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International Journal of Molecular... May 2024In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have...
In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have tested/are testing drugs in different phases. To the best of our knowledge, the aggregation of the proposed lists of drugs by previous studies has not been extensively exploited towards generating a dynamic reference matrix with enhanced resolution. To fill this knowledge gap, we performed weight-modulated majority voting of the modes of action, initial indications and targeted pathways of the drugs in a well-known repository, namely the Drug Repurposing Hub. Our method, Democracy, exploits this pile of information and creates frequency tables and, finally, a disease suitability score for each drug from the selected library. As a testbed, we applied this method to a group of neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's disease and Multiple Sclerosis). A super-reference table with drug suitability scores has been created for all four neurodegenerative diseases and can be queried for any drug candidate against them. Top-scored drugs for Alzheimer's Disease include agomelatine, mirtazapine and vortioxetine; for Parkinson's Disease, they include apomorphine, pramipexole and lisuride; for Huntington's, they include chlorpromazine, fluphenazine and perphenazine; and for Multiple Sclerosis, they include zonisamide, disopyramide and priralfimide. Overall, Democracy is a methodology that focuses on leveraging the existing drug-related experimental and/or computational knowledge rather than a predictive model for drug repurposing, offering a quantified aggregation of existing drug discovery results to (1) reveal trends in selected tracks of drug discovery research with increased resolution that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) score new candidate drugs for repurposing against a selected disease.
Topics: Drug Repositioning; Humans; Drug Discovery; Neurodegenerative Diseases
PubMed: 38791356
DOI: 10.3390/ijms25105319 -
Legal Medicine (Tokyo, Japan) May 2024Lacosamide is a relatively new antiepileptic drug that exerts its anticonvulsant effect by selectively inactivating sodium channels. Since its launch, it has been used...
Lacosamide is a relatively new antiepileptic drug that exerts its anticonvulsant effect by selectively inactivating sodium channels. Since its launch, it has been used widely for the treatment of intractable epilepsy, but there are scant data on the toxic or lethal blood concentrations. Here, we report a case of drug poisoning following simultaneous high-dose self-administration of lacosamide and mirtazapine. We developed and validated an approach that uses liquid chromatography coupled with electrospray ionization-tandem mass spectrometry to determine the concentrations of lacosamide and mirtazapine in cadaveric blood, urine and liver. Calibration curves showed good linearity (r > 0.995), and our method enabled repeatable and accurate quantification, with intra- and inter-assay coefficients of variation not exceeding 10.9 % and 12.8 %, respectively, for each target drug. We used the method to measure the drug concentrations in the blood of a dead victim and found a lacosamide concentration of 91.9 μg/mL and a mirtazapine concentration of 12.0 μg/mL. The blood mirtazapine concentration was in the lethal range, and that of lacosamide was about 10 times the therapeutic range. The synergistically central nervous system depressive and cardiotoxic effects of these drugs may have contributed to the cause of death. We concluded that the cause of death in this case was lacosamide and mirtazapine poisoning.
PubMed: 38772189
DOI: 10.1016/j.legalmed.2024.102457 -
Handbook of Experimental Pharmacology May 2024Presynaptic α-adrenoceptors are localized on axon terminals of many noradrenergic and non-noradrenergic neurons in the peripheral and central nervous systems. Their...
Presynaptic α-adrenoceptors are localized on axon terminals of many noradrenergic and non-noradrenergic neurons in the peripheral and central nervous systems. Their activation by exogenous agonists leads to inhibition of the exocytotic release of noradrenaline and other transmitters from the neurons. Most often, the α-receptor subtype is involved in this inhibition. The chain of molecular events between receptor occupation and inhibition of the exocytotic release of transmitters has been determined. Physiologically released endogenous noradrenaline elicits retrograde autoinhibition of its own release. Some clonidine-like α-receptor agonists have been used to treat hypertension. Dexmedetomidine is used for prolonged sedation in the intensive care; It also has a strong analgesic effect. The α-receptor antagonist mirtazapine increases the noradrenaline concentration in the synaptic cleft by interrupting physiological autoinhibion of release. It belongs to the most effective antidepressive drugs. β-Adrenoceptors are also localized on axon terminals in the peripheral and central nervous systems. Their activation leads to enhanced transmitter release, however, they are not activated by endogenous adrenaline.
PubMed: 38755350
DOI: 10.1007/164_2024_714 -
Food and Chemical Toxicology : An... Jul 2024Anemia poses a significant healthcare challenge across different socioeconomic groups and can result in reproductive system damage through the generation of free...
Anemia poses a significant healthcare challenge across different socioeconomic groups and can result in reproductive system damage through the generation of free radicals and lipid peroxidation. This study examines the protective effects of quercetin (QUE) and mirtazapine (MIR) against the reproductive damage caused by phenylhydrazine (PHZ) in mice. Fifty NMRI mice, aged 8-10 weeks with an average weight of 27.0 ± 2.0 g, were randomly divided into five groups. The control group (Group 1) received oral administration of 10 mL/kg/day of normal saline. Group 2 (PHZ group) received an initial intraperitoneal dose of 8 mg/100 g body weight of PHZ, followed by subsequent doses of 6 mg/100 g every 48 h. Group 3 received PHZ along with oral QUE at a dosage of 50 mg/kg/day. Group 4 received PHZ along with oral MIR at a dosage of 30 mg/kg/day. Group 5 received PHZ along with oral QUE at a dosage of 50 mg/kg/day and MIR at a dosage of 30 mg/kg/day. The treatment duration was 35 days. Sperm samples were collected from the caudal region of the epididymis post-euthanasia to assess the total mean sperm count, sperm viability, motility, DNA damage, and morphology. Testicular tissue was employed to quantify total antioxidant capacity (TAC), superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) concentrations, while serum levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were analyzed. Additionally, various aspects, including testicular histopathology, oxidative enzyme levels, gene expression related to apoptosis and antiapoptotic pathways, and in vivo fertility index, were evaluated after 35 days. The QUE, MIR, and QUE + MIR groups showed less abnormal morphology and DNA damage, as well as better total and progressive sperm motility, motility characteristics, viability, and plasma membrane function compared to the PHZ group. QUE, MIR, and QUE + MIR administration increased TAC, SOD, and GPx activities in testicular tissue, while reducing MDA levels compared to the PHZ group. Furthermore, QUE, MIR, and QUE + MIR significantly reduced Bax, and caspase-3 expression levels, and increased Bcl-2 expression levels, compared to the PHZ group. Mice treated with QUE, MIR, and QUE + MIR exhibited an increased in vivo fertility index and plasma sex hormone levels compared to the PHZ group. These results show that QUE, MIR, and QUE + MIR might be able to improve the fertility index, boost the testicular antioxidant defense system, and control the death of germ cells. This could mean that they could be used to treat mice with PHZ-induced testicular damage.
Topics: Animals; Male; Testis; Mice; Quercetin; Spermatogenesis; Mirtazapine; Phenylhydrazines; Antioxidants; Sperm Motility; Spermatozoa; Sperm Count
PubMed: 38740240
DOI: 10.1016/j.fct.2024.114732 -
Journal of Veterinary Cardiology : the... Mar 2024A nine-year-old spayed female domestic shorthair cat with a previous diagnosis of hypertrophic cardiomyopathy and treated for one month with atenolol (6.25 mg q 12 h)...
A nine-year-old spayed female domestic shorthair cat with a previous diagnosis of hypertrophic cardiomyopathy and treated for one month with atenolol (6.25 mg q 12 h) was referred for respiratory distress and anorexia. The cat was diagnosed with pulmonary oedema secondary to obstructive hypertrophic cardiomyopathy. After stabilisation, she was discharged with furosemide (1 mg/kg q 12 h), clopidogrel (18.75 mg q 24 h), atenolol (6.25 mg q 12 h), and mirtazapine (2 mg/cat q 24 h) to increase appetite. At recheck, the cat was lethargic and presented with severe bradycardia with a junctional escape rhythm and ventriculoatrial conduction. The mirtazapine was discontinued due to its possible side-effects on cardiac rhythm. After three days, the atenolol was halved because the bradyarrhythmia was still present. After 10 days, the rhythm returned to sinus; atenolol was reintroduced twice daily with no further side-effects. The absence of a sinus rhythm with a junctional escape rhythm and P' retroconduction is compatible with a third-degree sinus block or a sinus standstill; the differentiation of these rhythm disturbances is impossible, based on the surface electrocardiogram (ECG). The sinus rhythm was restored after mirtazapine was withdrawn. However, it is not possible to rule out the role of the atenolol or the combined effect of the two drugs. The cat was affected by hypertrophic cardiomyopathy, and the role of myocardial remodelling cannot be excluded. This is the first time that a bradyarrhythmia consequent to the treatment with atenolol and mirtazapine was described in a cat.
PubMed: 38735230
DOI: 10.1016/j.jvc.2024.03.003 -
The Primary Care Companion For CNS... May 2024To examine the complexities of psychotropic medication prescription in home-based palliative care for oncology patients. A retrospective analysis of 125 medical...
To examine the complexities of psychotropic medication prescription in home-based palliative care for oncology patients. A retrospective analysis of 125 medical records of patients receiving palliative home care for cancer was conducted at a tertiary hospital, with a specific focus on the prescription patterns of psychotropic medications. The data were collected in September 2023. Among 125 cases, the mean age was 64.4 ± 14.9 years, with 50.4% females. Breast cancer (14.4%) and lung cancer (13.6%) were the most common diagnoses. Psychotropic medication was administered to 35.2% of patients. Treatment was initiated by palliative care doctors in 75% of cases, while psychiatrists handled 25%. Medication selection was predominantly symptom driven (63%), with anxiety prompting benzodiazepine prescriptions in 50% of cases, depression resulting in antidepressant use in 22%, and psychosis leading to antipsychotic treatment in 18%. Specific diagnoses were the target in only 36% of prescriptions, with delirium (27%) being the most prevalent, followed by depression and bipolar disorder. Benzodiazepines were the most commonly prescribed class of medications (56.8%), with clonazepam being the most prevalent (40.9%), followed by alprazolam and lorazepam (15.9%). Atypical antipsychotics made up 43.1% of prescriptions, with quetiapine being the most frequently prescribed (34%), along with olanzapine and risperidone (11%). Antidepressants accounted for 31.8% of prescriptions, including selective serotonin reuptake inhibitors at 18% and mirtazapine and amitriptyline at 6% each. Haloperidol, a typical antipsychotic, was prescribed in 13.6% of cases. Polypharmacy was observed in 35.6% of patients. In palliative home care, psychotropic medications are frequently prescribed by palliative doctors primarily for symptom management, with limited psychiatric consultations and challenges in accessing psychological evaluations. Collaborative efforts among regional or institutional medical bodies, including psychiatrists, psychologists, palliative doctors, and social workers, are needed to establish ethical guidelines for appropriate and effective psychotropic prescription. .
Topics: Humans; Female; Male; Middle Aged; Palliative Care; Retrospective Studies; Psychotropic Drugs; Aged; Home Care Services; Neoplasms; Drug Prescriptions; Adult; Aged, 80 and over; Practice Patterns, Physicians'
PubMed: 38728674
DOI: 10.4088/PCC.23m03668 -
World Psychiatry : Official Journal of... Jun 2024Psychotic depression (PD) is a severe mental disorder leading to functional disability and high risk of suicide, but very little is known about the comparative...
Real-world effectiveness of antidepressants, antipsychotics and their combinations in the maintenance treatment of psychotic depression. Evidence from within-subject analyses of two nationwide cohorts.
Psychotic depression (PD) is a severe mental disorder leading to functional disability and high risk of suicide, but very little is known about the comparative effectiveness of medications used in its maintenance treatment. The objective of this study was to investigate the comparative effectiveness of specific antipsychotics and antidepressants, and their combinations, on the risk of psychiatric hospitalization among persons with PD in routine care. Persons aged 16-65 years with a first-time diagnosis of PD were identified from Finnish (years 2000-2018) and Swedish (years 2006-2021) nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. The main exposures were specific antipsychotics and antidepressants, and the main outcome measure was psychiatric hospitalization as a marker of severe relapse. The risk of hospitalization associated with periods of use vs. non-use of medications (expressed as adjusted hazard ratio, aHR) was assessed by a within-individual design, using each individual as his/her own control, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately, and then combined using a fixed-effect meta-analysis. The Finnish cohort included 19,330 persons (mean age: 39.8±14.7 years; 57.9% women) and the Swedish cohort 13,684 persons (mean age: 41.3±14.0 years; 53.5% women). Individual antidepressants associated with a decreased risk of relapse vs. non-use of antidepressants were bupropion (aHR=0.73, 95% CI: 0.63-0.85), vortioxetine (aHR=0.78, 95% CI: 0.63-0.96) and venlafaxine (aHR=0.92, 95% CI: 0.86-0.98). Any long-acting injectable antipsychotic (LAI) (aHR=0.60, 95% CI: 0.45-0.80) and clozapine (aHR=0.72, 95% CI: 0.57-0.91) were associated with a decreased risk of relapse vs. non-use of antipsychotics. Among monotherapies, only vortioxetine (aHR=0.67, 95% CI: 0.47-0.95) and bupropion (aHR=0.71, 95% CI: 0.56-0.89) were associated with a significantly decreased risk of relapse vs. non-use of both antidepressants and antipsychotics. In an exploratory analysis of antidepressant-antipsychotic combinations, a decreased relapse risk was found for amitriptyline-olanzapine (aHR=0.45, 95% CI: 0.28-0.71), sertraline-quetiapine (aHR=0.79, 95% CI: 0.67-0.93) and venlafaxine-quetiapine (aHR=0.82, 95% CI: 0.73-0.91) vs. non-use of antidepressants and antipsychotics. Benzodiazepines and related drugs (aHR=1.29, 95% CI: 1.24-1.34) and mirtazapine (aHR=1.17, 95% CI: 1.07-1.29) were associated with an increased risk of relapse. These data indicate that, in the maintenance treatment of PD, bupropion, vortioxetine, venlafaxine, any LAI, clozapine, and only few specific antidepressant-antipsychotic combinations are associated with a decreased risk of relapse. These findings challenge the current recommendation by treatment guidelines to combine an antipsychotic with an antidepressant (without further specification) as standard treatment in PD.
PubMed: 38727044
DOI: 10.1002/wps.21205 -
Heliyon May 2024- Cocaine use disorder (CUD) is a complex disease. Several studies have shown the efficacy of multitarget drugs used to treat CUD. Here we compare the efficacy of...
PURPOSE
- Cocaine use disorder (CUD) is a complex disease. Several studies have shown the efficacy of multitarget drugs used to treat CUD. Here we compare the efficacy of mirtazapine (MIR), pindolol (PIN), fluoxetine (FLX), risperidone (RIS), trazodone (TRZ), ziprasidone (ZPR), ondansetron (OND), yohimbine (YOH), or prazosin (PRZ), to reduce long-term cocaine-induced locomotor activity and the expression of cocaine-induced locomotor sensitization in rats.
METHODS
- The study consists of four experiments, which were divided into four experimental phases. Induction (10 days), cocaine withdrawal (30 days), expression (10 days), and post-expression phase (10 days). Male Wistar rats were daily dosed with cocaine (10 mg/kg; i.p.) during the induction and post-expression phases. During drug withdrawal, the MIR, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ were administered 30 min before saline. In the expression, the multitarget drugs were administered 30 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min.During the agonism phase, in experiment four, 8-OH-DPAT, DOI, CP-809-101, SR-57227A, or clonidine (CLO) was administered 30 min before MIR and 60 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min.
RESULTS
-MIR, FLX, RIS, ZPR, OND, or PRZ attenuated the cocaine-induced locomotor activity and cocaine locomotor sensitization. PIN, TRZ, and YOH failed to decrease cocaine locomotor sensitization. At the optimal doses used, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ failed to attenuate long-term cocaine locomotor activation. MIR generated a decrease in cocaine-induced locomotor activity of greater magnitude and duration than the other multitarget drugs evaluated.
CONCLUSION
- At the optimal doses of multitarget drugs evaluated, MIR was the multitarget drug that showed the greatest long-term cocaine-induced behavior effects compared to other multitarget drugs.
PubMed: 38726128
DOI: 10.1016/j.heliyon.2024.e29979 -
Therapeutic Advances in Drug Safety 2024Antidepressants are widely used to manage depression and other psychiatric diseases. A previous study revealed that hepatotoxicity was the main adverse event related to...
BACKGROUND
Antidepressants are widely used to manage depression and other psychiatric diseases. A previous study revealed that hepatotoxicity was the main adverse event related to antidepressants. Therefore, drug-induced liver injury (DILI) caused by antidepressants deserves more attention.
OBJECTIVES
To investigate DILI adverse events reported due to antidepressant use in the United States Food and Drug Administration Adverse Events Reporting System (FAERS) database.
RESEARCH DESIGN
A disproportionality analysis of spontaneously reported adverse events was conducted to assess the association between antidepressant drugs and DILI.
METHODS
FAERS data from 1 January 2004 to 31 December 2021 were compiled and analyzed using the reporting odds ratio (ROR) and information component (IC).
RESULTS
As per the FAERS database, of the 324,588 cases that were administered antidepressants, 10,355 were identified as cases with DILI. Among the identified 42 antidepressants, nefazodone ( = 47, ROR = 7.79, IC = 2.91), fluvoxamine ( = 29, ROR = 4.69, IC = 2.20), and clomipramine ( = 24, ROR = 3.97, IC = 1.96) had the highest ROR for cholestatic injury; mianserin ( = 3, ROR = 21.46, IC = 3.99), nefazodone ( = 264, ROR = 18.67, IC = 3.84), and maprotiline ( = 15, ROR = 5.65, IC = 2.39) for hepatocellular injury; and nefazodone ( = 187, ROR = 12.71, IC = 0.48), clomipramine ( = 35, ROR = 2.07, IC = 0.26), and mirtazapine ( = 483, ROR = 1.96, IC = 0.94) for severe drug-related hepatic disorders. Only nefazodone elicited hepatic failure signals ( = 48, ROR = 18.64, IC = 4.16). There are limited reports on the adverse reactions of relatively new antidepressant drugs, such as milnacipran, viloxazine, esketamine, and tianeptine, and those not approved by the Food and Drugs Administration, such as reboxetine and agomelatine.
CONCLUSION
A significant association was observed between DILI and nefazodone. Duloxetine and clomipramine were associated with three DILI categories, except hepatic failure. The disproportionality analysis cannot conclude on a definite causal link between antidepressants and DILI. Additional research is required to assess new-generation antidepressants for their propensity to cause DILI.
PubMed: 38715707
DOI: 10.1177/20420986241244585 -
World Journal of Urology May 2024Selective serotonin reuptake inhibitors are associated with high rates of nonadherence and sexual dysfunction, yet the correlation between these findings in young adult...
PURPOSE
Selective serotonin reuptake inhibitors are associated with high rates of nonadherence and sexual dysfunction, yet the correlation between these findings in young adult men is poorly characterized. We aimed to evaluate if young adult men are less willing to adhere to antidepressant treatment due to intolerable side effects, such as sexual dysfunction.
METHODS
Deidentified, compensated survey that assessed baseline demographics, PHQ-8 and GAD-7 scores, attitudes towards antidepressant medication side effects, and perceptions of antidepressant medications including selective serotonin reuptake inhibitors, bupropion, and mirtazapine.
RESULTS
From 665 delivered surveys, 505 respondents completed their survey (response rate: 76%), of which 486 were included for final analysis. After seeing common side effect profiles, our sample's willingness to take sexual function-sparing agents, such as bupropion or mirtazapine, was significantly greater than selective serotonin reuptake inhibitors (p < 0.001), with no significant difference between bupropion and mirtazapine (p = 0.263). The negative influence of erectile dysfunction and anorgasmia scored significantly higher than other common antidepressant side effects like weight gain, nausea, and dry mouth (range: p < 0.001, p = 0.043). With the exception of insomnia, participants indicated that experiencing sexual dysfunction while taking an antidepressant medication would lead to nonadherence at a significantly higher frequency than any other side effect assessed (range: p < 0.001, p = 0.005).
CONCLUSION
The risk of experiencing sexual side effects when taking antidepressants could lead young adult men to become nonadherent to these medications. Strategies to augment the effectiveness of antidepressants, such as shared decision-making and the use of sexual function-sparing agents, are critical.
Topics: Humans; Male; Cross-Sectional Studies; Medication Adherence; Young Adult; Sexual Dysfunction, Physiological; Adult; Antidepressive Agents; Mirtazapine; Selective Serotonin Reuptake Inhibitors; Bupropion
PubMed: 38709300
DOI: 10.1007/s00345-024-05003-3