Multi-faceted Anti-obesity Effects of N-Methyl-D-Aspartate (NMDA) Receptor Modulators: Central-Peripheral Crosstalk.

Hypothalamus is central to food intake and satiety. Recent data unveiled the expression of N-methyl-D-aspartate receptors (NMDAR) on hypothalamic neurons and their interaction with GABAA and serotoninergic neuronal circuits. However, the precise mechanisms governing energy homeostasis remain elusive. Notably, in females, the consumption of progesterone-containing preparations, such as hormonal replacement therapy and birth control pills, has been associated with hyperphagia and obesity-effects mediated through the hypothalamus. To elucidate this phenomenon, we employed the progesterone-induced obesity model in female Swiss albino mice. Four NMDAR modulators were selected viz. dextromethorphan (Dxt), minocycline, d-aspartate, and cycloserine. Obesity was induced in female mice by progesterone administration for 4 weeks. Mice were allocated into 7 groups, group-1 as vehicle control (arachis oil), group-2 (progesterone + arachis oil), and group-3 as positive-control (progesterone + sibutramine); other groups were treated with test drugs + progesterone. Various parameters were recorded like food intake, thermogenesis, serum lipids, insulin, AST and ALT levels, organ-to-body weight ratio, total body fat, adiposity index, brain serotonin levels, histology of liver, kidney, and sizing of fat cells. Dxt-treated group has shown a significant downturn in body weight (p < 0.05) by a decline in food intake (p < 0.01), organ-to-liver ratio (p < 0.001), adiposity index (p < 0.01), and a rise in body temperature and brain serotonin level (p < 0.001). Dxt demonstrated anti-obesity effects by multiple mechanisms including interaction with hypothalamic GABAA channels and anti-inflammatory and free radical scavenging effects, improving the brain serotonin levels, and increasing insulin release from the pancreatic ß-cells.

Double-Blind Comparison of the Two Hallucinogens Dextromethorphan and Psilocybin: Experience-Dependent and Enduring Psychological Effects in Healthy Volunteers.

Rationale: N-methyl-D-aspartate receptor-mediated dissociatives and serotonergic hallucinogens are being increasingly used in therapeutic interventions that involve nonordinary states of consciousness and may represent a unique mental health paradigm wherein pharmacologically induced experiences are conducive to psychological well-being. Objective: The aim of this study was to further understand how the phenomenological and health-promoting effects of high-dose dextromethorphan (DXM) compared to psilocybin in the same participants when administered under experimental conditions that are typical of therapeutic psychedelic trials. Methods: Single, acute oral doses of DXM (400 mg/70 kg), psilocybin (10, 20, 30 mg/70 kg), and inactive placebo were administered under double-blind and psychologically supportive conditions to 20 healthy participants with histories of hallucinogen use. Ratings of personal meaning, spiritual significance, psychological challenge, and psychological insight attributed to acute drug experiences were assessed 7 h (at session end) and 1 week after each drug administration. Persisting psychological effects were assessed 1 week after each drug administration. Results: High-dose DXM and psilocybin produced similar increases over placebo in ratings of drug experience that was predictive of psychological benefit at 1 week, even when expectancy effects were minimized. These effects tended to favor psilocybin in a dose-dependent manner and were limited by poor physical tolerability for DXM. Conclusions: This analysis suggests the utility of exploring clinical applications of dissociatives that occur within the supportive contexts that are characteristic of psychedelic research and that prioritize the optimization of psychologically valuable drug experiences. This study was registered with ClinicalTrials.gov (NCT02033707).

Impact of Pregnancy and Vitamin A Supplementation on CYP2D6 Activity.

The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated in humans. This study assessed the changes in CYP2D6 and CYP3A activities during pregnancy and postpartum, and the effect of vitamin A administration on CYP2D6 activity. Forty-seven pregnant CYP2D6 extensive metabolizers (with CYP2D6 activity scores of 1 to 2) received dextromethorphan (DM) 30 mg orally as a single dose during 3 study windows (at 25 to 28 weeks of gestation, study day 1; at 28 to 32 weeks of gestation, study day 2; and at ≥3 months postpartum, study day 3). Participants were randomly assigned to groups with no supplemental vitamin A (control) or with supplemental vitamin A (10 000 IU/day orally for 3 to 4 weeks) after study day 1. Concentrations of DM and its metabolites, dextrorphan (DX) and 3-hydroxymorphinan (3HM), were determined from a 2-hour post-dose plasma sample and cumulative 4-hour urine sample using liquid chromatography-mass spectrometry. Change in CYP2D6 activity was assessed using DX/DM plasma and urine metabolic ratios. The activity change in CYP3A was also assessed using the 3HM/DM urine metabolic ratio. The DX/DM urine ratio was significantly higher (43%) in pregnancy compared with postpartum (P = .03), indicating increased CYP2D6 activity. The DX/DM plasma ratio was substantially higher in the participants, with an activity score of 1.0 during pregnancy (P = .04) compared with postpartum. The 3HM/DM urinary ratio was significantly higher (92%) during pregnancy, reflecting increased CYP3A activity (P = .02). Vitamin A supplementation did not change CYP2D6 activity during pregnancy; however, plasma all-trans retinoic acid (atRA) concentrations were positively correlated with increased CYP2D6 activity during pregnancy and postpartum. Further research is needed to elucidate the mechanisms of increased CYP2D6 activity during pregnancy.

[Acute and chronic cough-What is new?] / Akuter und chronischer Husten ­ gibt es etwas Neues?

The most frequent cause of acute cough (lasting up to 3 weeks) or subacute cough (3-8 weeks) is a viral infection, which is mostly a self-limiting disease in otherwise healthy persons. Some herbal compounds, the antitussive dextromethorphan and ambroxol are effective for symptom relief. Antibiotics are ineffective and should not be used due to resistance development. If after appropriate diagnostic procedures the cause of chronic cough, i.e. cough lasting more than 8 weeks, cannot be attributed to a well-established respiratory disease, it meets the definition of a disease in its own right, chronic idiopathic (unexplained) cough (CIH). This is caused by hypersensitivity of the cough reflex. Thus, even weak low threshold stimuli, e.g. changing temperature, extensive speaking and odors can trigger the cough reflex. In the case of nonresponse to guideline-conform treatment the definition of chronic refractory cough is met.

Uso de coadyuvantes en dolor postoperatorio / Use of adjuvants in postoperative pain

Resumen: Los analgésicos coadyuvantes son compuestos que tienen una baja potencia analgésica. Sin embargo, la sinergia con opioides incrementa su efecto y favorece una reducción en los eventos adversos de los narcóticos para el control del dolor postoperatorio. Las estrategias ahorradoras de opioides están relacionadas con el efecto de una variedad de receptores, de los cuales podemos nombrar: los antagonistas NMDA como la ketamina, magnesio y dextrometorfano, los agonistas α-2 como la clonidina y la dexmedetomidina, los inhibidores de la subunidad α-2δ de los canales de calcio como la pregabalina y la gabapentina, los bloqueadores de los canales de sodio como la lidocaína y, finalmente, los glucocorticoides. En esta revisión se describirán las características, indicaciones, dosis y niveles de evidencia del uso de los coadyuvantes de uso intravenoso y regional en el contexto perioperatorio. (visite http://www.painoutmexico.com para ver artículo completo y Tablas).

Abstract: The adjuvant analgesics are compounds that have a low analgesic potency. However, with these compounds, the adverse effects of opioids may be diminished for the control of postoperative pain. Opioid-sparing strategies are related to the effect on a variety of receptors, of which we should name: the NMDA antagonists such as ketamine, magnesium and dextromethorphan, the α-2 agonists such as clonidine and dexmedetomidine, subunit α-2δ of calcium channels inhibitors; such as pregabalin and gabapentin, sodium channels blockers such as lidocaine and finally glucocorticoids. In this review we describe the characteristics, indications, doses and levels of evidence of use of adjuvants in the perioperative context (visit http://www.painoutmexico.com to see the full article and Tables).

Identification of Primary Natural Killer Cell Modulators by Chemical Library Screening with a Luciferase-Based Functional Assay.

Natural killer (NK) cells are essential players of the innate immune response that secrete cytolytic factors and cytokines such as IFN-γ when contacting virus-infected or tumor cells. They represent prime targets in immunotherapy as defects in NK cell functions are hallmarks of many pathological conditions, such as cancer and chronic infections. The functional screening of chemical libraries or biologics would greatly help identify new modulators of NK cell activity, but commonly used methods such as flow cytometry are not easily scalable to high-throughput settings. Here we describe an efficient assay to measure the natural cytotoxicity of primary NK cells where the bioluminescent enzyme NanoLuc is constitutively expressed in the cytoplasm of target cells and is released in co-culture supernatants when lysis occurs. We fully characterized this assay using either purified NK cells or total peripheral blood mononuclear cells (PBMCs), including some patient samples, as effector cells. A pilot screen was also performed on a library of 782 metabolites, xenobiotics, and common drugs, which identified dextrometorphan and diphenhydramine as novel NK cell inhibitors. Finally, this assay was further improved by developing a dual-reporter cell line to simultaneously measure NK cell cytotoxicity and IFN-γ secretion in a single well, extending the potential of this system.

PKCδ Knockout Mice Are Protected from Dextromethorphan-Induced Serotonergic Behaviors in Mice: Involvements of Downregulation of 5-HT1A Receptor and Upregulation of Nrf2-Dependent GSH Synthesis.

We investigated whether a specific serotonin (5-HT) receptor-mediated mechanism was involved in dextromethorphan (DM)-induced serotonergic behaviors. We firstly observed that the activation of 5-HT1A receptor, but not 5-HT2A receptor, contributed to DM-induced serotonergic behaviors in mice. We aimed to determine whether the upregulation of 5-HT1A receptor induced by DM facilitates the specific induction of certain PKC isoform, because previous reports suggested that 5-HT1A receptor activates protein kinase C (PKC). A high dose of DM (80 mg/kg, i.p.) induced a selective induction of PKCδ out of PKCα, PKCßI, PKCßII, PKCξ, and PKCδ in the hypothalamus of wild-type (WT) mice. More importantly, 5-HT1A receptor co-immunoprecipitated PKCδ in the presence of DM. Consistently, rottlerin, a pharmacological inhibitor of PKCδ, or PKCδ knockout significantly protected against increases in 5-HT1A receptor gene expression, 5-HT turnover rate, and serotonergic behaviors induced by DM. Treatment with DM resulted in an initial increase in nuclear factor erythroid-2-related factor 2 (Nrf2) nuclear translocation and DNA-binding activity, γ-glutamylcysteine (GCL) mRNA expression, and glutathione (GSH) level. This compensative induction was further potentiated by rottlerin or PKCδ knockout. However, GCL mRNA and GSH/GSSG levels were decreased 6 and 12 h post-DM. These decreases were attenuated by PKCδ inhibition. Our results suggest that interaction between 5-HT1A receptor and PKCδ is critical for inducing DM-induced serotonergic behaviors and that inhibition of PKCδ attenuates the serotonergic behaviors via downregulation of 5-HT1A receptor and upregulation of Nrf2-dependent GSH synthesis.

Protective effect of Lycium Barbarum polysaccharides on dextromethorphan-induced mood impairment and neurogenesis suppression.

Dextromethorphan (DXM) is one of the common drugs abused by adolescents. It is the active ingredient found in cough medicine which is used for suppressing cough. High dosage of DXM can induce euphoria, dissociative effects and even hallucinations. Chronic use of DXM may also lead to depressive-related symptoms. Lycium barbarum, commonly known as wolfberry, has been used as a traditional Chinese medicine for the treatment of ageing-related neurodegenerative diseases. A recent study has shown the potential beneficial effect of Lycium barbarum to reduce depression-like behavior. In the present study, we investigated the role of Lycium barbarum polysaccharide (LBP) to alleviate DXM-induced emotional distress. Sprague Dawley rats were divided into 4 groups (n=6 per group), including the normal control (vehicles only), DXM-treated group (40 mg/kg DXM), LBP-treated group (1 mg/kg LBP) and DXM+ LBP-treated group (40 mg/kg DXM and 1 mg/kg LBP). After two-week treatment, the DXM-treated group showed increased depression-like and social anxiety-like behaviors in the forced swim test and social interaction test respectively. On the other hand, the adverse behavioral effects induced by DXM were reduced by LBP treatment. Histological results showed that LBP treatment alone did not promote hippocampal neurogenesis when compared to the normal control, but LBP could lessen the suppression of hippocampal neurogenesis induced by DXM. The findings provide insights for the potential use of wolfberry as an adjunct treatment option for alleviating mood disturbances during rehabilitation of cough syrup abusers.

Antipyretic effects of Paracetamol Tablets, Compound Paracetamol and Amantadine Hydrochloride Tablets, Compound Dextromethorphan Hydrobromide Tablets, and Chaiqin Qingning capsules on rat model with LPS and dry yeast induced fever / 药物评价研究

Objective To study the antipyretic effect of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules on the fever model induced by LPS and dry yeast in rats.Methods Fever was induced by ip injecting LPS (100 μg/kg) or sc injecting dry yeast (20％) in rats.We observed the changes of temperature of the rats after administration of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets (the acetaminophen contents were 205.67,102.83,and 51.42 mg/kg)and Chaiqin Qingning Capsules (1110.60,555.30,and 277.65 mg/kg).Maximum temperature rise height (△T) and temperature response index (TRI) were calculated,and the curve of average rise in temperature was drawn.Results Each dose group of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules had obvious antipyretic effect on the fever model induced by LPS and dry yeast in rats,and there was a certain dose-effect relationship.Conclusion Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules has certain antipyretic effect on LPS and dry yeast fever model in rats,and on the whole,the Western medicine acts rapid but continue for a short time,while the traditional Chinese medicine acts slow but continues for a long time.

Use of Compounded Dextromethorphan-Quinidine Suspension for Pseudobulbar Affect in Hospice Patients.

BACKGROUND: Pseudobulbar affect (PBA) consists of unprovoked and uncontrollable episodes of laughing and/or crying. In end-of-life situations, PBA symptoms can be especially distressing to family and friends during an already heightened emotional time. Although a commercial product combining dextromethorphan and quinidine (DMQ) is FDA approved for use in PBA, many hospice patients are unable to swallow any solids or semisolids. An alternative formulation for these patients is needed. OBJECTIVE: We present here two cases in which we used a compounded DMQ suspension successfully to treat PBA symptoms in the weeks before the patients' death. DESIGN: A retrospective chart review was completed on the two cases where the DMQ suspension was used. A description of the DMQ suspension formula is described. SETTING/SUBJECTS: Both patients were under the care of a hospice program; one in home care and one in a skilled nursing facility. MEASUREMENTS: Episodes of PBA symptoms were summarized in a narrative of the patients' symptom relief. RESULTS: Both patients tolerated the administration of the DMQ suspension and there were noted improvements in PBA symptoms. CONCLUSIONS: DMQ suspension is an effective alternative for PBA symptoms in patients who cannot swallow oral solid medication.

Mechanisms of Nicotinic Modulation of Glutamatergic Neuroplasticity in Humans.

The impact of nicotine (NIC) on plasticity is thought to be primarily determined via calcium channel properties of nicotinic receptor subtypes, and glutamatergic plasticity is likewise calcium-dependent. Therefore glutamatergic plasticity is likely modulated by the impact of nicotinic receptor-dependent neuronal calcium influx. We tested this hypothesis for transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity, which is abolished by NIC in nonsmokers. To reduce calcium influx under NIC, we blocked N-methyl-d-aspartate (NMDA) receptors. We applied anodal tDCS combined with 15 mg NIC patches and the NMDA-receptor antagonist dextromethorphan (DMO) in 3 different doses (50, 100, and 150 mg) or placebo medication. Corticospinal excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor-evoked potential amplitudes after plasticity induction. NIC abolished anodal tDCS-induced motor cortex excitability enhancement, which was restituted under medium dosage of DMO. Low-dosage DMO did not affect the impact of NIC on tDCS-induced plasticity and high-dosage DMO abolished plasticity. For DMO alone, the low dosage had no effect, but medium and high dosages abolished tDCS-induced plasticity. These results enhance our knowledge about the proposed calcium-dependent impact of NIC on plasticity in humans and might be relevant for the development of novel nicotinic treatments for cognitive dysfunction.

Effects of the Chinese herbal formula "Zuojin Pill" on the pharmacokinetics of dextromethorphan in healthy Chinese volunteers with CYP2D6*10 genotype.

OBJECTIVE: Zuojin Pill has been shown to inhibit the cytochrome P450 (CYP) 2D6 isoenzyme in vitro. In Chinese individuals, CYP 2D6*10 is the most common allele with reduced enzyme activity. In this study, we investigated the pharmacokinetic interaction between Zuojin Pill and the sensitive CYP2D6 probe dextromethorphan in healthy Chinese volunteers with CYP2D6*10 genotype. METHODS: A pharmacokinetics interaction study was carried out in three groups with CYP2D6*1/*1 (n = 6), CYP2D6*1/*10 (n = 6), and CYP2D6*10/*10 (n = 6) genotypes. Each participant received a single oral dose of dextromethorphan (15 mg) followed by Zuojin Pill (3 g twice daily) for 7 days, and received 3 g Zuojin Pill with 15 mg dextromethorphan in the last day. Blood samples (0-24 h) and urine samples (0-12 h) were collected at baseline and after the administration of Zuojin Pill, and the samples' concentration of dextromethorphan and its main metabolite dextrorphan was determined. RESULTS: Compared to baseline values, co-administration of Zuojin Pill (3 g twice daily) for 7 days increased the AUC0-24 of dextromethorphan [mean (90 % CI)] by 3.00-fold (2.49∼3.61) and 1.71-fold (1.42∼2.06), and decreased oral clearance(CL/F) by 0.27-fold (0.2-0.40) and 0.57-fold (0.48-0.67) in the participants with CYP2D6*1/*1 and CYP2D6*1/*10 genotypes, respectively. In contrast, no significant change was observed in these pharmacokinetic parameters of the participants with CYP2D6*10/*10 genotype. CONCLUSION: These data demonstrated that administration of Zuojin Pill inhibited moderately CYP2D6-mediated metabolism of dextromethorphan in healthy volunteers. The inhibitory influence of CYP2D6 was greater in CYP2D6*1/*1 and CYP2D6*1/*10 groups than CYP2D6 *10/*10 group.

Honey for acute cough in children.

BACKGROUND: Cough causes concern for parents and is a major cause of outpatient visits. It can impact on quality of life, cause anxiety and affect sleep in parents and children. Several remedies, including honey, have been used to alleviate cough symptoms. OBJECTIVES: To evaluate the effectiveness of honey for acute cough in children in ambulatory settings. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2011) which contains the Cochrane Acute Respiratory Infections Group's Specialised Register; MEDLINE (1950 to December week 4, 2011); EMBASE (1990 to January 2012); CINAHL (1981 to January 2012); Web of Science (2000 to January 2012); AMED (1985 to January 2012); LILACS (1982 to January 2012); and CAB abstracts (2009 to January 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing honey given alone, or in combination with antibiotics, versus nothing, placebo or other over-the-counter (OTC) cough medications to participants aged from two to 18 years for acute cough in ambulatory settings. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results for eligible studies and extracted data on reported outcomes. MAIN RESULTS: We included two RCTs of high risk of bias involving 265 children. The studies compared the effect of honey with dextromethorphan, diphenhydramine and 'no treatment' on symptomatic relief of cough using the 7-point Likert scale. Honey was better than 'no treatment' in reducing frequency of cough (mean difference (MD) -1.07; 95% confidence interval (CI) -1.53 to -0.60; two studies; 154 participants). Moderate quality evidence suggests honey did not differ significantly from dextromethorphan in reducing cough frequency (MD -0.07; 95% CI -1.07 to 0.94; two studies; 149 participants). Low quality evidence suggests honey may be slightly better than diphenhydramine in reducing cough frequency (MD -0.57; 95% CI -0.90 to -0.24; one study; 80 participants). Adverse events included mild reactions (nervousness, insomnia and hyperactivity) experienced by seven children (9.3%) from the honey group and two (2.7%) from the dextromethorphan group; the difference was not significant (risk ratio (RR) 2.94; 95% Cl 0.74 to 11.71; two studies; 149 participants). Three children (7.5%) in the diphenhydramine group experienced somnolence (RR 0.14; 95% Cl 0.01 to 2.68; one study; 80 participants) but there was no significant difference between honey versus dextromethorphan or honey versus diphenhydramine. No adverse event was reported in the 'no treatment' group. AUTHORS' CONCLUSIONS: Honey may be better than 'no treatment' and diphenhydramine in the symptomatic relief of cough but not better than dextromethorphan. There is no strong evidence for or against the use of honey.

An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions.

BACKGROUND: Pseudobulbar affect (PBA) is associated with neurological disorders or injury affecting the brain, and characterized by frequent, uncontrollable episodes of crying and/or laughing that are exaggerated or unrelated to the patient's emotional state. Clinical trials establishing dextromethorphan and quinidine (DM/Q) as PBA treatment were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This trial evaluated DM/Q safety in patients with PBA secondary to any neurological condition affecting the brain. OBJECTIVE: To evaluate the safety and tolerability of DM/Q during long-term administration to patients with PBA associated with multiple neurological conditions. METHODS: Fifty-two-week open-label study of DM/Q 30/30 mg twice daily. Safety measures included adverse events (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. CLINICAL TRIAL REGISTRATION: #NCT00056524. RESULTS: A total of 553 PBA patients with >30 different neurological conditions enrolled; 296 (53.5%) completed. The most frequently reported treatment-related AEs (TRAEs) were nausea (11.8%), dizziness (10.5%), headache (9.9%), somnolence (7.2%), fatigue (7.1%), diarrhea (6.5%), and dry mouth (5.1%). TRAEs were mostly mild/moderate, generally transient, and consistent with previous controlled trials. Serious AEs (SAEs) were reported in 126 patients (22.8%), including 47 deaths, mostly due to ALS progression and respiratory failure. No SAEs were deemed related to DM/Q treatment by investigators. ECG results suggested no clinically meaningful effect of DM/Q on myocardial repolarization. Differences in AEs across neurological disease groups appeared consistent with the known morbidity of the primary neurological conditions. Study interpretation is limited by the small size of some disease groups, the lack of a specific efficacy measure and the use of a DM/Q dose higher than the eventually approved dose. CONCLUSIONS: DM/Q was generally well tolerated over this 52 week trial in patients with PBA associated with a wide range of neurological conditions.

A randomized placebo controlled trial to evaluate the effects of butamirate and dextromethorphan on capsaicin induced cough in healthy volunteers.

AIMS: The examination of cough reflex sensitivity through inhalational challenge can be utilized to demonstrate pharmacological end points. Here we compare the effect of butamirate, dextromethorphan and placebo on capsaicin-induced cough in healthy volunteers. METHODS: In this randomized, placebo-controlled, six way crossover study the effect of dextromethrophan 30 mg, four doses of butamirate and placebo was evaluated on incremental capsaicin challenges performed at baseline and 2, 4, 6, 8, 12 and 24 h following dosing. The primary end point was the area under the curve (AUC(0,12h)) of log10 C5 from pre-dose to 12 h after dosing. Plasma butamirate metabolites were analyzed to evaluate pharmacokinetic and pharmacodynamic relationships. RESULTS: Thirty-four subjects (13 males, median age 25 years) completed the study. Cough sensitivity decreased from baseline in all arms of the study. Dextromethorphan was superior to placebo (P = 0.01) but butamirate failed to show significant activity with maximum attenuation at the 45 mg dose. There was no apparent relationship between pharmacokinetic and pharmacodynamic parameters for butamirate. CONCLUSIONS: We have demonstrated for the first time that dextromethorphan attenuates capsaicin challenge confirming its broad activity on the cough reflex. The lack of efficacy of butamirate could be due to formulation issues at higher doses.

Dextromethorphan/quinidine for the treatment of pseudobulbar affect.

OBJECTIVE: To evaluate the role of dextromethorphan/quinidine (DM/Q; Nuedexta™) in the treatment of pseudobulbar affect (PBA). DATA SOURCES: A literature search of MEDLINE/PubMed (January 1966-June 2013) was conducted using search terms pseudobulbar affect, pathological laughing and/or crying, emotional lability, dextromethorphan, and quinidine. STUDY SELECTION AND DATA EXTRACTION: English language clinical trials and case reports evaluating the safety and efficacy of DM/Q in PBA were included for review. Bibliographies of all relevant articles were reviewed for additional citations. DATA SYNTHESIS: PBA, a poorly understood disorder, is characterized by involuntary crying and/or laughing. In the past, antidepressants and antiepileptics have been used off-label with mixed results. Four clinical trials have evaluated the use of DM/Q for the treatment of PBA. Although the therapeutic outcomes with DM/Q have been positive, interpretation of the published evidence is limited by small sample size and short treatment duration. CONCLUSIONS: Based on the data available, DM/Q may be a viable, short-term treatment alternative for PBA. Long-term safety and efficacy data are lacking.

Effects of hydroxysafflor yellow A on the activity and mRNA expression of four CYP isozymes in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional therapy with Chinese medicine, hydroxysafflor yellow A (HSYA), a main active component isolated from the dried flower of Carthamus tinctorius L., is the principal efficiency ingredient of Safflor Yellow Injection. Now HSYA has been demonstrated to have good pharmacological activities of antioxidation, myocardial and cerebral protective and neuroprotective effects. The purpose of this study was to find out whether HSYA influences the effect on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C11, CYP2D4 and CYP3A1) by using cocktail probe drugs in vivo; the influence on the levels of CYP mRNA was also studied. MATERIALS AND METHODS: A cocktail solution at a dose of 5 mL/kg, which contained phenacetin (20 mg/kg), tolbutamide (5 mg/kg), dextromethorphan (20 mg/kg) and midazolam (10 mg/kg), was given as oral administration to rats treated with short or long period of intravenous HSYA via the caudal vein. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0. In addition, real-time RT-PCR was performed to determine the effect of HSYA on the mRNA expression of CYP1A2, CYP2C11, CYP2D4 and CYP3A1 in rat liver. RESULTS: HSYA had significant inhibition effects on CYP1A2 and CYP2C11 in rats as oriented from the pharmacokinetic profiles of the probe drugs. Furthermore, HSYA had no effects on rat CYP2D4. However, CYP3A1 enzyme activity was induced by HSYA. The mRNA expression results were in accordance with the pharmacokinetic results. CONCLUSIONS: HSYA can either inhibit or induce activities of CYP1A2, CYP2C11 and CYP3A1. Therefore, co-administration of some CYP substrates with HSYA may need dose adjustment to avoid an undesirable herb-drug interaction.

Effects of Preincisional Infiltration with Bupivacaine and Oral Dextromethorphan on Postoperative Pain in Uvulopalatopharyngoplasty / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Uvulopalatopharyngoplasty is one of the most painful surgical procedures in otolaryngology. Repetitive nociceptive impulses from injured peripheral tissues and activation of N-methyl-D-aspartic acid (NMDA) receptors induce central sensitization and post-injury pain hypersensitivity states. We aimed this study to evaluate whether bupivacaine for preincisional block of nociceptive afferent inputs and dextromethorphan, a clinically available NMDA receptor antagonist could reduce postoperative pain after uvulopalatopharyngoplasty. MATERIALS AND METHOD: Thirty patients scheduled for uvulopalatopharyngoplasty were randomly assigned to one of the three groups : control, bupivacaine, and bupivacaine- dextromethorphan groups. The second and third group had 10 ml of 0.25% bupivacaine hydrochloride infiltrated around tonsils and soft palate before incision. The third group was given oral doses of dextromethorphan before and after surgery. Pain was assessed using numeric rating scale at rest and on swallowing on postoperative day 0, 1, 2, 3, and 5. Daily consumption of supplementary diclofenac sodium was also recorded. RESULTS: Resting pain scores were significantly lower in the groups treated with bupivacaine infiltration with or without dextromethorphan on postoperative days 0, 1, 2, 3, and 5. Swallowing pain scores were significantly lower in the bupivacaine-dextromethorphan group on days 0, 1, and 2. CONCLUSION: Preincisional infiltration with bupivacaine and oral dextromethorphan could decrease the intensity of postoperative pain following uvulupalatopharyngoplasty.

Effects of Peritonsillar Infiltration with Bupivacaine and Oral Dextromethorphan on Post-Tonsillectomy Pain / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Peripheral tissue or nerve injury often leads to post-injury pain hypersensitivity caused by peripheral and central sensitization. Central sensitization which plays a significant role is triggered by nociceptive afferent inputs and mainly results from N-methyl-D-aspartic acid (NMDA) receptor activation. If the afferent impulses are prevented from gaining access to the CNS or if NMDA receptor is blocked by antagonist, central sensitization will not develop and then less pain will result. Previous studies demonstrated that preoperative infiltration of local anesthetics or oral NMDA receptor antagonist could alleviate postoperative pain. We investigated the effects of peritonsillar infiltration with bupivacaine and oral dextromethorphan on post-tonsillectomy pain. MATERIALS AND METHODS: Forty consecutive patients were randomly allocated to one of four groups. Group I was bupivacaine-treated group, and group II was dextromethorphan-treated group. Group III was both bupivacaine and dextromethorphan-treated group, and group IV was control group. Pain scores were assessed using self-rating numeric rating scale ( NRS) at rest and on swallowing during the postoperative day 0, 1, 2, and 7. Doses of supplementary diclofenac administered postoperatively were also recorded. RESULTS: Group I, II, and III showed significantly lower NRS pain scores compared with control group at rest and on swallowing throughout the postoperative 7 days. Diclofenac doses were not statistically different among the four groups. CONCLUSION: Preoperative peritonsillar infiltration with bupivacaine and/or medication with dextromethorphan contributed to decrease the intensity of postoperative pain after tonsillectomy.