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141.
Ro 11-2465 (cianopramine, cyan-imipramine) and citalopram (CIT), putative antidepressant drugs, are very potent and selective 5-hydroxytryptamine (5-HT) uptake inhibitors in vitro. This study investigated the effects of these drugs and their desmethyl metabolites, Ro 12-5419 (desmethylcianopramine, cyan-desipramine) and desmethylcitalopram (DCIT), respectively, on the uptake of 5-HT and noradrenaline (NA) in vivo [protection against H 77/77 (4, alpha-dimethyl-metatyramine)-induced displacement of 5-HT and NA] and on related pharmacological activities. All the investigated drugs antagonized H 77/77-induced displacement of 5-HT in the rat brain, though the effects of the metabolites were considerably weaker than those of the parent compounds. The H 77/77-induced displacement of brain NA in rats and mice was antagonized only by Ro 12-5419 and Ro 11-2465. All the drugs potentiated the pressor response to 5-HT in pithed rats; however, Ro 12-5419 and particularly Ro 11-2465 could also block the response when used in higher doses (0.1 mg/kg). Only Ro 12-5419 and Ro 11-2465 were able to potentiate the pressor response to NA. Ro 12-5419 also potentiated thyrotropin releasing hormone (TRH) hyperthermia and antagonized reserpine hypothermia in mice; Ro 11-2465 potentiated the TRH hyperthermia only. CIT and DCIT were inactive in both these tests. Of all the four drugs only CIT and Ro 12-5419 considerably stimulated the hind limb flexor reflex in spinal rats. However, whereas the stimulatory effect of CIT was inhibited by the 5-HT antagonists metergoline and cyproheptadine, that of Ro 12-5419 was counteracted by the NA antagonist phenoxybenzamine only. Ro 11-2465, when used in low doses (ca. 1 mg/kg), slightly potentiated the flexor reflex, whereas in higher doses (4–16 mg/kg) it had no effect itself but antagonized the stimulatory action of the 5-HT agonists fenfluramine, quipazine and LSD. The results obtained indicate that Ro 11-2465 and CIT, as well as their desmethyl metabolites, are also potent 5-HT uptake inhibitors in vivo. However, only CIT and DCIT are concurrently devoid of effect on uptake of NA. In contrast, Ro 11-2465 and particularly Ro 12-5419 appear to also inhibit the uptake of NA. Moreover, Ro 11-2465 appears to block central and peripheral 5-HT receptors.The results were presented at the 14th CINP Congress, Florence, June 19–23, 1984 相似文献
142.
van Andel FG 《Health policy (Amsterdam, Netherlands)》1985,4(3):231-239
In the course of this century all industrial nations witnessed a growth in the influence of the state over the individual. Usually, state intervention in private life is justified by the state's mandate to protect the health and security of its constituents, either through general, uniform precepts such as laws or decrees, or through individual arrangements such as licences or subsidies. The principle of state protection has also long been established in the pharmaceutical sector, and entails that regulatory agencies should only approve those drugs for market use, which--according to scientific knowledge--have benefits which outweigh their potential harmful effects. Although 'the state of scientific knowledge' seems to imply that safety decisions concerning drugs are predominantly based on medical, scientific criteria, it is argued in this paper, that regulatory agencies nevertheless have wide discretionary margins, which allow for a political dimension to such decisions. For this reason it is briefly examined how drug authorities react under political pressure, i.e. when a drug has become a public problem. Additionally, the issue is considered why especially so-called non-steroidal anti-inflammatory drugs (NSAID's) have recently been the focus of controversy in the media. This attention has led to a situation in which it seems that regulatory agencies only accept drugs for market use with zero risk. The paper concludes by recommending that safety decisions of health authorities should involve two expert levels: in order to make precise risk assessments on the scientific level all relevant information about risks and benefits of drugs should be collated, whereas safety decisions should be taken by experts knowledgeable in the field of societal proportions. 相似文献
143.
Lemmer Björn Winkler Horst Ohm Thomas Fink Markus 《Naunyn-Schmiedeberg's archives of pharmacology》1985,330(1):42-49
Summary Comparative pharmacokinetic studies with the -receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 moles/kg) or multiple (6x6 moles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C0-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance,V
d) with the exception inV
d of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L. It is concluded that L-D-differences in drug half-lives after single dose application are mainly due to circadian variations in drug elimination with a higher hepatic (propranolol, metoprolol) or renal (sotalol, atenolol) elimination in the activity period of rats during D. Additional studies with propranolol on heart rate of conscious rats revealed that a maximum in -receptor blockade was achieved at 10 moles/kg in L but not in D. Thus, it is assumed that abolition of circadian-phase-dependency in half-lives after 6x6 moles/kg of the drugs may be due to the longer lasting and more pronounced -receptor blockade after multiple drug dosing over a period of several hours in D. Thereby, liver-flow-dependent elimination of propranolol and metoprolol and renal elimination of sotalol and atenolol is reduced to base-line levels found in L.Parts of this work were presented at the 22nd Spring Meeting (Lemmer 1981) and at the Joint Meeting (Lemmer et al. 1983a) of the German Pharmacological Society 相似文献
144.
Eric N. Juberg Kenneth P. Minneman Peter W. Abel 《Naunyn-Schmiedeberg's archives of pharmacology》1985,330(3):193-202
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 相似文献
145.
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. 相似文献
146.
C. Gramsch H. M. Emrich S. John S. Haas H. Beckmann M. Zaudig D. von Zerssen 《Journal of neural transmission (Vienna, Austria : 1996)》1984,60(2):133-141
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. 相似文献
147.
Animal models and treatment of prostate cancer 总被引:1,自引:0,他引:1
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. 相似文献
148.
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。 相似文献
149.
目的:基于药症相应,探讨历代本草治窍思路,以指导临床辨治用药。方法:检索《中华医典》数据库中本草类的全部文献数据,涉及本草著作76部,涵盖汉至明清各时期具有代表性的存世的本草著作,收集整理其治窍的本草信息,依照《中药学》(第十一版)及2020年版《中华人民共和国药典》,对筛选纳入的本草进行性味归经统计分析,以治窍病机要素进行分类统计,提取各类本草的辨治论述内容。结果:在76部历代本草专著中,筛选出93味治窍本草。在治窍本草性味归经上,药性以温性为主,其次为寒性、平性等;药味以辛味为主,其次为苦味、甘味等;归经以肺经为主,其次为胃经、心经、肝经、脾经、肾经等。在以治窍病机要素本草分类中,可划分为风邪袭扰、浊阻气滞、水湿停滞、血瘀络阻、火热毒损、正虚寒凝六类病机要素。结论:治窍辨治用药以祛风散邪药、化浊行滞药、利水渗湿药、活血通络药、清热泻火药、补虚散寒药为主,且互相联合运用;祛邪通利、补虚泻实为治窍辨治主要特点,符合窍失空灵、邪阻正虚的生理功能紊乱状态。 相似文献
150.
《Value in health》2021,24(10):1484-1489
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. 相似文献