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Psychological Medicine Oct 2019Accumulating evidence shows that a propensity towards a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Accumulating evidence shows that a propensity towards a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might compensate this propensity. This study provides an update regarding the efficacy of agents with some anti-inflammatory actions for schizophrenia symptoms tested in randomized controlled trials (RCTs).
METHODS
PubMed, Embase, the National Institutes of Health website (http://www.clinicaltrials.gov), and the Cochrane Database of Systematic Reviews were systematically searched for RCTs that investigated clinical outcomes.
RESULTS
Our search yielded 56 studies that provided information on the efficacy of the following components on symptom severity: aspirin, bexarotene, celecoxib, davunetide, dextromethorphan, estrogens, fatty acids, melatonin, minocycline, N-acetylcysteine (NAC), pioglitazone, piracetam, pregnenolone, statins, varenicline, and withania somnifera extract. The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06-0.54], estrogens (ES: 0.78; n = 723; CI 0.36-1.19), minocycline (ES: 0.40; n = 946; CI 0.11-0.68), and NAC (ES: 1.00; n = 442; CI 0.60-1.41) were significant in meta-analysis of at least two studies. Subgroup analysis yielded larger positive effects for first-episode psychosis (FEP) or early-phase schizophrenia studies. Bexarotene, celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline showed no significant effect.
CONCLUSIONS
Some, but not all agents with anti-inflammatory properties showed efficacy. Effective agents were aspirin, estrogens, minocycline, and NAC. We observed greater beneficial results on symptom severity in FEP or early-phase schizophrenia.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Schizophrenia
PubMed: 31439071
DOI: 10.1017/S0033291719001995 -
Pharmaceuticals (Basel, Switzerland) Oct 2023Huntington's Disease (HD) is a severely debilitating neurodegenerative disorder in which sufferers exhibit different combinations of movement disorders, dementia, and... (Review)
Review
Huntington's Disease (HD) is a severely debilitating neurodegenerative disorder in which sufferers exhibit different combinations of movement disorders, dementia, and behavioral or psychiatric abnormalities. The disorder is a result of a trinucleotide repeat expansion mutation that is inherited in an autosomal dominant manner. While there is currently no treatment to alter the course of HD, there are medications that lessen abnormal movement and psychiatric symptoms. ClinicalTrials.gov was searched to identify drugs that are currently in or have completed phase III drug trials for the treatment of HD. The described phase III trials were further limited to interventional studies that were recruiting, active not recruiting, or completed. In addition, all studies must have posted an update within the past year. PubMed was used to gather further information on these interventional studies. Of the nine clinical trials that met these criteria, eight involved the following drugs: metformin, dextromethorphan/quinidine, deutetrabenazine, valbenazine, Cellavita HD, pridopidine, SAGE-718, and RO7234292 (RG6042). Of these drug treatments, four are already FDA approved. This systematic review provides a resource that summarizes the present therapies for treating this devastating condition that are currently in phase III clinical trials in the United States.
PubMed: 38004378
DOI: 10.3390/ph16111513 -
Journal of Clinical Pharmacology Jun 2022The risk of infant exposure to dextromethorphan (DM) and its active metabolite, dextrorphan (DX), through breast milk has not been evaluated. In this study, bound and...
The risk of infant exposure to dextromethorphan (DM) and its active metabolite, dextrorphan (DX), through breast milk has not been evaluated. In this study, bound and unbound DM and DX concentrations in breast milk and plasma at 2 hours post-dose were measured in 20 lactating women (n = 20) following a single 30 mg oral dose of DM. The DM and DX concentrations in breast milk were positively correlated with their respective plasma concentrations. The breast milk-to-plasma (M/P) ratios of 1.0 and 1.6 and the unbound M/P ratios of 1.1 and 2.0 for DM and DX, respectively, suggested that DM and DX are extensively distributed into breast milk. The infant exposure following a single dose of 30 mg DM was estimated using breast milk concentrations of 0.33 ± 0.32 and 1.8 ± 1.0 μg/kg/day for DM and DX, respectively. The steady-state infant exposure was estimated using the M/P ratios and previously reported area under the concentration-time curve (AUC) of DM and DX following repeated dosing of DM 60 mg orally, twice daily, to be 0.64 ± 0.22 and 1.23 ± 0.38 μg/kg/day, respectively. Based on these estimated infant doses, the relative infant doses (RIDs) were estimated to be <1%, suggesting the infant is only exposed to a minor fraction of adult dose through breast milk; however, one nursing infant developed an erythematous rash during this study, which warrants additional research to fully elucidate the risks of infant exposure to DM and DX through breast milk.
Topics: Adult; Cytochrome P-450 CYP2D6; Dextromethorphan; Dextrorphan; Female; Humans; Lactation; Milk, Human; Mothers
PubMed: 34889461
DOI: 10.1002/jcph.2012 -
Lung Oct 2020Most medicines are white bitter powders that are formulated as tablets and capsules but cough medicines are an exception where the taste and appearance of the medicine... (Review)
Review
Most medicines are white bitter powders that are formulated as tablets and capsules but cough medicines are an exception where the taste and appearance of the medicine are more important to the patient than the pharmacology of the active ingredient. Excipients are generally defined as any ingredient in a medicine other than the active ingredient. In most medicines excipients play a supportive role in delivering the medicine, but in the case of cough medicines, excipients have more important and complex roles and they can also be the main active ingredient of the cough medicine as menthol, glycerol, and sugars, which are declared as active ingredients. This review searched the United Kingdom electronic medicines compendium (emc) and found over 100 excipients in 60 different liquid formulations of over the counter cough medicines. The excipients were divided into functional groups: sweeteners, thickeners, flavors, colors, antimicrobials, and buffers, and the incidence and function of the different excipients is discussed. When considering the efficacy of a cough medicine, clinicians and pharmacists tend to think of the pharmacology of antitussives such as dextromethorphan or expectorants such as guaifenesin, and they rarely consider the role of excipients in the efficacy of the medicine. This review discusses the functions and importance of excipients in cough medicines and provides some new information for clinicians, pharmacists, and all interested in the treatment of cough when considering the composition and efficacy of a cough medicine.
Topics: Humans; Antitussive Agents; Cough; Drug Compounding; Excipients; Nonprescription Drugs; Pharmaceutical Solutions; Treatment Outcome
PubMed: 32889596
DOI: 10.1007/s00408-020-00390-x -
Antimicrobial Agents and Chemotherapy Oct 2023Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug...
Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.
Topics: Adult; Humans; Cytochrome P-450 CYP1A2; Midazolam; Cytochrome P-450 CYP2D6; Caffeine; Rifampin; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Dextromethorphan; Tolbutamide; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Omeprazole; Drug Interactions; Tuberculosis, Pulmonary; Digoxin
PubMed: 37768317
DOI: 10.1128/aac.00683-23 -
Drug Design, Development and Therapy 2019Intravenous ketamine is often prescribed in severe neuropathic pain. Oral -methyl-D-aspartate receptor (NMDAR) antagonists might prolong pain relief, reducing the... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Intravenous ketamine is often prescribed in severe neuropathic pain. Oral -methyl-D-aspartate receptor (NMDAR) antagonists might prolong pain relief, reducing the frequency of ketamine infusions and hospital admissions. This clinical trial aimed at assessing whether oral dextromethorphan or memantine might prolong pain relief after intravenous ketamine.
PATIENTS AND METHODS
A multicenter randomized controlled clinical trial included 60 patients after ketamine infusion for refractory neuropathic pain. Dextromethorphan (90 mg/day), memantine (20 mg/day) or placebo was given for 12 weeks (n=20 each) after ketamine infusion. The primary endpoint was pain intensity at one month. Secondary endpoints included pain, sleep, anxiety, depression, cognitive function and quality of life evaluations up to 12 weeks.
RESULTS
At 1 month, dextromethorphan maintained ketamine pain relief (Numeric Pain Scale: 4.01±1.87 to 4.05±2.61, =0.53) and diminished pain paroxysms (=0.03) while pain intensity increased significantly with memantine and placebo (=0.04). At 3 months, pain remained lower than at inclusion (=0.001) and was not significantly different in the three groups. Significant benefits were observed on cognitive-affective domains and quality of life for dextromethorphan and memantine (<0.05).
CONCLUSIONS
Oral dextromethorphan given after ketamine infusion extends pain relief during one month and could help patients to better cope with pain. Future studies should include larger populations stratified on pharmacogenetics screening. Optimization of an oral drug that could extend ketamine antihyperalgesia, with fewer hospital admissions, remains a prime challenge in refractory neuropathic pain.
Topics: Administration, Oral; Adult; Aged; Analgesia; Dextromethorphan; Female; Humans; Infusions, Intravenous; Ketamine; Male; Memantine; Middle Aged; Neuralgia
PubMed: 31447547
DOI: 10.2147/DDDT.S207350 -
IBRO Neuroscience Reports Jun 2023Alzheimer's disease (AD) is the most common cause of dementia worldwide. Because Alzheimer's disease has no known treatment, sufferers and their caregivers must... (Review)
Review
Alzheimer's disease (AD) is the most common cause of dementia worldwide. Because Alzheimer's disease has no known treatment, sufferers and their caregivers must concentrate on symptom management. Astrocytes and microglia are now known to play distinct physiological roles in synaptic function, the blood-brain barrier, and neurovascular coupling. Consequently, the search for drugs that can slow the degenerative process in dementia sufferers continues because existing drugs are designed to alleviate the symptoms of Alzheimer's disease. Drugs that address pathological changes without interfering with the normal function of glia, such as eliminating amyloid-beta deposits, are prospective treatments for neuroinflammatory illnesses. Because neuron-astrocytes-microglia interactions are so complex, developing effective, preventive, and therapeutic medications for AD will necessitate novel methodologies and strategic targets. This review focused on existing medications used in treating AD amongst which include Donepezil, Choline Alphoscerate, Galantamine, Dextromethorphan, palmitoylethanolamide, citalopram, resveratrol, and solanezumab. This review summarizes the effects of these drugs on neurons, astrocytes, and microglia interactions based on their pharmacokinetic properties, mechanism of action, dosing, and clinical presentations.
PubMed: 36593897
DOI: 10.1016/j.ibneur.2022.11.005 -
Journal of Diabetes Research 2022Diabetes is the 4 most common disease affecting the world's population. It is accompanied by many complications that deteriorate the quality of life. Painful diabetic... (Review)
Review
Diabetes is the 4 most common disease affecting the world's population. It is accompanied by many complications that deteriorate the quality of life. Painful diabetic neuropathy (PDN) is one of the debilitating consequences of diabetes that effects one-third of diabetic patients. Unfortunately, there is no internationally recommended drug that directly hinders the pathological mechanisms that result in painful diabetic neuropathy. Clinical studies have shown that anticonvulsant and antidepressant therapies have proven fruitful in management of pain associated with PDN. Currently, the FDA approved medications for painful diabetic neuropathies include duloxetine, pregabalin, tapentadol extended release, and capsaicin (for foot PDN only). The FDA has also approved the use of spinal cord stimulation system for the treatment of diabetic neuropathy pain. The drugs recommended by other regulatory bodies include gabapentin, amitriptyline, dextromethorphan, tramadol, venlafaxine, sodium valproate, and 5 % lidocaine patch. These drugs are only partially effective and have adverse effects associated with their use. Treating painful symptoms in diabetic patient can be frustrating not only for the patients but also for health care workers, so additional clinical trials for novel and conventional treatments are required to devise more effective treatment for PDN with minimal side effects. This review gives an insight on the pathways involved in the pathogenesis of PDN and the potential pharmacotherapeutic agents. This will be followed by an overview on the FDA-approved drugs for PDN and commercially available topical analgesic and their effects on painful diabetic neuropathies.
Topics: Analgesics; Diabetic Neuropathies; Humans; Pain Management; Quality of Life
PubMed: 35127954
DOI: 10.1155/2022/9989272 -
Frontiers in Pharmacology 2023Vortioxetine is a novel anti-major depression disorder drug with a high safety profile compared with other similar drugs. However, little research has been done on...
Vortioxetine is a novel anti-major depression disorder drug with a high safety profile compared with other similar drugs. However, little research has been done on drug-drug interactions (DDI) about vortioxetine. In this paper, the inhibitory effect of vortioxetine on cytochrome P450 (CYP450) and the type of inhibitory mechanism were investigated in human and rat liver microsomes. We set up an incubation system of 200 μL to measure the metabolism of probe substrates at the present of vortioxetine at 37°C. The concentrations of the metabolites of probe substrates were all measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. It was found no time-dependent inhibition (TDI) of vortioxetine through determination of half-maximal inhibitory concentration (IC) shift values. The enzymes and metabolites involved in this experiment in human and rats were as follows: CYP3A4/CYP3A (midazolam); CYP2B6/CYP2B (bupropion); CYP2D6/CYP2D (dextromethorphan); CYP2C8/CYP2C-1 (amodiaquine); CYP2C9/CYP2C-2 (losartan); and CYP2C19/CYP2C-3 (mephenytoin). We found that vortioxetine competitively inhibited CYP2C19 and CYP2D6 in human liver microsomes (HLMs) with inhibition constant (K) values of 2.17 μM and 9.37 μM, respectively. It was noncompetitive inhibition for CYP3A4 and CYP2C8, and its K values were 7.26 μM and 6.96 μM, respectively. For CYP2B6 and CYP2C9, vortioxetine exhibited the mixed inhibition with K values were 8.55 μM and 4.17 μM, respectively. In RLMs, the type of vortioxetine inhibition was uncompetitive for CYP3A and CYP2D (K = 4.41 and 100.9 μM). The inhibition type was competitive inhibition, including CYP2B and CYP2C-2 (K = 2.87 and 0.12 μM). The inhibition types of CYP2C-1 and CYP2C-3 (K = 39.91 and 4.23 μM) were mixed inhibition and noncompetitive inhibition, respectively. The study of the above mechanism will provide guidance for the safe clinical use of vortioxetine so that the occurrence of DDI can be avoided.
PubMed: 37790811
DOI: 10.3389/fphar.2023.1199548