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Progress in Neuro-psychopharmacology &... Jun 2024Substance dependence represents a pervasive global concern within the realm of public health. Presently, it is delineated as a persistent and recurrent neurological... (Review)
Review
Substance dependence represents a pervasive global concern within the realm of public health. Presently, it is delineated as a persistent and recurrent neurological disorder stemming from drug-triggered neuroadaptations in the brain's reward circuitry. Despite the availability of various therapeutic modalities, there has been a steady escalation in the mortality rate attributed to drug overdoses. Substantial endeavors have been directed towards the exploration of innovative interventions aimed at mitigating cravings and drug-induced repetitive behaviors. Within this review, we encapsulate the most auspicious contemporary treatment methodologies, accentuating meta-analyses of efficacious pharmacological and non-pharmacological approaches: including gabapentin, topiramate, prazosin, physical exercise regimens, and cerebral stimulation techniques.
PubMed: 38908501
DOI: 10.1016/j.pnpbp.2024.111070 -
Brain Research Dec 2023The norepinephrine (NE) system is involved in pathways that regulate morphine addiction. Here, we investigated the role of α adrenoceptor in the ventrolateral orbital...
The norepinephrine (NE) system is involved in pathways that regulate morphine addiction. Here, we investigated the role of α adrenoceptor in the ventrolateral orbital cortex (VLO) of rats with repeated morphine treatment and underlying molecular mechanisms. The rewarding properties of morphine were assessed by the conditioned place preference (CPP) paradigm. Prazosin, an α adrenoceptor antagonist, was microinjected into the VLO. The expression of α adrenoceptor, p-CaMKII/CaMKII, CRTC1, BDNF and PSD95 in the VLO were determined by immunohistochemistry or western blotting. Neurotransmitter NE in the VLO and inflammatory factors in serum were detected separately through high-performance liquid chromatography and enzyme-linked immunosorbent assay. Our experimental results showed that repeated morphine administration induced stable CPP and prazosin promoted the morphine-induced CPP. Microinjection of prazosin in the VLO not only blocked the activity of α adrenoceptor, decreased CaMKII phosphorylation and CRTC1, which eventually resulted in a regression of synaptic plasticity-related proteins, but also was accompanied by significantly decreasing of NE in the VLO and increasing of inflammatory cytokines in peripheral blood. These findings suggested that prazosin potentiates the addictive effects of morphine. The effect of increased CPP through reducing α adrenoceptor and NE was associated with the CaMKII-CRTC1 pathway and synaptic plasticity-related proteins in the VLO and inflammatory cytokines in the peripheral blood. The NE system may therefore be an underlying therapeutic target in morphine addiction. Additionally, we believe that the clinical use of prazosin in hypertensive patients with morphine abuse may be a potential risk because of its reinforcing effect on addiction.
Topics: Humans; Rats; Animals; Morphine; Prazosin; Rats, Sprague-Dawley; Morphine Dependence; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Receptors, Adrenergic, alpha-1; Cytokines
PubMed: 37783262
DOI: 10.1016/j.brainres.2023.148614 -
Sleep Medicine Jul 2024Sleep disturbances are an important symptom dimension of post-traumatic-stress-disorder (PTSD). There is no meta-analytic evidence examining the effects of all types of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Sleep disturbances are an important symptom dimension of post-traumatic-stress-disorder (PTSD). There is no meta-analytic evidence examining the effects of all types of pharmacotherapy on sleep outcomes among patients with PTSD.
METHODS
Medline/Embase/PsychInfo/CENTRAL/clinicaltrials.gov/ICTRP, reference lists of published reviews and all included studies were searched for Randomised Controlled Trials (RCTs) examining any pharmacotherapy vs. placebo or any other drug among patients with PTSD.
PRIMARY OUTCOMES
total sleep time, nightmares, sleep quality.
SECONDARY OUTCOMES
sleep onset latency, number of nocturnal awakenings, time spent awake following sleep onset, dropouts due to sleep-related adverse-effects, insomnia/somnolence/vivid-dreams as adverse-effects. Pairwise and network meta-analyses were performed.
RESULTS
99 RCTs with 10,481 participants were included. Prazosin may be the most effective treatment for insomnia (SMD = -0.88, 95%CI = [-1.22;-0.54], nightmares (SMD = -0.44, 95%CI = [-0.84;-0.04]) and poor sleep quality (SMD = -0.55, 95%CI = [-1.01;-0.10]). Evidence is scarce and indicates lack of efficacy for SSRIs, Mirtazapine, z-drugs and benzodiazepines, which are widely used in daily practice. Risperidone and Quetiapine carry a high risk of causing somnolence without having a clear therapeutic benefit. Hydroxyzine, Trazodone, Nabilone, Paroxetine and MDMA-assisted psychotherapy may be promising options, but more research is needed.
CONCLUSIONS
Underpowered individual comparisons and very-low to moderate confidence in effect estimates hinder the generalisability of the results. More RCTs, specifically reporting on sleep-related outcomes, are urgently needed.
Topics: Humans; Stress Disorders, Post-Traumatic; Network Meta-Analysis; Sleep Wake Disorders; Prazosin; Randomized Controlled Trials as Topic; Dreams; Sleep Initiation and Maintenance Disorders
PubMed: 38795401
DOI: 10.1016/j.sleep.2024.05.032 -
Pharmaceutical Research Nov 2023The brain is protected from circulating metabolites and xenobiotics by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Previous studies...
PURPOSE
The brain is protected from circulating metabolites and xenobiotics by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Previous studies report that P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) are expressed apically or subapically at the blood-CSF barrier (BCSFB), implying a paradoxical function to mediate blood-to-CSF transport of xenobiotics. As evidence of P-gp and Bcrp activity at the BCSFB is limited, the goal of this study is to investigate functional activity of P-gp and Bcrp at the murine BCSFB using a live tissue imaging approach.
METHODS
The choroid plexuses (CP) forming the BCSFB were freshly isolated from mouse brain ventricles and incubated with fluorescent probes calcein-AM and BODIPY FL-Prazosin. Using quantitative fluorescence microscopy, the functional contributions of Bcrp and P-gp were examined using inhibitors and mice with targeted deletion of the Abcb1a/b or Abcg2 gene.
RESULTS
Apical transport of calcein-AM in choroid plexus epithelial (CPE) cells is sensitive to inhibition by elacridar and Ko143 but is unaffected by P-gp deletion. In wild-type mice, elacridar increased CPE accumulation of BODIPY FL-Prazosin by 220% whereas deletion of Bcrp increased BODIPY FL-Prazosin accumulation by 43%. There was no change in Mdr1a/1b mRNA expression in CP tissues from the Bcrp mice.
CONCLUSIONS
This study demonstrated functional activity of Bcrp at the BCSFB apical membrane and provided evidence supporting an additional contribution by P-gp. These findings contribute to the understanding of transport mechanisms that regulate CSF drug concentrations, which may benefit future predictions of CNS drug disposition, efficacy, and toxicity.
Topics: Animals; Mice; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Blood-Brain Barrier; Brain; Neoplasm Proteins; Prazosin
PubMed: 37704894
DOI: 10.1007/s11095-023-03598-7 -
Medical Oncology (Northwood, London,... Mar 2024Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to...
Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to ineffective treatment options and limited surgical interventions, hepatocellular carcinoma is notoriously difficult to treat. Nonetheless, drugs utilized for other medical conditions, such as the antihypertensive medication prazosin, the neuroleptic medication chlorpromazine, and the neuroleptic medication haloperidol, have gained attention for their potential anti-cancer effects. Therefore, this study used these medications for investigating toxicity to hepatocellular carcinoma while testing the adverse effects on a noncancerous liver cell line model THLE-2. After treatment, an XTT cell viability assay, cell apoptosis assay, reactive oxygen species (ROS) assay, apoptotic proteome profile, and western blot were performed. We calculated IC values for chlorpromazine and prazosin to have a molar range of 35-65 µM. Our main findings suggest the capability of both of these treatments to reduce cell viability and generate oxidative stress in HepG2 and THLE-2 cells (p value < 0.05). Haloperidol, however, failed to demonstrate any reduction in cell viability revealing no antitumor effect up to 100 µM. Based on our findings, a mechanism of cell death was not able to be established due to lack of cleaved caspase-3 expression. Capable of bypassing many aspects of the lengthy, costly, and difficult cancer drug approval process, chlorpromazine and prazosin deserve further investigation for use in conjunction with traditional chemotherapeutics.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Haloperidol; Chlorpromazine; Antipsychotic Agents; Prazosin; Hep G2 Cells; Antineoplastic Agents; Apoptosis; Cell Line, Tumor
PubMed: 38472423
DOI: 10.1007/s12032-024-02323-7 -
British Journal of Clinical Pharmacology Nov 2023Prazosin is an antihypertensive medication which can be used to help with post-traumatic stress disorder (PTSD) symptoms. Little data is currently available on its...
AIMS
Prazosin is an antihypertensive medication which can be used to help with post-traumatic stress disorder (PTSD) symptoms. Little data is currently available on its safety in pregnancy. The aim of this study was to assess the fetal and pregnancy safety associated with prazosin exposures in early pregnancy.
METHODS
Subjects were 11 patients who took prazosin during pregnancy and were counselled at the FRAME clinic in London Health Sciences Centre (Ontario, Canada) between 1 January 2000 and 31 December 2021. Data on their other exposures and pregnancy outcomes were collected from medical records and through telephone questionnaires.
RESULTS
It was found that 6/11 (54.5%) subjects did not report any adverse outcomes and experienced uneventful pregnancies. There were two miscarriages. Birthweights were within the normal range for the remaining nine pregnancies. Adverse events reported were consistent with background population expectation, including: one postpartum haemorrhage, one case of preeclampsia, one preterm birth, two NICU admissions, and two caesarean sections.
CONCLUSIONS
For these 11 subjects, pregnancy outcomes after exposure to prazosin were consistent with typical outcomes from unexposed pregnancies. More data are needed to conclude that prazosin is safe for use in pregnant subjects. However, the lack of adverse effects above baseline is reassuring to future patients who may be unintentionally exposed to prazosin while pregnant. Therefore, this study contributes valuable data towards monitoring safety of prazosin in pregnancy.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Pregnancy Outcome; Prazosin; Premature Birth; Ontario; London
PubMed: 37323115
DOI: 10.1111/bcp.15829 -
The Journal of Obstetrics and... Jul 2023The aim of this study is to investigate the effect of trimethylamine (TMA) and trimethylamine-n-oxide (TMAO) on the contractility of human umbilical artery and the...
BACKGROUND
The aim of this study is to investigate the effect of trimethylamine (TMA) and trimethylamine-n-oxide (TMAO) on the contractility of human umbilical artery and the possible mechanisms involved.
METHODS
Vasoactive responses to TMA and TMAO on human umbilical artery rings were measured in isolated organ baths. Cumulative dose-response curves for TMA and TMAO were obtained before and after incubation with atropine, yohimbine, prazosin, indomethacin, verapamil, and Ca -free Krebs-Henselite solution.
RESULTS
Administration of cumulative TMA and TMAO resulted in dose-dependent contraction at concentrations ranging from 10 to 100 mM on human umbilical artery rings. TMA-induced contractions were more potent than TMAO-induced contractions (TMA: -logEC50 = 1.00 ± 0.02, TMAO: -logEC50 = 0.57 ± 0.02). Contraction responses to TMA were significantly lower in the presence of verapamil and in the absence of external Ca (p < 0.001, p < 0.05, respectively).
CONCLUSION
Our results showed that TMA and TMAO caused vasoconstriction in isolated human umbilical artery rings. Our findings also indicated that TMA but not TMAO-induced vasoconstriction was partially dependent on extracellular Ca and calcium influx through L-type Ca channels. Our results suggest that TMA and TMAO may have the potential to contribute to cardiovascular diseases through their direct effect on vascular contractility in human arteries.
Topics: Humans; Methylamines; Oxides; Umbilical Arteries
PubMed: 37045561
DOI: 10.1111/jog.15656 -
Burns : Journal of the International... Apr 2024Post-traumatic stress disorder (PTSD) afflicts a significant portion of burn patients. This study aims to analyze the morbidity, prevalence, and treatment of PTSD in the...
INTRODUCTION
Post-traumatic stress disorder (PTSD) afflicts a significant portion of burn patients. This study aims to analyze the morbidity, prevalence, and treatment of PTSD in the burn population.
METHODS
Using the TriNetX database, we identified burned patients > 18 years of age without (A) or with (B) a PTSD diagnosis. Patients were then stratified by percent of total body surface area (TBSA) burned. Morbidity and mortality was analyzed in each cohort. Prevalence and pharmacologic treatments for PTSD were analyzed from 2002 to 2022.
RESULTS
PTSD incidence increased from 2.4% (n = 2281) in patients with < 10% to 3.1% (n = 542) in 10-30%, 7.4% (n = 285) in 30-59%, and 5.3% (n = 90) in > 60% TBSA burned. In patients with < 60% TBSA burned, PTSD diagnosis increased the risk of depression (p = <0.0003) and anxiety (p = <0.0001). In those with < 30% TBSA burned, PTSD diagnosis also increased risk of insomnia (p = <0.0001) and pruritus (p = 0.0211 for TBSA <10% and 0.0059 for TBSA 10-29%). PTSD diagnosis was associated with a decreased risk of mortality in patients with > 30% TBSA burned (p = 0.0179 for TBSA 30-59% and p = 0.0089 for TBSA >60%). From 2002 to 2022, the prevalence of PTSD in all burn patients was relatively stable between 2.2% and 3.2%. We found an increase in the use of serotonergic agents and prazosin for the treatment of PTSD during this timeframe.
CONCLUSION
PTSD is not uncommon in the burn population, and those with burns and concomitant PTSD have an increased risk of morbidity. Screening and preventative measures to reduce morbidity and early implementation of care in burned patients with PTSD are indicated.
Topics: Humans; Burns; Stress Disorders, Post-Traumatic; Incidence; Prevalence; Anxiety Disorders; Retrospective Studies
PubMed: 38233276
DOI: 10.1016/j.burns.2023.12.016 -
Heliyon Dec 2023To determine the concentrations of nine drugs used in the treatment of cardiovascular diseases in human plasma through QuEChERS pre-treatment combined with...
To determine the concentrations of nine drugs used in the treatment of cardiovascular diseases in human plasma through QuEChERS pre-treatment combined with ultra-performance liquid chromatography-tandem mass spectrometry. Plasma samples were extracted with 3 mL of acetonitrile, 400 mg of anhydrous magnesium sulfate as a salting agent, and 20 mg of C18 as a sorbent. An Agilent Poroshell 120 EC-C18 column (4.6 × 100 mm, 2.7 μm) was selected and methanol-0.1 % water was used as the mobile phase, and ESI positive ion detection mode was selected. Results: The plasma concentrations of nisoldipine, metoprolol, and prazosin exhibited good linearity within the range of 0.05-4.0 ng/mL (r > 0.99), while atenolol, bisoprolol, propranolol, rosuvastatin, and atorvastatin showed linearity within the range of 0.5-40 ng/mL (r > 0.99). Fluvastatin showed good linearity within the range of 5.0-400 ng/mL. The accuracy of the method ranged from 94.15 to 110.62 %, while the recovery levels were in the range of 85.23 %-115.13 %. The matrix effects were observed between-6.54 % and 12.43 %. The intra-day and inter-day RSD was <15 % for the three concentrations of low, medium, and high. Conclusion The proposed method is rapid, accurate, specific, simple, reproducible, and suitable for the simultaneous measurement of the concentrations of nine drugs used in the treatment of cardiovascular diseases in human plasma.
PubMed: 38094060
DOI: 10.1016/j.heliyon.2023.e22543 -
The Journal of Urology Oct 2023Male lower urinary tract symptoms have been correlated with an increased risk of death; however, it is unclear if treatment will reduce this risk. Our objective was to... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Male lower urinary tract symptoms have been correlated with an increased risk of death; however, it is unclear if treatment will reduce this risk. Our objective was to determine whether a reduction in lower urinary tract symptoms is associated with a reduced risk of mortality.
MATERIALS AND METHODS
We conducted a secondary analysis of the MTOPS (Medical Treatment of Prostate Symptoms) randomized trial of placebo, doxazosin, finasteride, or doxazosin and finasteride. Men in the United States between 1993 and 1998 who were >50 years of age with moderate to severe lower urinary tract symptoms were included. We used various Cox regression models to assess the relationship between AUA Symptom Score (modeled as a time-varying exposure) and death.
RESULTS
A total of 3,046 men (median age 62, quartiles 57-68) were randomized and had a baseline AUA Symptom Score. For each 1-point improvement in the AUA Symptom Score, the hazard ratio for death was 0.96 (0.94-0.99, = .01). Our sensitivity analyses found a similar significant reduction in the hazard ratio for death within men who had active treatment, but not among men who were randomized to the placebo arm; our results did not change when men were censored at the time of transurethral prostate resection, with adjustment for potential confounders, or with a shorter observation period after the last study visit. A comparable significant reduction in death was seen with 1-point improvements in the storage (HR 0.94, 95% CI 0.88-0.99, = .04) and voiding (HR 0.95, 95% CI 0.91-0.99, = .03) subscales individually.
CONCLUSIONS
Improvement in male lower urinary tract symptoms was associated with a reduced risk of death. Further study is warranted to determine if the male treatment paradigm should shift toward symptom treatment independent of bother.
Topics: Humans; Male; Middle Aged; Doxazosin; Finasteride; Prostate; Pelvis; Lower Urinary Tract Symptoms
PubMed: 37681541
DOI: 10.1097/JU.0000000000003602