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Progress in Neuro-psychopharmacology &... Jun 2024The various pharmacological interventions, ranging from mood stabilizers and antipsychotics to antidepressants, reflect the diff/iculty of treating depressive/manic... (Review)
Review
BACKGROUND
The various pharmacological interventions, ranging from mood stabilizers and antipsychotics to antidepressants, reflect the diff/iculty of treating depressive/manic symptomatology of bipolar disorder (BD). Among a broad range of mechanisms implicated, immune dysregulation may contribute to the increased inflammation that influences the course of BD. Inflammatory, neurotrophic and oxidative stress factors may be identified as promising peripheral biomarkers in brain functioning, perhaps serving as predictors of an effective response to treatment for BD. The present systematic review aimed to examine the evidence supporting the pharmacotherapeutic value of inflammatory and neurotrophic biomarkers in BD.
METHODS
PubMed, PsychINFO, Scopus and Web of Science were searched from inception to May 2024 by two independent reviewers. A total of 40 studies with 3371 patients with diagnosis and intervention of BD were selected.
RESULTS
Inconsistencies in the effects of pharmacological treatments on the connection between the expected anti-inflammatory response and symptomatologic improvement were identified. Mood stabilizers (lithium), antipsychotics (quetiapine), antidepressants (ketamine) or their combination were described to increase both pro-inflammatory (TNFα, IL-6) and anti-inflammatory (IL-4, IL-8) factors. Other medications, such as memantine and dextromethorphan, autoimmune (infliximab) non-steroidal anti-inflammatory (aspirin, celecoxib) drugs, antidiabetics (pioglitazone), and even dietary supplementation (omega-3), or their combination, clearly decrease inflammatory factors (TNFα, IL-6, IL-1β, C-reactive protein) and/or increase the neurotrophic factor BDNF in BD patients.
CONCLUSION
Inflammation in BD requires further investigation to understand the underlying immunologic mechanism, to identify predictors of treatment response, and to make informed decisions about the use and development of more effective pharmacological interventions for BD.
PubMed: 38879067
DOI: 10.1016/j.pnpbp.2024.111056 -
ACS Omega Jun 2024(Willd.) Miers (Menispermaceae) is a traditional rejuvenator and a conventional medicine used to manage oxidative stress-related diseases, including those associated...
(Willd.) Miers (Menispermaceae) is a traditional rejuvenator and a conventional medicine used to manage oxidative stress-related diseases, including those associated with the central nervous system. Decreased dextromethorphan (DEM) metabolism is necessary for high bioavailability and application against Alzheimer's disease (AD). Since stem extract (TCE) can potentially inhibit several metabolic enzymes, it can also enhance dextromethorphan bioavailability. This study investigates the potential of TCE to improve DEM's bioavailability and efficacy for the management of AD. analysis was carried out to find the inhibition potential of phytocomponents of for CYP2D6 and CYP3A4. The LC-MS method was revalidated for the analysis of DEM and metabolite dextrorphan (DEX) in the presence of quinidine (QN). The ratio of DEM to DEX was estimated with varying doses of TCE following pharmacokinetic analysis. Network pharmacology analysis was carried out to understand the complementary potential of phytocomponents. This was further validated in the scopolamine-induced dementia model through behavioral and histopathological analyses. TCE (100 mg/kg) for 14 days increased the DEM to DEX ratio by 2.8-fold compared to QN treatment. While was comparable to that of QN treatment at this dose (100 mg/kg) of TCE, it increased significantly at the higher dose (400 mg/kg) of TCE pretreatment. All other pharmacokinetic parameters were also enhanced at this dose with a 4.7-fold increase in DEM/DEX compared with QN. Network pharmacology analysis indicated the ability of TCE to target multiple factors associated with AD. Furthermore, it improved spatial memory and reduced hyperactivity in rodents better than the combination of QN and DEM.
PubMed: 38854540
DOI: 10.1021/acsomega.4c01219 -
Journal of UOEH 2024A woman in her 30s who was being treated for a mental illness with several psychotropic drugs was admitted to the hospital after being found in a state of...
A woman in her 30s who was being treated for a mental illness with several psychotropic drugs was admitted to the hospital after being found in a state of unconsciousness and respiratory arrest at home. She was pronounced dead 12 hours after she was discovered. Her autopsy revealed symmetrical hemorrhagic necrosis in the putamen on both sides of her cerebrum. Although many drugs were detected in her blood, all of those other than dextromethorphan (DXM) were within or below the therapeutic range. Her blood DXM was 1.73 μg/ml at admission and 1.61 μg/ml at autopsy, which were within the toxic range or coma-to-death range. The cause of death was diagnosed as DXM poisoning. DXM can cause hallucinations and euphoria if taken in excess, but since it is available as an over-the-counter drug at general pharmacies, an increasing number of young people are overdosing on it, mistakenly believing it to be a safe drug with few side effects. We believe that further social measures against DXM are necessary in Japan, such as disseminating correct knowledge in society and regulating over-the-counter sales.
Topics: Humans; Dextromethorphan; Female; Autopsy; Adult; Fatal Outcome
PubMed: 38839290
DOI: 10.7888/juoeh.46.221 -
Acta Medica Philippina 2024Lung cancer is the leading cause of cancer death worldwide. It may present as airway obstruction in a patient with endobronchial masses. Endobronchial brachytherapy...
Lung cancer is the leading cause of cancer death worldwide. It may present as airway obstruction in a patient with endobronchial masses. Endobronchial brachytherapy (EBBT) has been shown to provide palliative therapy. It is the insertion of a radioactive material near the mass to reduce tumor size, thereby improving airway obstruction. This is the first case of EBBT done in our institution during the COVID-19 pandemic. A 53-year-old male, 60 kg, ASA Physical Status 2 for hypertension, smoker, malignancy, and previous pulmonary tuberculosis patient, presented with a cough and dyspnea. An endobronchial mass almost obstructing the right mainstem bronchus was seen on a computed tomography (CT) scan. He was diagnosed with squamous cell carcinoma of the lung and underwent radiotherapy and erlotinib chemotherapy. On repeat CT scan, there was no noted decrease in the size of the mass. EBBT was suggested, and a multi-disciplinary team was formed for the planned procedure. Pulmonology, radiation oncology, and anesthesiology teams were identified, and thorough planning was done prior to the actual procedure. Three fractions of EBBT were done under sedation using midazolam, fentanyl, and dexmedetomidine infusion. Lidocaine spray and transtracheal block were also performed as adjuncts prior to sedation. The procedure went as planned, and points for improvement were discussed for subsequent fractions. Due to persistent cough and discomfort from the catheter, additional ipratropium nebulization for minimization of secretions, and oral dextromethorphan for cough suppression were incorporated. After each fraction, the patient was monitored post-procedure for any side effects both from the radiotherapy and anesthetic technique. Qualitative reduction in mass size was noted in subsequent fractions. The patient was able to complete 3 fractions and was advised to follow-up after a month. EBBT is an emerging palliative and treatment modality for lung cancer, especially for intraluminal masses. Anesthetic considerations will depend on each case's characteristics such as airway anatomy, patient comfort and capacity, and procedural requirements. Conscious sedation with topical anesthesia is an adequate and appropriate anesthetic option, especially in cases where severe airway obstruction may compromise ventilation if airway reflexes are blunted. A multidisciplinary approach with different services and stakeholders is important for the proper planning, execution, and management of such patients.
PubMed: 38836083
DOI: 10.47895/amp.v58i9.8839 -
Cureus Apr 2024Stiff Person Syndrome (SPS) is a rare autoimmune condition marked by extremely painful muscle spasms, stiffness, and rigidity throughout the body. Its rarity often...
Stiff Person Syndrome (SPS) is a rare autoimmune condition marked by extremely painful muscle spasms, stiffness, and rigidity throughout the body. Its rarity often translates to limited treatment options for patients and, occasionally, challenges in obtaining a definitive diagnosis. SPS also impacts patients' mental health, social and economic involvement, and overall quality of life. A 43-year-old man was initially being seen for lumbar radicular pain. A clinical diagnosis of SPS was made by a neurologist and confirmed by in-clinic follow-ups and anti-glutamic acid decarboxylase (anti-GAD) antibody testing. The Pain Management doctor agreed with this diagnosis and offered intravenous (IV) ketamine treatment, which he has found to positively impact the treatment of similar disorders. After an initial 10-day infusion, the patient reported improvement in pain and function. For almost two years, the patient received intravenous immunoglobulin (IVIg) and IV ketamine treatments to manage their condition and maintain pain control as well as quality of life. When the patient's symptoms began worsening after IVIg infusions, the decision to withdraw IVIg infusions and continue ketamine infusions was made. After discontinuing IVIg infusions, the patient reported improvement in function and pain level and continues to receive monthly two-day ketamine boosters. Outside of the infusions, the patient was able to discontinue the use of fentanyl patches and continued taking ketamine lozenges, oxycodone-acetaminophen, and dextromethorphan for at-home pain management. The patient's symptoms continue to be managed effectively with their current regimen, enabling their return to work and experiencing an enhanced quality of life. This case illustrates the potential benefits of IV ketamine treatment for patients with treatment-resistant SPS and similar neurologic and autoimmune disorders. Understanding and examining treatment alternatives for rare syndromes is crucial for achieving optimal patient outcomes. Additionally, documenting such cases offers valuable insights into the mechanism of ketamine, extending beyond these syndromes.
PubMed: 38817534
DOI: 10.7759/cureus.59397 -
Turkish Journal of Pharmaceutical... May 2024The aim of this study was to develop a simple, accurate, and precise method for the estimation of bupropion and dextromethorphan in a fixed-dose combination of tablets...
OBJECTIVES
The aim of this study was to develop a simple, accurate, and precise method for the estimation of bupropion and dextromethorphan in a fixed-dose combination of tablets and robust high-performance liquid chromatography for assay analysis of such a fixed combination.
MATERIALS AND METHODS
Chromatographic analysis was performed and separations were achieved on a Denali C18 150 × 4.6 mm, 5 micron using a mobile phase composition of acid and acetonitrile in the ratio of 600:400 (), flow rate of 1.0 mL/min, injection volume is 10 µL and run time of 6 min in isocratic elution. Ultraviolet (UV) detection was performed at a wavelength of 221 nm. The temperature was maintained at 30 °C. Well-resolved peaks were observed with a high number of theoretical plates, lower tailing factor, and reproducible relative retention time. The method was validated, and all validation parameters were found to be within the acceptance limits.
RESULTS
A simple, accurate, and precise method has been developed for estimating bupropion and dextromethorphan in a fixed dose combination of tablets. The optimized method included the following parameters: column temperature of 30 °C, 40% acetonitrile as the mobile phase, and flow rate of 1.0 mL/min. Retention times were 2.25 min and 3.12 min for bupropion and dextromethorphan, respectively. The method was found to be linear in the range of 17.5-105 µg/mL [for R < 0.999) and 7.5-45 µg/mL (for R > 0.999] for bupropion and dextromethorphan, respectively. Both active pharmaceutical ingredients dissolved more than 90% within 5 min.
CONCLUSION
The current study describes a new, simple, reliable, and economical elution reversed-phase high performance liquid chromatography method for estimating bupropion and dextromethorphan in a fixed combination tablet dosage form. The forced degradation studies were conducted using several degradation conditions such as acidic, alkali, oxidation, thermal, UV, and neutral conditions; the proposed method was effectively employed from the resolution of sample peaks. To the best of our knowledge, no such detailed and stability-indicating method has been reported for a fixed tablet dosage form.
PubMed: 38742814
DOI: 10.4274/tjps.galenos.2023.87522 -
American Journal of Veterinary Research May 2024Develop a cytochrome P450 (CYP) phenotyping cocktail for dogs using specific substrates for hepatic P450 enzymes CYP2B11, CYP2D15, and CYP3A12 and determine whether...
OBJECTIVE
Develop a cytochrome P450 (CYP) phenotyping cocktail for dogs using specific substrates for hepatic P450 enzymes CYP2B11, CYP2D15, and CYP3A12 and determine whether alternative sampling methods (saliva and urine) or single time point samples could be used instead of multiple blood sampling.
ANIMALS
12 healthy client-owned dogs (8 females and 4 males) from February 2019 to May 2019.
METHODS
In a randomized crossover study, dogs received oral administration of the probe drug bupropion (75 mg), dextromethorphan (30 mg), or omeprazole (40 mg) alone or as a 3-drug combination (Program in Individualized Medicine [PrIMe] cocktail) to evaluate simultaneous phenotyping of CYP2B11, CYP2D15, and CYP3A12. Pharmacokinetic profiles for the probe drugs and metabolites were determined using plasma, saliva, and urine. Dogs received probe drugs alone or combined. Pharmacokinetic profiles up to 6 hours postdose for the probe drugs and metabolites were determined using plasma, saliva, and urine.
RESULTS
The PrIMe cocktail was well tolerated. There was no statistically significant interaction between the probe drugs when administered together. Single time point plasma metabolic ratios at 4 hours postdose for all probe drugs strongly correlated with the corresponding area under the plasma concentration-versus-time curve (AUC) ratios. Saliva AUC metabolic ratios for CYP3A12 and CYP2D15 and 6-hour urine for CYP2B11 and CYP2D15 were correlated with plasma AUC ratios.
CONCLUSIONS
The PrIMe cocktail can be used for simultaneous CYP phenotyping using plasma 4-hour single time point sample metabolic ratios. Saliva and urine sampling are suitable for specific CYPs.
CLINICAL RELEVANCE
The PrIMe cocktail has potential as a useful tool in dogs to detect clinically important CYP-mediated drug-drug interactions, identify novel pharmacogenes, determine the drug-metabolizing phenotype of individual dogs, aid in individualized dose selection, and evaluate the effects of various physiological states on drug metabolism.
PubMed: 38718826
DOI: 10.2460/ajvr.24.02.0049 -
Clinical and Translational Science May 2024St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and...
St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.
Topics: Humans; Hypericum; Blood-Brain Barrier; Phloroglucinol; Plant Extracts; Male; Adult; Positron-Emission Tomography; Terpenes; Female; Young Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B; Bridged Bicyclo Compounds; Terfenadine; Cytochrome P-450 Enzyme System; Healthy Volunteers
PubMed: 38700454
DOI: 10.1111/cts.13804 -
BMJ Open Apr 2024Therapeutic latency, lack of efficacy and adverse drug reactions are the major concerns in current antidepressant therapies. To overcome these treatment hurdles, add-on...
Repurposing of dextromethorphan as an adjunct therapy in patients with major depressive disorder: a randomised, group sequential adaptive design, controlled clinical trial protocol.
BACKGROUND
Therapeutic latency, lack of efficacy and adverse drug reactions are the major concerns in current antidepressant therapies. To overcome these treatment hurdles, add-on therapy to conventional antidepressant medications may lead to better therapeutic outcomes. The present randomised controlled trial has been planned to evaluate the efficacy and safety of add-on dextromethorphan to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD).
METHODS AND ANALYSIS
A randomised, double-blind, add-on, placebo-controlled, group sequential design clinical trial will be conducted on patients with MDD who will be randomly assigned to the control and the test group in a 1:1 ratio. Patients in the test group will get dextromethorphan 30 mg once daily, whereas patients in the control group will receive a placebo once daily as an add-on to ongoing SSRI treatment for 8 weeks. All patients will be evaluated for the primary outcome (change in the Montgomery-Åsberg Depression Rating Scale score) and secondary outcomes (treatment response rate, remission rate, Clinical Global Impression, serum brain-derived neurotrophic factor, serum dextromethorphan and treatment-emergent adverse events) over the period of 8 weeks. Intention-to-treat analysis will be done for all parameters using suitable statistical tools.
ETHICS AND DISSEMINATION
This study was approved by the Institutional Ethics Committee of All India Institute of Medical Sciences, Bhubaneswar, India, and the study conformed to the provisions of the Declaration of Helsinki and ICMR's ethical guidelines for biomedical research on human subjects (2017). Written informed consent will be obtained from the participants before recruitment. The results of this study will be published in peer-reviewed publications.
TRIAL REGISTRATION NUMBER
NCT05181527.
Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Young Adult; Antidepressive Agents; Depressive Disorder, Major; Dextromethorphan; Double-Blind Method; Drug Repositioning; Drug Therapy, Combination; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 38688675
DOI: 10.1136/bmjopen-2023-080500