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Frontiers in Pharmacology 2021Depression is a common mental disorder. Its treatment with selective serotonin reuptake inhibitors (SSRIs) is effective only in a fraction of patients, and...
Depression is a common mental disorder. Its treatment with selective serotonin reuptake inhibitors (SSRIs) is effective only in a fraction of patients, and pharmacoresistance is increasing steadily. Intranasal (IN) drug delivery to the brain stands out as a promising strategy to improve current therapeutic approaches by operating as a shuttle to overcome the blood-brain barrier. This work aimed to simultaneously administer escitalopram and paroxetine by IN route to mice. For this purpose, three nanostructured lipid carriers (NLC1, NLC2, and BorNLC) and one nanoemulsion (NE) were tested for drug loading. After their characterization, investigation of their impact on nasal cell viability and SSRI permeability assays were performed, using a human nasal RPMI 2650 cell line in air-liquid interface. assays demonstrated that NLCs, including borneol (BorNLC), significantly increased escitalopram permeability ( < 0.01) and paroxetine recovery values ( < 0.05) in relation to the other formulations and non-encapsulated drugs. IN and intravenous (IV) pharmacokinetic studies performed with a single dose of 2.38 mg/kg demonstrated similar results for escitalopram brain-to-plasma ratios. IN administrations delayed escitalopram peak concentrations in the brain for 15-60 min and no direct nose-to-brain delivery was detected. However, encapsulation with BorNLC considerably decreased escitalopram exposure in the lungs (124 μg min/g) compared with free escitalopram by IN (168 μg min/g) and IV (321 μg min/g) routes. Surprisingly, BorNLC IN instillation increased concentration levels of paroxetine in the brain by five times and accelerated brain drug delivery. Once again, lung exposure was considerably lower with BorNLC (AUC = 0.433 μg min/g) than that with IV administration (AUC = 1.01 μg min/g) and non-encapsulated IN formulation (AUC = 2.82 μg min/g). Direct nose-to-brain delivery was observed for paroxetine IN administration with a direct transport percentage (DTP) of 56.9%. If encapsulated, it increases to 74.2%. These results clearly emphasize that nose-to-brain delivery and lung exposure depend on the formulation and on the characteristics of the drug under investigation. NLCs seem to be an advantageous strategy for nose-to-brain delivery of lipophilic molecules, since they reduce systemic and lung exposure, thereby decreasing adverse effects. For hydrophilic compounds, NLCs are particularly important to decrease lung exposure after IN administration.
PubMed: 34925013
DOI: 10.3389/fphar.2021.751321 -
Antidepressant and Neuroprotective Effects of 3-Hydroxy Paroxetine, an Analog of Paroxetine in Rats.The International Journal of... Mar 2023Paroxetine (PX) is a widely used antidepressant with side effects such as weakness, dizziness, and trouble sleeping. In search of novel compounds with better efficacy...
BACKGROUND
Paroxetine (PX) is a widely used antidepressant with side effects such as weakness, dizziness, and trouble sleeping. In search of novel compounds with better efficacy and fewer side effects, we synthesized 3HPX, a hydroxylated analog of PX, and compared the 2 in silico for their pharmacokinetic and binding properties and in vivo for their antidepressant and potential neuroprotective effects.
METHODS
In silico studies compared pharmacological properties as well as interactions of PX and 3HPX with the serotonin transporter. In vivo studies utilized an animal model of comorbid depression-Parkinson disease. Adult male Wistar rats were injected (sterotaxically) with lipopolysaccharide in the striatum (unilaterally), followed by 14 days of once-daily injections (i.p.) of 10 mg/kg PX or 3HPX. Animals were tested for motor asymmetry and locomotor activity as well as indices of anhedonia and helplessness using sucrose preference and forced swim tests, respectively. Brains of these animals were collected after the last test, and tyrosine hydroxylase-positive neurons in substantia nigra pars compacta and Iba-1-positive stained microglia in ipsilateral striatum were measured.
RESULTS
In silico findings indicated that 3HPX could bind stronger to serotonin transporter and also have a better clearance and hence less toxicity compared with PX. In vivo results revealed a more effective reversal of immobility in the swim test, substantial increase in tyrosine hydroxylase-positive cells in the substantia nigra pars compacta, and more ramified Iba-1+ cells by 3HPX compared with PX.
CONCLUSION
The findings suggest superior effectiveness of 3HPX as an antidepressant and neuroprotectant compared with PX and hence potential utility in Parkinson disease depression co-morbidity.
Topics: Rats; Male; Animals; Paroxetine; Parkinson Disease; Neuroprotective Agents; Rats, Wistar; Substantia Nigra; Tyrosine 3-Monooxygenase; Serotonin Plasma Membrane Transport Proteins; Antidepressive Agents; Disease Models, Animal
PubMed: 36433759
DOI: 10.1093/ijnp/pyac077 -
Current Neuropharmacology 2024Antidepressants are a commonly used, easily accessible, and overall safe treatment option for post-traumatic stress disorder (PTSD). The present review aims to evaluate... (Review)
Review
Antidepressants are a commonly used, easily accessible, and overall safe treatment option for post-traumatic stress disorder (PTSD). The present review aims to evaluate the efficacy and safety of antidepressants in treating sleep disturbances in patients with PTSD. PubMed and the Cochrane Library were searched (July 2022) for systematic reviews and meta-analyses on the treatment of PTSD. Moreover, PubMed and ClinicalTrials.gov were searched for individual trials investigating the antidepressant treatment of PTSD (up to September 2022), and reference lists of all possibly relevant identified studies were screened. Sleep-related outcomes, i.e., total sleep time, sleep quality, dreams/ nightmares, insomnia, and somnolence, were extracted independently by at least two reviewers. Metaanalytic evaluations were performed wherever possible. 39 randomised controlled trials (RCTs) were identified; data from pooled analyses, reviews, and observational studies were used for antidepressants with a weak evidence base or when their findings were deemed important. Overall, scarce data exist on the effects of antidepressants on sleep outcomes among patients with PTSD. Some evidence may support the use of amitriptyline, nefazodone, paroxetine, and sertraline for improving sleep in patients with PTSD. Τhere was a meta-analytical trend indicating improvement of nightmares with fluoxetine, less insomnia with amitriptyline and more with brofaromine, as well as more somnolence with paroxetine vs. placebo, respectively. However, data from more than 1 RCT with a considerable number of patients were only available for paroxetine. Evidence is insufficient to draw safe conclusions. More and better-designed RCTs, with consistent reporting of sleep-related outcomes, are needed.
Topics: Humans; Stress Disorders, Post-Traumatic; Paroxetine; Amitriptyline; Sleep Initiation and Maintenance Disorders; Sleepiness; Systematic Reviews as Topic; Antidepressive Agents
PubMed: 37533247
DOI: 10.2174/1570159X21666230801144328 -
Neuroscience Letters May 2020Progress in PTSD pharmacotherapy has lagged far behind that of other major mental illnesses. Unfortunately, due to the enormous costs and lengthy process involved in... (Review)
Review
Progress in PTSD pharmacotherapy has lagged far behind that of other major mental illnesses. Unfortunately, due to the enormous costs and lengthy process involved in bringing drugs to market, delivering new treatments to patients with PTSD in the near future will remain a challenge. However, by capitalizing on recent advances in the pharmacogenetics of antidepressants, precision psychiatry approaches can be leveraged to optimize the delivery of currently-available medications in a fraction of the time and cost required to develop novel therapeutics. This paper provides a review of the pharmacogenetics of the four serotonin reuptake inhibitors (SRIs) that are currently endorsed for the treatment of PTSD (paroxetine, sertraline, fluoxetine and venlafaxine). It focuses on genes involved in SRI pharmacokinetics (including the liver enzyme genes CYP2D6 and CYP2C19 and blood-brain barrier-relevant gene ABCB1) as well as those implicated in both SRI pharmacodynamics and the pathophysiology of PTSD and related conditions (e.g., BDNF, FKBP5, HTR1A, HTR2A, TPH2). The review concludes with an overview of emerging commercial platforms for pharmacogenetic-guided prescription and a discussion of challenges and directions for future pharmacogenetic research on PTSD.
Topics: Animals; Antidepressive Agents; Humans; Pharmacogenetics; Selective Serotonin Reuptake Inhibitors; Stress Disorders, Post-Traumatic; Treatment Outcome
PubMed: 29689343
DOI: 10.1016/j.neulet.2018.04.039 -
American Journal of Translational... 2022To systematically evaluate the clinical efficacy of acupuncture combined with paroxetine in the treatment of depression. (Review)
Review
OBJECTIVE
To systematically evaluate the clinical efficacy of acupuncture combined with paroxetine in the treatment of depression.
METHODS
The research literature on the treatment of depression with acupuncture and moxibustion combined with paroxetine was collected using keywords in PubMed, Embase, Web of Science, Cochrane Library, CNKI, World Wide Web, Chinese Biomedical Literature and other public publication databases. Collaborative screening of literature was performed according to pre-established inclusion and exclusion criteria. The data in the literature were extracted, the quality of the literature was evaluated, and the RevMan software was used for statistical analysis.
RESULTS
This study finally included 21 research papers involving 1733 clinical patients. The main evaluation indicators for clinical patients were Hamilton Depression Rating Scale (HAMD), total clinical response rate, Rating Scale for Side Effects (SERS) and Treatment Emergent Symptom Scale (TESS). SERS was developed by Asberg. The Chinese version was revised by Zhang Mingyuan (Chairman of the Chinese Medical Association Mental Health Society) et al. The SERS is divided into 14 items, all of which use a 4-point scoring method (none, mild, moderate and severe, respectively). This scale is mainly used to assess the side effects of antidepressants. TESS was compiled by the NIMH of the United States in 1973. It has the most comprehensive items and the widest coverage among the scales of its kind, including not only common adverse symptoms and signs, but also several laboratory test results. Meta-analysis of the above results showed that compared with the control group, the acupuncture combined with paroxetine treatment group showed lower HAMD score (WMD=-4.18 [-5.04, -3.31], P<0.001), higher total response rate (OR=4.01 [3.01, 5.33], P<0.001), lower SERS score (WMD=-2.54 [-4.58, -0.51], P<0.001) and lower TESS score (WMD=-4.39 [-5.15, -3.62], P<0.001), and the differences were statistically significant.
CONCLUSION
The therapeutic effect of acupuncture combined with paroxetine on depression is better than that of conventional drug treatment, and its safety is comparable to that of conventional treatment.
PubMed: 36628233
DOI: No ID Found -
Biomedical Chromatography : BMC Jan 2020LC separation of biologically and pharmaceutically important enantiomers (from racemic or non-racemic mixtures) remains a subject of importance. The present review... (Review)
Review
LC separation of biologically and pharmaceutically important enantiomers (from racemic or non-racemic mixtures) remains a subject of importance. The present review article deals with the liquid chromatographic enantioseparation of chiral selective serotonin reuptake inhibitors (SSRIs), namely citalopram, paroxetine, sertraline and fluoxetine. It is now known that the enantiomers of numerous psychotropic drugs exhibit distinct pharmacodynamics, pharmacokinetic patterns and receptor binding properties, and psychiatric patients are frequently taking more than one medication. Therefore, monitoring of the levels of these analytes in biological fluids is important to determine the levels of enantiomer concentrations; the present paper may be helpful in understanding the present state of available methods (along with a critical discussion of applicability of the methods) and in developing the new ones for this purpose. Different approaches using LC discussed herein may be applied for determining the enantiomeric composition (and enantiomeric purity) of SSRIs and numerous other racemic drugs, of current/future pharmaceutical importance and utility, using simple separation methods, instrumentation, inexpensive reagents and potentially significant analytical approaches. The contents cover the essential data to understand the various separation techniques and associated issues, if any, with documented examples.
Topics: Animals; Chromatography, Liquid; Humans; Rats; Selective Serotonin Reuptake Inhibitors; Stereoisomerism
PubMed: 31652353
DOI: 10.1002/bmc.4730 -
MedRxiv : the Preprint Server For... Feb 2023Paroxetine is an older "selective" serotonin reuptake inhibitor (SSRI) that is notable for its lack of selectivity, resulting in a cholinergic adverse-effect profile,...
INTRODUCTION
Paroxetine is an older "selective" serotonin reuptake inhibitor (SSRI) that is notable for its lack of selectivity, resulting in a cholinergic adverse-effect profile, especially among older adults (65+).
METHODS
Paroxetine prescription rates and costs per state were ascertained from the Medicare Specialty Utilization and Payment Data. States' annual prescription rate, corrected per thousand Part D enrollees, outside 95% confidence interval were considered significantly different from the average.
RESULTS
There was a steady decrease in paroxetine prescriptions (-34.52%) and spending (-16.69%) from 2015-2020 but a consistent, five-fold state-level difference. From 2015-2020, Kentucky (194.9, 195.3, 182.7, 165.1, 143.3, 132.5) showed significantly higher prescriptions rates relative to the national average, and Hawaii (42.1, 37.9, 34.3, 31.7, 27.7, 26.6) showed significantly lower prescription rates. North Dakota was often a frequent elevated prescriber of paroxetine (2016: 170.7, 2018: 143.3), relative to the average. Neuropsychiatry and geriatric medicine frequently prescribed the largest amount of paroxetine prescriptions, relative to the number of providers in that specialty, from 2015-2020.
DISCUSSION
Despite the American Geriatrics Society prohibition against paroxetine use in the older adults and many effective treatment alternatives, paroxetine was still commonly used in this population, especially in Kentucky and North Dakota and by neuropsychiatry and geriatric medicine. These findings provide information on the specialty types and states where education and policy reform would likely have the greatest impact on improving adherence to the paroxetine prescription recommendations.
PubMed: 36824839
DOI: 10.1101/2023.02.15.23285973 -
FP Essentials Apr 2021Human sexual function is complex and multidimensional, with physiologic and psychological components. The common sexual dysfunctions in men have significant overlap. Low...
Human sexual function is complex and multidimensional, with physiologic and psychological components. The common sexual dysfunctions in men have significant overlap. Low sexual desire in men includes a lack of interest in thinking about sex or in being sexual, alone or with a partner. Sexual health counseling often is helpful. Physicians should prescribe supplemental testosterone only if it is clearly indicated. (Sexual dysfunction is an off-label use of testosterone.) Supplementation is not beneficial for men with a normal total testosterone level. Erectile dysfunction (ED) is the consistent or recurrent inability to attain or maintain a penile erection sufficient for sexual satisfaction. The cause typically is multifactorial. The oral phosphodiesterase type 5 inhibitors are the first-line pharmacotherapies for most patients with ED. Their use is contraindicated in patients taking nitrates. Peyronie disease is an acquired penile abnormality that causes curvature or other deformities of the erect penis. Premature ejaculation is defined as a lack of ejaculatory control that is associated with distress. All pharmacotherapies for premature ejaculation are used off label. First-line treatment options include daily selective serotonin reuptake inhibitors (eg, paroxetine), on-demand clomipramine, and topical penile anesthetics. Psychotherapeutic and physical therapies also have been shown to be effective.
Topics: Ejaculation; Erectile Dysfunction; Humans; Male; Men's Health; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological; Testosterone
PubMed: 33856181
DOI: No ID Found -
Aging Oct 2023G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary...
G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary fibrosis. Paroxetine (PRXT) serves as a selective GRK2 inhibitor which is widely used to treat anxiety and depression for several decades. However, whether PRXT could inhibit TGF-β1-induced activation of lung fibroblasts and combat bleomycin-induced pulmonary fibrosis remains unclear. Here, we investigated the effects of PRXT on pulmonary fibrosis in C57/BL6 caused by bleomycin as well as on the activation of murine primary lung fibroblasts stimulated with TGF-β1. The results demonstrated that PRXT markedly improved the pulmonary function and 21-day survival in bleomycin-induced mice. Meanwhile, PRXT significantly decreased collagen deposition, inflammation, and oxidative stress in lung tissues from bleomycin-induced mice. Furthermore, we found that PRXT could inhibit the protein and mRNA expression of GRK2 and Smad3 in lung tissues from bleomycin-induced mice. experiments also PRXT could inhibit cell activation and collagen synthesis in a concentration-dependent manner in TGF-β1-induced lung fibroblasts. In addition, we found that Smad3 overexpression by adenovirus transfection could offset anti-fibrotic and antioxidative effects from PRXT in TGF-β1-induced lung fibroblasts, which showed no effects on the protein expression of GRK2. In conclusion, PRXT mediates the inhibition of GRK2, which further blocks the transcription of Smad3 in TGF-β1-induced lung fibroblasts, providing an attractive therapeutic target for pulmonary fibrosis.
Topics: Mice; Animals; Pulmonary Fibrosis; Bleomycin; Transforming Growth Factor beta1; Paroxetine; Lung; Fibroblasts; Collagen; Mice, Inbred C57BL
PubMed: 37815883
DOI: 10.18632/aging.205092 -
Parasites & Vectors Jan 2021Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter,...
BACKGROUND
Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter, serotonin acts as a morphogen and regulates developmental processes. Although several studies have focused on the serotonergic nervous system in parasitic flatworms, little is known on the role of serotonin in flatworm development.
METHODS
To study the effects of serotonin on proliferation and development of the cestode Echinococcus multilocularis, we cloned the genes encoding the E. multilocularis serotonin transporter (SERT) and tryptophan hydroxylase (TPH), analyzed gene expression by transcriptome analysis and whole mount in situ hybridization (WMISH) and performed cell culture experiments.
RESULTS
We first characterized orthologues encoding the SERT and TPH, the rate-limiting enzyme in serotonin biosynthesis. WMISH and transcriptomic analyses indicated that the genes for both SERT and TPH are expressed in the parasite nervous system. Long-term treatment of parasite stem cell cultures with serotonin stimulated development towards the parasite metacestode stage. Mature metacestode vesicles treated with serotonin showed increased rates of incorporation of the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU), indicating stimulated cell proliferation. In contrast, treatment with the selective serotonin reuptake inhibitor paroxetine strongly affected the viability of parasite cells. Paroxetine also caused structural damage in metacestode vesicles, suggesting that serotonin transport is crucial for the integrity of parasite vesicles.
CONCLUSIONS
Our results indicate that serotonin plays an important role in E. multilocularis development and proliferation, providing evidence that the E. multilocularis SERT and TPH are expressed in the nervous system of the protoscolex. Our results further suggest that the E. multilocularis SERT has a secondary role outside the nervous system that is essential for parasite integrity and survival. Since serotonin stimulated E. multilocularis metacestode development and proliferation, serotonin might also contribute to the formation and growth of the parasite in the liver.
Topics: Animals; Cell Proliferation; Echinococcus multilocularis; Gene Expression; Gene Expression Profiling; Helminth Proteins; In Situ Hybridization; Larva; Nervous System; Paroxetine; Serotonin; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Tryptophan Hydroxylase
PubMed: 33407815
DOI: 10.1186/s13071-020-04533-0