氢溴酸右美沙芬对实验性咳嗽的镇咳作用

目的：研究氢溴酸右美沙芬对实验性咳嗽的镇咳作用。方法：化学品引咳法，电刺激引咳法。结果：氢溴酸右美沙芬１０ｍｇ／ｋｇ和２０ｍｇ／ｋｇ给小白鼠灌胃能有效地抑制氨水所致小鼠咳嗽的次数和延长潜伏期；５．５ｍｇ／ｋｇ和１１ｍｇ／ｋｇ给豚鼠灌胃给药对丙烯醛所致咳嗽有明显镇咳作用；３．２ｍｇ／ｋｇ和６．４ｍｇ／ｋｇ给豚鼠腹腔注射，对电刺激引起的咳嗽有明显镇咳作用。咳嗽次数减少率大于５０％，抑制率分别为５９．０２％和６３．９４％。结论：氢溴酸右美沙芬对多种实验方法引起的咳嗽有明显的镇咳作用。     

Möglichkeiten und Grenzen der Behandlung der nonketotischen Hyperglyzinämie 4 Fälle

Zusammenfassung Patienten: Wir berichten über Therapie und Verlauf bei 4 Patienten mit nonketotischer Hyperglyzin?mie, 3 M?dchen mit neonataler und 1 Junge mit infantiler Form. Trotz früher Diagnosestellung und Mehrfachtherapie inklusive Dextromethorphan und Na-Benzoat kam es bei 2 M?dchen mit neonataler Form zu einem therapierefrakt?ren Verlauf und zum Exitus im Alter von 16 bzw. 50 Monaten, die 3. Patientin überlebte mit schwerster psychomotorischer Retardierung, Opisthotonus, Tetraspastik und Anfallsleiden. Na-Benzoat führte zwar zu einer Absenkung der Glyzinkonzentration (bei stets pathologischer Liquor-Serum-Glyzin-Ratio), konnte den delet?ren Verlauf jedoch nicht beeinflussen. Der Patient mit der infantilen Form ist schwer psychomotorisch retardiert, zeigt aber unter Dextromethorphan seit nunmehr über 3 Jahren stete Entwicklungsfortschritte und Anfallsfreiheit. Diskussion: Bei der neonatalen nonketotischen Hyperglyzin?mie kann derzeit nur eine symptomatische Therapie inklusive eines Grand-mal-Schutzes empfohlen werden, da die Hirnl?sion bereits intrauterin erworben und keine effektive Therapie bekannt ist, bei der infantilen Form ist ein Therapieansatz mit Dextromethorphan gerechtfertigt. Eine Pr?nataldiagnose in „Risikofamilien” ist unverzichtbar.      

Current and future centrally acting antitussives

The purpose of this review is to highlight some important issues regarding current centrally acting antitussive drugs as well as discuss the implications of these matters on the development of future cough suppressants. Drugs that act in the central nervous system to inhibit cough are termed centrally acting and this designation is based exclusively on evidence obtained from animal models. This classification can include drugs that act both at peripheral and central sites following systemic administration. These drugs are intended to reduce the frequency and/or intensity of coughing resulting from disorders of any etiology. There are a number of central cough suppressants identified by their efficacy in animal models and the most prominent of these are codeine and dextromethorphan. Although the exact neural elements on which these drugs act are currently unknown, they are thought to inhibit a functionally identified component of the central system for cough known as the gating mechanism. The efficacy of codeine and dextromethorphan in humans has recently been questioned. These drugs are less effective on cough induced by upper airway disorders than in pathological conditions involving the lower airways in humans. The reasons for this difference in antitussive sensitivity are not clear. We propose that sensory afferents from different regions of the airways actuate coughing in humans by antitussive sensitive and insensitive control elements in the central nervous system. This hypothesis is consistent with results from an animal model in which laryngeal and tracheobronchial cough had different sensitivities to codeine. Other factors that may be very important in the action of central antitussive drugs in humans include the role of sensations produced by a tussigenic stimulus as well as plasticity of central pathways in response to airway inflammation. Resolution of these issues in the human will be a challenging process, but one which will lay the foundation for the development of more effective cough suppressants.     

Mesenteric Artery Clamping/Unclamping-Induced Acute Lung Injury Is Attenuated by N-Methyl-D-Aspartate Antagonist Dextromethorphan

Lung N-methyl-D-aspartate receptors (NMDAR) may cause excitotoxic pulmonary edema if activated. Acute lung injury may be mediated by oxidative stress, frequently generated by local or remote ischemia and reperfusion (IR). This experimental study assessed the effects of intravenous dextromethorphan, an NMDAR antagonist, on reperfusion lung injury following superior mesenteric artery (SMA) clamping/unclamping. SMA of 48 (12 per group) anesthetized adult male Wistar rats was clamped for 90 min (IR); 48 additional rats underwent a sham laparotomy (control). The experimental timeframe was identical in all groups. Ten minutes before unclamping, three dextromethorphan doses were administered intravenously in three IR and three control groups, followed by 3 h of respiratory and hemodynamic assessment and postexperimental assessment of survival. Intravenous 10 and 20 mg/kg dextromethorphan attenuated an 85% increase in peak ventilatory pressure, a 45% reduction in PO₂/FiO₂, 4–12-fold increase in bronchoalveolar lavage-retrieved volume, and polymorphonuclear leukocytes/bronchoalveolar cells ratio, all associated with SMA unclamping in the IR-nontreated and the IR-40 mg/kg dextromethorphan-treated rats. Lung tissue polymorphonuclear leukocyte count, total xanthine oxidase activity, reduced glutathione, and wet-to-dry weight ratio were all within normal ranges in the two lower-dose-treated groups. These effective regimens were also associated with longer postexperimental animal survival. Dextromethorphan was not associated with changes in three control groups. Thus, Intravenous dextromethorphan mitigates lung reperfusion injury following SMA clamping/unclamping in a dose-dependent manner. This is a novel potential use of dextromethorphan in vivo. This study was supported in part by the Italian Anonymous Family Fund, Milan, Italy.     

Evidence for using dextromethorphan-quinidine for the treatment of agitation in dementia

Behavioral and psychological symptoms including agitation are common in dementia, and are associated with decreased quality of life, increased risk of institutionalization, and greater patient and caregiver distress. Pharmacological agents used for management of behavioral and psychological symptoms of dementia are limited by their tolerability, prompting a need for identifying efficacious and safe pharmacological treatments for managing agitation in dementia. The combination of dextromethorphan and quinidine sulfate is approved for pseudobulbar affect, and may be effective in managing agitation in dementia. A review of literature found only one randomized controlled trial that evaluated the use of dextromethorphan-quinidine for the management of agitation in dementia when compared to placebo. Data from this trial demonstrated that dextromethorphan-quinidine decreased agitation in dementia, and was well tolerated. Although promising, further research is needed before dextromethorphan-quinidine combination can be accepted as a standard treatment for agitation in dementia.     

Development of a chromatographic bioreactor based on immobilized beta-glucuronidase on monolithic support for the determination of dextromethorphan and dextrorphan in human urine

We here reported the development and application of an immobilized enzyme reactor (IMER) based on β-glucuronidase to the on-line determination of urinary molar ratios of dextromethorphan (DOMe)/dextrorphan (DOH) for the assessment of the metabolic activity of CYP2D6, a genetically variable isoform of cytochrome P-450 (CYP).

β-Glucuronidase was immobilized on an HPLC monolithic aminopropyl silica support. Catalytic activity and stability of the chromatographic reactor were evaluated using 8-hydroxyquinoline glucuronide (8-HQG) as substrate. The IMER was coupled through a switching valve to a reversed-phase column (C8) for the simultaneous determination of dextromethorphan and its main metabolite dextrorphan. On purpose a selective reversed-phase ion pair HPLC method coupled with fluorescence detection was developed. Urine samples were first centrifuged to remove insoluble materials and then aliquots of the supernatants were injected into the coupled-column analyser.

Linearity, precision and accuracy of the method were established. The method reliability was verified by comparing our data with previous data of a phenotyping study carried out by the Poison Control Centre of Pavia-Clinical Toxicology Division.     

Differential antinociception by morphine and methadone in two sub-strains of Sprague-Dawley rats and its potentiation by dextromethorphan

The antinociceptive effect of morphine and methadone was tested in two substrains of Sprague-Dawley (SD) rats, from B&K Universal, Sweden (BK) and Molleg?rd, Denmark (DK). In both sub-strains of SD rats subcutaneous morphine or methadone produced dose-dependent antinociception on the hot plate test. However, the effect of the opioids was less in DK-SD than BK-SD rats, particularly for morphine as it failed to produce maximal antinociception even at high doses. Dextromethorphan, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, potentiated the antinociceptive effect of morphine and methadone in the DK-SD rats. The potentiation of morphine by dextromethorphan was significantly greater than its effect on methadone at equipotent doses. The results showed that there is a sub-strain difference for SD rats in the response to the antinociceptive effect of opioids, which may be due to greater NMDA receptor activity in DK-SD than in BK-SD rats. The higher efficacy of methadone may be derived from its proposed NMDA receptor blocking property and/or high intrinsic activity.     

Cytochrome P-450IID6 phenotyping in cancer patients: debrisoquin and dextromethorphan as probes

The usefulness of substituting dextromethorphan for debrisoquin as a probe for cytochrome P450IID6 deficiency was investigated in 20 male cancer patients. Each patient was studied on two occasions. An oral dose of dextromethorphan (60 mg) was administered to 13 patients and are week later an oral dose of debrisoquin (10 mg) was administered to each patient. The order was reversed for the other 7 patients. An 8-h urine sample was collected after administration of each test drug and assayed for parent drug and metabolites. Five poor metabolizers (PMs) and 15 extensive metabolizers (EMs) of debrisoquin were tested. The debrisoquin metabolic ratio (DMR), calculated as [parent drug]/[metabolite], correlated with the metabolic ratio of dextromethorphan (R ²=0.58,P=0.0001). All PMs of debrisoquin (metabolic ratio >12.0) were easily identified as being PMs of dextromethorphan (metabolic ratio >0.30). Within the EM group, there was a significant correlation between the metabolic ratios of debrisoquin and dextromethorphan (R ²=0.82, P<0.0001). There was not as clear a correlation in the PM group (R ²=0.32, P=0.32). These findings suggest that dextromethorphan can be substituted for debrisoquin in establishing the debrisoquin phenotype in a patient population with metastatic cancer.     

Drugs that antagonize limb flick behavior induced by d-lysergic acid diethylamide (LSD) in cats

In cats observed in their home cages limb flicks (LF) are a sensitive measure of the behavioral effects of LSD. LF induced by LSD (50 g/kg) were blocked by dextrorphan (0.6 mg/kg), dextromethorphan (0.6 mg/kg), and imipramine (5 mg/kg) at doses that did not produce ataxia or sleep. Levorphanol (0.6 mg/kg), a narcotic that is a congener of dextrorphan, did not block LF induced by LSD possibly because it produced an excitatory effect when given alone. Pentobarbital at low doses (2 and 4 mg/kg) increased the number of LF induced by LSD but at a high dose (8 mg/kg) decreased LF induced by LSD either by producing ataxia, so the cats tended to remain immobile, or by producing sleep. Chlorpromazine (CPZ) at three doses (2,4, and 8 mg/kg) attenuated the effects of LSD on LF, but did not block LF as completely as the above three blocking drugs, and produced ataxia and sleep.     

右美沙芬对小鼠大脑5-羟色胺含量的影响

目的 初步探讨右美沙芬通过增加小鼠脑部5-羟色胺(5-HT)的含量的镇咳机制. 方法 采用反相高效液相 荧光检测(RP-HPLC-FLD)法,以磷酸可待因为对照药,测定右美沙芬对小鼠脑部5种单胺类神经递质含量的影响. 结果右美沙芬的镇咳机制与单胺类神经递质5-HT有关,右美沙芬组的5-HT含量比空白组增加了43.50%,差异有统计学意义(P <0.01),5-羟基吲哚乙酸(5-HIAA)含量比空白组增加35.00%,差异有统计学意义(P<0.05). 结论 右美沙芬镇咳作用与小鼠脑部5-HT的释放有关.