对抗肿瘤药物溶剂的耐受性。将这些材料的标准测试样条固定在弯曲应变为1.5%的自制夹具上,分别浸泡在Etoposide?药物溶剂、Busulflex?药物溶剂或DMSO(以50%为例)等3种抗肿瘤药物溶剂,然后观察试样的外观,测试试样的拉伸强度、断裂伸长率和缺口冲击强度等性能的变化情况,采用定量化的评分,对6种材料的抗肿瘤药物溶剂的耐受性进行了评价。结果表明,两款超硬质热塑性聚氨酯(TPU)材料对三种抗肿瘤药物溶剂的耐受性均优于其他4种评价的材料,为接触抗肿瘤药物类的医疗器械产品的较优选择,比如PICC,CVC,输液器等。     

Toward Better Data Dashboards for US Drug Value Assessments

ObjectivesTo explore the use of data dashboards to convey information about a drug’s value, and reduce the need to collapse dimensions of value to a single measure.MethodsReview of the literature on US Drug Value Assessment Frameworks, and discussion of the value of data dashboards to improve the manner in which information on value is displayed.ResultsThe incremental cost per quality-adjusted life-year ratio is a useful starting point for conversation about a drug’s value, but it cannot reflect all of the elements of value about which different audiences care deeply. Data dashboards for drug value assessments can draw from other contexts. Decision makers should be presented with well-designed value dashboards containing various metrics, including conventional cost per quality-adjusted life-year ratios as well as measures of a drug’s impact on clinical and patient-centric outcomes, and on budgetary and distributional consequences, to convey a drug’s value along different dimensions.ConclusionsThe advent of US drug value frameworks in health care has forced a concomitant effort to develop appropriate information displays. Researchers should formally test different formats and elements.     

Drug Prices and Value of Oncology Drugs in Italy

ObjectiveThe main objective of this study was to evaluate the potential role of efficacy data and other information available at the time of price and reimbursement (P&R) decision-making process within the definition of oncology treatment costs in Italy.MethodsThe study included all P&R dossiers submitted to the Italian Medicines Agency between July 2015 and December 2017. It prospectively collected the data of the P&R process starting from dossier submission up to the Italian Health Service reimbursement decision. The cost of treatment per patient was estimated using both the list price (“gross cost”) and the confidential net price (“net cost”) of drug packages and applied to the median duration of treatment. A 2-sample stage Heckman decomposition model was used to evaluate the potential role of efficacy data and other information available at the time of P&R decision making on the gross and net cost.ResultsA total of 37 oncology drugs related to 58 therapeutic indications were analyzed. The multivariate model showed that the variation of progression-free survival is the only variable predictor statistically associated with treatment cost, but this effect was observed only when confidential net prices were used (P=.026).ConclusionsConsidering the perspective of a developed country having a public healthcare service with a central reimbursement negotiation is determined a relevant reduction in the treatment cost purchased by public payers. This is a useful approach to guarantee the affordability of innovative oncology drugs and to contain public expenditures on healthcare. Furthermore, the negotiation of confidential discounts and agreement clauses in managed entry agreements seemed to reward oncology drugs displaying an added therapeutic benefit.     

益气活血药对低氧性肺动脉高压大鼠神经肽Y、降钙素基因相关肽的影响

目的：探讨由黄芪、川芎组方的益气活血药对低氧性肺动脉高压大鼠神经肽Y（NPY）、 降钙素基因相关肽（CGRP）的影响。方法：采用常压低氧21天复制大鼠肺动脉高压模型,应用放射免疫技术测定大鼠血浆、肺组织中NPY、CGRP的含量变化。结果：益气活血药可降低肺动脉压,改善心功能及血液流变学。益气活血药中剂量组血浆及肺组织中NPY含量与缺氧组比较明显降低;而CGRP含量较缺氧组有所回升,肺组织中CGRP含量与缺氧组比较则趋于下降。结论：益气活血药可防止低氧性肺动脉高压的形成,也提示益气活血药的降压作用可能通过影响NPY、CGRP的含量来调节肺血管舒缩,从而降低肺动脉压。     

蒙药毛勒日—达布斯—4汤中微量元素及氨基酸含量的测定

目的：测定蒙药毛勒日-达布斯-4汤中微量元素和氨基酸的含量。方法：用原子吸收分光光度计,测定蒙药毛勒日-达布斯-4汤中几种重要的微量元素含量;用氨基酸自动分析仪测定氨基酸的含量。结果与结论：蒙药毛勒日-达布斯-4汤中含有较高的Mn、Fe、Zn和Mg;含有17种氨基酸,包括7种人体必需氨基酸,氨基酸总量为4.615%（mg/g）。     

慢性乙型肝炎患者TNF-α和IL-6的变化及双利肝对其影响

目的探讨TNF-α、IL-6在慢性乙肝不同阶段的作用及双利肝对于两种细胞因子的影响.方法 55 例慢性乙肝患者在治疗前测定血清TNF-α、IL-6水平及肝功能.在一般保肝治疗基础上口服双利肝,在治疗前后测定血清TNF-α、IL-6水平及肝功能.结果随着肝功能损害加重,TNF-α、IL-6水平显著升高(P＜0.01,P＜0.05),经过双利肝治疗,患者转氨酶、胆红素、TNF-α水平明显下降(P＜0.01),IL-6水平略有上升但无显著性差异(P＞0.05).结论慢性乙肝病程中,TNF-α与肝细胞坏死程度有关,可作为病情轻重的判别指示.IL-6与肝脏损伤过程有关.双利肝可明显降低慢性乙肝患者TNF-α水平,有效地改善肝功能.