Studies on the localization of central cough mechanism; site of action of antitussive drugs.

The localization of the central cough mechanism was studied by electrically stimulating the lower brainstem in cats lightly anesthetized with pentobarbital sodium or in unanesthetized midcollicular decerebrate preparations. Cough responses were recorded with the aid of a microphone. The cough responsive region was concentrated in an area dorsomedial to the trigeminal tract and nucleus. The sites of action of antitussive agents (dextromethorphan, codeine, clonazepam, diazepam and caramiphen) were studied on the centrally induced cough responses. Each of these drugs was administered intravenously to determine the dorsal levels for cough suppression. In other series, the threshold dose via the intravertebral route was determined first. Because the agent necessary to prevent cough via this route was so small in amount, recovery usually occurred in 20 to 90 minutes. Then the same agent was given intravenously in an attempt to obtain an effective dose which was close to the minimum dose for blocking the cough. The mean effective doses of these agents to abolish the cough via the vertebral artery were only about 1/20 of those required via intravenous injection. The findings suggest that these agents act centrally to suppress the cough responses. Clonazepam was found to be the most potent antitussive among these agents, the mean effective dose being about 1/35 of that of codeine. The antitussive potency of benzodiazepines is not well correlated with their muscle relaxant activity. For instance, clonazepam and diazepam have the same potency in depressing polysynaptic spinal reflexes, whereas the former is 6 times more potent than diazepam as an antitussive. This finding indicates that clonazepam has a high specificity as an antitussive.     

Central analgesic effects of aspirin-like drugs

Summary— Aspirin-like drugs mainly include paracetamol, salicylates and other non-steroidal anti-inflammatory drugs, and metamizole. Their analgesic effect is classically ascribed to a peripheral site of action, within the pain-processing site. There is, however, convincing evidence that a central component contributes to the overall analgesia provided by these agents. Experimental and clinical studies referring to this challenging proposal are reviewed here. The exact site and mode of action of aspirin-like drugs within the central nervous system remains controversial. It is likely that supraspinal mechanisms play an important role. Some experiments lend support to the involvement of monoaminergic control systems. Other data indicate that these drugs act centrally through the inhibition of cyclo-oxygenase activity. The interactions between prostaglandins and various neurotransmitters suggest that both mechanisms may be linked.     

Dextromethorphan and codeine: objective assessment of antitussive activity in patients with chronic cough

Dextromethorphan, the most widely used cough suppressant in the U.S.A., was compared with codeine, the traditional European antitussive, in a double-blind, crossover trial using both an objective and subjective assessment of efficacy in sixteen patients with chronic, stable cough. Both preparations, at a dose of 20 mg, were similarly effective in reducing cough frequency. Dextromethorphan lowered cough intensity to a greater degree than codeine (p less than 0.0008) and was considered the better antitussive by the majority of patients (p less than 0.001). In view of its lack of side-effects, its safety even in overdose and its non-narcotic status, the increasing trend in Europe to use dextromethorphan as a substitute for codeine in the treatment of cough is to be welcomed.     

Comparative study of two antitussive drugs in the treatment of acute dry cough of infectious origin (prospective,randomized, single blind study)

The objective was to compare, during a 5-day therapy, the efficacy and tolerability of an antihistaminic antitussive syrup, oxomemazine, combining a small quantity of guaifenesine (T), with a centrally acting antitussive, clobutinol (S), in adult patients aged from 18 to 70 years and presenting with a dry cough of infectious origin. This study was performed by 22 general practitioners and 130 ambulatory patients were enrolled. The primary criterion of this multicenter, randomized, single blind study was to compare the evolution of cough intensity using a Visual Analog Squale (VAS) graduated from 0 to 10 cm. Nine secondary criteria including tolerability were also assessed. With regard to cough intensity, the treatments were not equivalent. A greater reduction was observed with T (-5.2 +/- 2.3 versus -4.3 +/- 2.3). This result was confirmed by a further reduction in cough intensity at days: 2 (p = 0.04), 4 (p = 0.05), and 5 (p = 0.02). The frequency of cough disappearance before the end of the study was significantly greater for T than for S: 46% versus 29% (p = 0.05). The time before disappearance of the cough was 4.0 + 1.1 days for both medicines. Induction of sleep and the frequency of nocturnal wakening were significantly better for T from day 4 (p = 0.02). The drowsiness induced by T meant that diurnal quality of life was better with S on days 1 (p = 0.002) and 2 (p = 0.01). Tolerability was similar for both medicines. In conclusion, as a symptomatic treatment of dry cough, T is efficient and well tolerated. Moreover, we have observed a tendency towards superior efficacy of T than S. T is therefore a useful alternative in the therapeutic armamentarium available to the general practitioner.     

Central sleep apnea syndrome and Cheyne-Stokes respiration

This overview discusses pathogenesis, clinical presentation, prognostic implications and therapy of central sleep apnea with special reference to Cheyne-Stokes-Respiration or periodic breathing. In contrast to obstructive sleep apnea due to upper airway collapse during sleep, central sleep apnea (CSA) is mainly due to an instability of the breathing control system. Causes of central sleep apnea include alveolar hypoventilation disorders, heart failure, neurologic and autonomic disorders and idiopathic forms of CSA. Patients with idiopathic CSA often complain of insomnia and awakening during sleep but may also suffer from daytime sleepiness. Cheyne-Stokes-Respiration or peridic breathing is often associated with heart failure and neurological disorders especially those involving the brainstem. In heart failure periodic breathing has enormous prognostic implications. Treatment options for central sleep apnea are oxygen supplementation, medical therapy (i.e. acetazolamide) and CPAP. For patients with central sleep apnoea associated with alveolar hypoventilation nasal ventilation is treatment of choice. Newer nasal ventilation techniques (BiPAP, AutoSetCS) are under investigation for heart failure patients with Cheyne-Stokes-Respiration.     

舒芬太尼诱发呛咳反应机制及预防用药的研究进展

舒芬太尼常用于抑制全麻诱导时气管插管引起的心血管反应,但在注射时可引起患者呛咳,剧烈呛咳可导致闭合空腔脏器压力骤增,尤其可增加颅高压及气胸等患者的麻醉诱导风险。注射不同剂量的舒芬太尼时,呛咳的发生率为28%～65%。多种药物及方法能不同程度地抑制全麻诱导中舒芬太尼所致的呛咳反应,但效能方面的比较文献相对较少。舒芬太尼诱导所用的浓度不同,预给药时机为2～15 min。本文对近年来不同药物抑制全麻诱导中舒芬太尼所致呛咳反应的文献进行总结,从舒芬太尼所致呛咳反应的机制、影响因素、预防给药方面作一综述。     

Mitochondrial antibodies--heterogeneity and effects on mitochondrial respiration.

Sera containing antimitochondrial antibodies (MTA) were tested for binding to intact mitochondria, sonic fragments (SMP), Complex I + III and to oligomycin sensitive ATPase (OS-ATPase) from bovine heart by indirect immunofluorescence. Antigens capable of binding to MTA were present in mitochondria and its fragments tested. Maximum binding was observed with SMP. It appears that one or more antigen binding sites are present on the matrix side of the inner mitochondrial membrane or some location exterior to the inner membrane. Normal human serum or sera containing MTA did not effect the respiration of intact mitochondria or sonic particles. However, NADH-cytochrome c reductase activity of complex I + III was enhanced by 10-60% by sera containing MTA antibodies.     

Temperature and cell-type dependency of sulfide effects on mitochondrial respiration

ABSTRACT: Previous studies suggest that sulfide-induced inhibition of cytochrome c oxidase (cCox) and, consequently, the metabolic and toxic effects of sulfide are less pronounced at low body temperature. Because the temperature-dependent effects of sulfide on the inflammatory response are still a matter of debate, we investigated the impact of varying temperature on the cCox excess capacity and the mitochondrial sulfide oxidation by the sulfide-ubiquinone oxidoreductase in macrophage-derived cell lines (AMJ2-C11 and RAW 264.7). Using an oxygraph chamber, the inhibition of mitochondrial respiration was measured by stepwise titrations with sulfide and the nonmetabolizable cCox inhibitor sodium azide at 25°C and 37°C. Using the latter of the two inhibitors, the excess capacity of the cCox was obtained. Furthermore, we quantified the capacity of these cells to withstand sulfide inhibition by measuring the amount required to inhibit respiration by 50% and 90% and the viability of the cells after 24-h exposure to 100 ppm of hydrogen sulfide. At low titration rates, the AMJ2-C11 cells, but not the RAW 264.7 cells, increased their capacity to withstand exogenously added sulfide. This effect was even greater at 25°C than at 37°C. Furthermore, only the AMJ2-C11 cells remained viable after sulfide exposure for 24 h. In contrast, only in the RAW 264.7 cells that an increase in cCox excess capacity was found at low temperatures. In macrophage-derived cell lines, both the excess capacity of cCox and the efficiency of sulfide elimination may increase at low temperatures. These properties may modify the effects of sulfide in immune cells and, potentially, the inflammatory response during sulfide exposure at different body temperatures.     

The effects of drugs on thermoregulation

Body temperature is a balance of the hypothalamic set point, neurotransmitter action, generation of body heat, and dissipation of heat. Drugs affect body temperature by different mechanisms. Antipyretics lower body temperature when the body's thermoregulatory set point has been raised by endogenous or exogenous pyrogens. The use of antipyretics may be unnecessary or may interfere with the body's resistance to infection, mask an important sign of illness, or cause adverse drug effects. Drugs may cause increased body temperature in five ways: altered thermoregulatory mechanisms, drug administration-related fever, fever from the pharmacologic action of the drug, idiosyncratic reactions, and hypersensitivity reactions. Certain drugs cause hypothermia by depression of the thermoregulatory set point or prevention of heat conservation. By affecting the balance of thermoregulatory neurotransmitters, drugs may prevent the signs and symptoms of hot flashes.     

The effects of drugs upon a graded cough response obtained in sensitized guinea pigs exposed to aerosol of specific antigen

A technique is described for measuring objectively and quantitatively the reaction of sensitized guinea pigs when exposed to an aerosol of specific antigen. The principle involves registration by semi-automatic means of the number of coughs produced in animals passively sensitized with known amounts of antibody. The number of coughs is shown to be linearly related to log dose of antibody within a limited range and a dose-response curve is presented. The cough produced by this procedure is not inhibited by the antitussive drugs, codeine and propadrine, but can be inhibited by anti-allergic agents, such as cortisone and an antihistaminic drug. It is also inhibited by narcotine. The last is the only compound so far tested which suppresses both the cough produced by this procedure and that produced by a simple irritant. The action of cortisone and the antihistaminic drug, pyrilamine, is shown to be synergistic. A small dose of pyrilamine in animals pretreated with cortisone gives a degree of inhibition which cannot be obtained by increasing the dose of pyrilamine in animals not treated with cortisone.     

Evidence for a central site of action for the antitussive effects of caramiphen

The antitussive properties of caramiphen edisylate were studied in the decerebrate cat in which cough was elicited by direct electrical stimulation of the cough center. In this preparation dextromethorphan hydrobromide was compared to caramiphen as an antitussive agent. Dextromethorphan was somewhat more potent when given i.v. as well as when given directly into the left vertebral artery (i.a.). Both agents were far more effective when given i.a. than when given i.v. The effective dose ratios of i.v./i.a. were about 12 and 14 for caramiphen and 11 and 7 for dextromethorphan (actual and cumulative doses). These ratios indicate that both agents have a central rather than a peripheral site of antitussive action. Both drugs had antitussive effects in i.a. doses which did not alter arterial blood pressure or respiration greatly. However, after i.v. administration transient changes in both arterial blood pressure and respiration were observed with both agents. It was concluded that the antitussive action of both caramiphen and dextromethorphan is due to a selective effect on the cough center in the brainstem of the cat. On a milligram per kilogram basis, caramiphen required a 3 to 4 times larger dose than dextromethorphan for equieffective antitussive effects.     

呼吸对右心室充盈的影响及其机制研究

目的研究平静呼吸对三尖瓣血流的影响及其规律,进而探讨呼吸对右心室充盈的影响,为验证呼吸影响心功能机制假说以及利用多普勒超声技术研究右心室舒张功能提供依据。方法20名健康志愿者,采用Sequoia 512彩色电脑声像仪,同步记录三尖瓣血流速度曲线、心电图和呼吸曲线。连续测量5个呼吸周期吸气相和呼气相血流速度及速度时间积分(VTI),取平均值。分别计算吸气相和呼气相三尖瓣舒张早期E波与舒张晚期A波的血流速度比值以及VTI比值。结果三尖瓣舒张早期E波血流速度及VTI在吸气相高于呼气相[(82.35±16.13)cm/s vs(68.62±14.82)cm/s,P<0.0001;(18.25±4.75)cm vs(15.45±4.22)cm,P<0.0001];舒张晚期A波血流速度及VTI在吸气相高于呼气相[(50.62±9.82)cm/s vs(42.25±8.27)cm/s,P<0.0001;(9.81±1.51)cm vs(7.78±1.37)cm,P<0.0001];E波与A波的血流速度比值及VTI比值在吸气相高于呼气相(1.53±0.42 vs 1.42±0.31,P=0.002;1.41±0.30 vs 1.33±0.27,P=0.003)。结论平静呼吸对三尖瓣血流影响具有规律性,这对进一步验证呼吸影响心功能机制假说以及利用多普勒超声技术研究右心室舒张功能提供了重要的资料。