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American Journal of Neurodegenerative... 2016Anxiety is common in the Mild Cognitive Impairment (MCI) stage of Alzheimer's disease (AD) and the pre-motor stages of Parkinson's disease (PD). A concomitant and... (Review)
Review
Anxiety is common in the Mild Cognitive Impairment (MCI) stage of Alzheimer's disease (AD) and the pre-motor stages of Parkinson's disease (PD). A concomitant and possible cause of this anxiety is microglial activation, also considered a key promoter of neurodegeneration in MCI and early PD via inflammatory mechanisms and the generation of degenerative proinflammatory cytokines. Psychiatric disorders, prevalent in AD and PD, are often treated with psychiatric drugs (psychotropics), raising the question of whether psychotropics might therapeutically affect microglial activation, MCI, and PD. The literature of common psychotropics used in treating psychiatric disorders was reviewed for preclinical and clinical findings regarding microglial activation. Findings potentially compatible with reduced microglial activation or reduced microglial inflammogen release were evident for: antipsychotics including neuroleptics (chlorpromazine, thioridazine, loxapine) and atypicals (aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone); mood stabilizers (carbamazepine, valproate, lithium); antidepressants including tricyclics (amitriptyline, clomipramine, imipramine, nortriptyline), SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), venlafaxine, and bupropion; benzodiazepine anxiolytics (clonazepam, diazepam); cognitive enhancers (donepezil, galantamine, memantine); and other drugs (dextromethorphan, quinidine, amantadine). In contrast, pramipexole and methylphenidate might promote microglial activation. The most promising replicated findings of reduced microglial activation are for quetiapine, valproate, lithium, fluoxetine, donepezil, and memantine but further study is needed and translation of their microglial effects to human disease still requires investigation. In AD-relevant models, risperidone, valproate, lithium, fluoxetine, bupropion, donepezil, and memantine have therapeutic microglial effects in need of replication. Limited clinical data suggest some support for lithium and donepezil in reducing MCI progression, but other drugs have not been studied. In PD-relevant models, lamotrigine, valproate, fluoxetine, dextromethorphan, and amantadine have therapeutic microglial effects whereas methylphenidate induced microglial activation and pramipexole promoted NO release. Clinical data limited to pramipexole do not as of yet indicate faster progression of early PD while the other drugs remain to be investigated. These tantalizing psychotropic neuroprotective findings now invite replication and evidence in AD-and PD-specific models under chronic administration, followed by consideration for clinical trials in MCI and early stage PD. Psychiatric features in early disease may provide opportunities for clinical studies that also employ microglial PET biomarkers.
PubMed: 27073741
DOI: No ID Found -
Molecules (Basel, Switzerland) Oct 2022Common methodologies such as liquid-liquid extraction and solid-phase extraction are applied for the extraction of opioids from biological specimens i.e., blood and...
Common methodologies such as liquid-liquid extraction and solid-phase extraction are applied for the extraction of opioids from biological specimens i.e., blood and urine. Techniques including LC-MS/LC-MSMS, GC-MS, etc. are used for qualitative or quantitative determination of opioids. The goal of the present work is to design a green, economic, rugged, and simple extraction technique for famous opioids in human blood and urine and their simultaneous quantification by GC-MS equipped with an inert plus electron impact (EI) ionization source at SIM mode to produce reproducible and efficient results. Morphine, codeine, 6-acetylmorphine, nalbuphine, tramadol and dextromethorphan were selected as target opioids. Anhydrous Epsom salt was applied for dSPE of opioids from blood and urine into acetonitrile extraction solvent with the addition of sodium phosphate buffer (pH 6) and n-hexane was added to remove non-polar interfering species from samples. BSTFA was used as a derivatizing agent for GC-MS. Following method validation, the LOD/LLOQ and ULOQ were determined for morphine, codeine, nal-buphine, tramadol, and dextromethorphan at 10 ng/mL and 1500 ng/mL, respectively, while the LOD/LLOQ and ULOQ were determined for 6-acetylmorphine at 5 ng/mL and 150 ng/mL, respectively. This method was applied to real blood and urine samples of opioid abusers and the results were found to be reproducible with true quantification.
Topics: Acetonitriles; Analgesics, Opioid; Codeine; Dextromethorphan; Gas Chromatography-Mass Spectrometry; Humans; Morphine; Morphine Derivatives; Nalbuphine; Solid Phase Extraction; Solvents; Substance Abuse Detection; Tramadol
PubMed: 36235294
DOI: 10.3390/molecules27196761 -
Journal of Clinical Pharmacology Mar 2023The 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... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Female; Humans; Pregnancy; Cytochrome P-450 CYP2D6; Vitamin A; Cytochrome P-450 CYP3A; Phenotype; Dextromethorphan; Dietary Supplements
PubMed: 36309846
DOI: 10.1002/jcph.2169 -
International Journal of Molecular... Mar 2018Osteoarthritis (OA) is the most common joint disorder and primarily affects older people. The ideal anti-OA drug should have a modest anti-inflammatory effect and only...
Osteoarthritis (OA) is the most common joint disorder and primarily affects older people. The ideal anti-OA drug should have a modest anti-inflammatory effect and only limited or no toxicity for long-term use. Because the antitussive medication dextromethorphan (DXM) is protective in atherosclerosis and neurological diseases, two common disorders in aged people, we examined whether DXM can be protective in pro-inflammatory cytokine-stimulated chondrocytes and in a collagen-induced arthritis (CIA) animal model in this study. Chondrocytes were prepared from cartilage specimens taken from pigs or OA patients. Western blotting, quantitative PCR, and immunohistochemistry were adopted to measure the expression of collagen II (Col II) and matrix metalloproteinases (MMP). DXM significantly restored tumor necrosis factor-alpha (TNF-α)-mediated reduction of collagen II and decreased TNF-α-induced MMP-13 production. To inhibit the synthesis of MMP-13, DXM blocked TNF-α downstream signaling, including I kappa B kinase (IKK)α/β-IκBα-nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)-activator protein-1 (AP-1) activation. Besides this, DXM protected the CIA mice from severe inflammation and cartilage destruction. DXM seemed to protect cartilage from inflammation-mediated matrix degradation, which is an irreversible status in the disease progression of osteoarthritis. The results suggested that testing DXM as an osteoarthritis therapeutic should be a focus in further research.
Topics: Animals; Antitussive Agents; Cells, Cultured; Chondrocytes; Collagen Type II; Dextromethorphan; Humans; I-kappa B Kinase; Male; Matrix Metalloproteinases; Mice; Mice, Inbred DBA; Osteoarthritis; Swine; Transcription Factor AP-1; Tumor Necrosis Factor-alpha
PubMed: 29534535
DOI: 10.3390/ijms19030825 -
Journal of Opioid Management 2011Studies have suggested that the N-methyl-D-aspartate antagonist dextromethorphan may be useful in the treatment of opioid dependence. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Studies have suggested that the N-methyl-D-aspartate antagonist dextromethorphan may be useful in the treatment of opioid dependence.
DESIGN
This double-blinded, placebo-controlled inpatient study evaluated the effects of 0, 30, and 60 mg of dextromethorphan and quinidine (DMQ) on the reinforcing and subjective effects of heroin in recently detoxified heroin abusers.
PARTICIPANTS
Nine heroin-dependent participants were admitted and then detoxified from heroin over the course of several days.
INTERVENTIONS
Participants were subsequently stabilized on 0, 30, or 60 mg of DMQ. Each dose of DMQ was administered for two consecutive weeks, and the effects of heroin (0, 12.5, and 50 mg) were studied under each DMQ maintenance dose condition. DMQ and heroin dose were administered in random order both within and between participants.
RESULTS
Planned comparisons revealed statistically significant increases in progressive ratio breakpoint values and positive subjective ratings as a function of heroin dose. There were no consistent changes in any of the responses as a function of DMQ maintenance dose, other than a modest reduction in craving.
CONCLUSIONS
In summary, results from this study suggest that maintenance on dextromethorphan in combination with quinidine has a limited role in the treatment of opioid dependence.
Topics: Adult; Dextromethorphan; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Excitatory Amino Acid Antagonists; Heroin; Heroin Dependence; Humans; Male; Quinidine; Reinforcement, Psychology; Self Administration
PubMed: 22320027
DOI: 10.5055/jom.2011.0086 -
Research in Pharmaceutical Sciences Feb 2023Lysosomal-targeted drug delivery can open a new strategy for drug therapy. However, there is currently no universally accepted simulated or artificial lysosomal fluid...
BACKGROUND AND PURPOSE
Lysosomal-targeted drug delivery can open a new strategy for drug therapy. However, there is currently no universally accepted simulated or artificial lysosomal fluid utilized in the pharmaceutical industry or recognized by the United States Pharmacopeia (USP).
EXPERIMENTAL PROCEDURE
We prepared a simulated lysosomal fluid (SLYF) and compared its composition to a commercial artificial counterpart. The developed fluid was used to test the dissolution of a commercial product (Robitussin) of a lysosomotropic drug (dextromethorphan) and to investigate lysosomal trapping of two model drugs (dextromethorphan and (+/-) chloroquine).
FINDINGS/RESULTS
The laboratory-prepared fluid or SLYF contained the essential components for the lysosomal function in concentrations reflective of the physiological values, unlike the commercial product. Robitussin passed the acceptance criteria for the dissolution of dextromethorphan in 0.1 N HCl medium (97.7% in less than 45 min) but not in the SLYF or the phosphate buffer media (72.6% and 32.2% within 45 min, respectively). Racemic chloroquine showed higher lysosomal trapping (51.9%) in the model than dextromethorphan (28.3%) in a behavior supporting findings and based on the molecular descriptors and the lysosomal sequestration potential of both.
CONCLUSION AND IMPLICATION
A standardized lysosomal fluid was reported and developed for investigations of lysosomotropic drugs and formulations.
PubMed: 36846734
DOI: 10.4103/1735-5362.363591 -
Scandinavian Journal of Pain Oct 2018Background and aims The clinical management of neuropathic pain remains a challenge. We examined the interaction between gabapentin and NMDA receptor antagonists...
Background and aims The clinical management of neuropathic pain remains a challenge. We examined the interaction between gabapentin and NMDA receptor antagonists dextromethrophan and MK-801 in alleviating neuropathic pain-like behaviors in rats after spinal cord or sciatic nerve injury. Methods Female and male rats were produced with Ischemic spinal cord injury and sciatic nerve injury. Gabapentin, dextromethorphan, MK-801 or drug combinations were injected with increasing doses. Mechanical response thresholds were tested with von Frey hairs to graded mechanical touch/pressure, and ethyl chloride spray was applied to assess the cold sensitivity before and after injuries. Results In spinally injured rats, gabapentin and dextromethorphan did not affect allodynia-like behaviors at doses of 30 and 20 mg/kg, respectively. In contrast, combination of 15 or 30 mg/kg gabapentin with dextromethorphan at 10 mg/kg produced total alleviation of allodynia to mechanical or cold stimulation. Further reducing the dose of gapapentin to 7.5 mg/kg and dextromethorphan to 5 mg/kg still produced significant effect. MK-801, another NMDA receptor antagonist, also enhanced the effect of gabapentin in spinally injured rats. Similar synergistic anti-allodynic effect between dextromethorphan and gabapentin was also observed in a rat model of partial sciatic nerve injury. No increased side effect was seen following the combination between gabapentin and dextromethorphan. Conclusions In conclusion, the present study suggested that combining NMDA receptor antagonists with gabapentin could provide synergistic effect to alleviate neuropathic pain and reduced side effects. Implications Combining NMDA receptor antagonists with gabapentin may provide a new approach in alleviating neuropathic pain with increased efficacy and reduced side effects.
Topics: Animals; Behavior, Animal; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Gabapentin; Hyperalgesia; Male; Neuralgia; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Spinal Cord Injuries; Touch
PubMed: 29975670
DOI: 10.1515/sjpain-2018-0083 -
British Medical Journal Nov 1946
Topics: Cough; Dextromethorphan; Guaifenesin; Humans; Pharmaceutical Solutions
PubMed: 20273996
DOI: 10.1136/bmj.2.4480.735 -
Evaluation of the neuroprotective effect of dextromethorphan in the acute phase of ischaemic stroke.Archives of Medical Science : AMS Jun 2011Stroke is the second leading cause of death in the world. However, there is still no approved neuroprotective drug for acute ischaemic stroke. To clarify the...
INTRODUCTION
Stroke is the second leading cause of death in the world. However, there is still no approved neuroprotective drug for acute ischaemic stroke. To clarify the neuroprotective efficacy and safety of dextromethorphan in stroke, the following study was carried out.
MATERIAL AND METHODS
Forty patients with acute stroke causing moderate deficit were randomized to be treated with either dextromethorphan 300 mg per day or placebo for 5 days. Plasma level of dextromethorphan and its active metabolite was not evaluated in this study. The NIHSS score was calculated on day 5 and the Barthel activities of daily living index and Rankin score were checked after 3 months by a blinded investigator. Collected data were analysed using the t-test and χ(2) test.
RESULTS
In the dextromethorphan-treated group, the mean NIHSS score was 16.8 ±3.9 at baseline, and was 14.2 ±4.8 for the placebo-treated group (p = 0.069). At day 5, there was also no significant difference regarding NIHSS score (p = 0.167). At the 3-month follow-up, there was no significant difference regarding Barthel scale and Rankin score between the dextromethorphan and placebo groups.
CONCLUSIONS
The results of our study suggest that although low-dose and short-term oral administration of dextromethorphan seems to be not neuroprotective, it does not worsen either patients' condition or NIHSS score. Moreover, patients treated with dextromethorphan showed a significant reduction in seizures (complication after stroke), but had increased chance of MI and renal failure by almost 5% when compared to the placebo-treated groups. More prolonged studies with a higher number of cases are recommended.
PubMed: 22295030
DOI: 10.5114/aoms.2011.23413 -
European Journal of Clinical... May 2010To evaluate variability in cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO) activity in HIV-infected patients and...
AIMS
To evaluate variability in cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO) activity in HIV-infected patients and compare this with data from uninfected, healthy volunteers.
METHODS
Ten HIV-infected men and seven women on medication affecting CYP enzyme activity were phenotyped four times over 2 months using caffeine, dextromethorphan, and midazolam. Urinary caffeine and dextromethorphan metabolite ratios were used to phenotype CYP1A2, NAT2, XO, and CYP2D6 activity and midazolam plasma clearance was used to phenotype CYP3A activity. Plasma and urine samples were analyzed by validated LC/UV or LC/MS methods for midazolam, caffeine, and dextromethorphan. Noncompartmental pharmacokinetics and nonparametric statistical analyses were performed, and the data compared with those of healthy volunteer historic controls.
RESULTS
Compared with age and sex-matched healthy volunteers, HIV-infected subjects had 18% lower hepatic CYP3A4 activity, 90% lower CYP2D6 activity, 53% lower NAT2 activity, and 22% higher XO activity. No significant difference was found in CYP1A2 activity. Additionally, 25% genotype-phenotype discordance in CYP2D6 activity was noted in HIV-infected subjects. Intraindividual variability in enzyme activity increased by 42-62% in HIV-infected patients for CYP1A2, NAT2, and XO, and decreased by 33% for CYP2D6. Interindividual variability in enzyme activity increased by 27-63% in HIV-infected subjects for CYP2D6, CYP1A2, and XO, and decreased by 38% for NAT2. Higher plasma TNFalpha concentrations correlated with lower CYP2D6 and CYP3A4 activity.
CONCLUSIONS
Infection with HIV or stage of HIV infection may alter Phase I and II drug metabolizing enzyme activity. HIV infection was related to an increase in variability of these drug-metabolizing enzymes. Altered metabolism may be a consequence of immune activation and cytokine exposure.
Topics: Adult; Arylamine N-Acetyltransferase; Caffeine; Cytochrome P-450 Enzyme System; Dextromethorphan; Female; HIV Infections; Humans; Interleukin-6; Male; Midazolam; Phenotype; Tumor Necrosis Factor-alpha; Xanthine Oxidase
PubMed: 20084375
DOI: 10.1007/s00228-009-0777-6