Prazosin

The importance of neuronal and lumenal vascular adrenoceptors in the regulation of vascular reactivity was examined in rainbow trout (Oncorhynchus mykiss), in vivo and in vitro. In vivo, ganglionic blockade with hexamethonium or alpha-adrenoceptor blockade, with either phentolamine or prazosin, produced similar (7mmHg) decreases in dorsal aortic blood pressure. The drop in dorsal aortic pressure produced by phentolamine or prazosin was due to reduced systemic vascular resistance. Neither the alpha-adrenoceptor antagonist, phenoxybenzamine nor chemical sympathectomy with 6-hydroxy-dopamine affected dorsal aortic pressure. However, after chemical sympathectomy, phenoxybenzamine lowered dorsal aortic pressure to levels similar to that produced by either phentolamine or prazosin. Plasma epinephrine and norepinephrine concentrations increased four- and twofold, respectively, in sympathectomized fish. Sympathectomy also produced a leftward shift in the epinephrine dose/response curve of t...

Aggressive behavior in dementia is a major clinical management problem. Postmortem brain tissue was obtained from 24 patients with Alzheimer disease (AD) and 25 comparison cases. [3H] Prazosin binding to alpha1-AdR was determined. Aggressive behavior was significantly correlated with alpha1-adrenoceptor number in patients with AD (R(s)=0.454, N=24). Furthermore, patients receiving ongoing neuroleptics had significantly higher Bmax for [3H] prazosin (21 +/- 2, N=9) than those who were not (16 +/- 1, N=15). Upregulation of alpha1-AdR is associated with aggressive behavior and chronic treatment with neuroleptic medication.

The α1-adrenoceptor antagonist doxazosin has been compared with placebo in 40 elderly hypertensive patients (mean age 71.4 years). At the end of 10 weeks once daily treatment with doxazosin the mean 24-h post-dose changes in standing and supine blood pressure compared with placebo were −6.9/−5.6 mmHg (systolic/diastolic) and −6.2/−5.5 mmHg respectively. The reductions in standing and supine diastolic blood pressures were statistically significant compared with placebo. At the end of treatment steady-state pharmacokinetics were evaluated in 18 patients. The plasma elimination half-life during the dose interval in these patients was 16.1 h (range 10.1–27.1 h) and the median time to peak plasma concentration was 3 h (range 1–4 h). One patient was withdrawn because of adverse effects (headache, weakness, and sweating) during doxazosin treatment. Once daily doxazosin reduced diastolic blood pressure and was well tolerated in these elderly hypertensive patients.

Objective To evaluate the perinatal outcome of expectant management of early onset, severe pre-eclampsia.Design Prospective case series extending over a five-year period.Setting Tertiary referral centre.Population All women (n= 340) presenting with early onset, severe pre-eclampsia, where both mother and the fetus were otherwise stable.Methods Frequent clinical and biochemical monitoring of maternal status with careful blood pressure control. Fetal surveillance included six-hourly heart rate monitoring, weekly Doppler and ultrasound evaluation of the fetus every two weeks. All examinations were carried out in a high care obstetric ward.Main outcome measures Prolongation of gestation, perinatal mortality rate, neonatal survival and major complications.Results A mean of 11 days were gained by expectant management. The perinatal mortality rate was 24/1000 (≥ 1000 g/7 days) with a neonatal survival rate of 94%. Multivariate analysis showed only gestational age at delivery to be significantly associated with neonatal outcome. Chief contributors to neonatal mortality and morbidity were pulmonary complications and sepsis. Three pregnancies (0.8%) were terminated prior to viability and only two (0.5%) intrauterine deaths occurred, both due to placental abruption. Most women (81.5%) were delivered by caesarean section with fetal distress the most common reason for delivery. Neonatal intensive care was necessary in 40.7% of cases, with these babies staying a median of six days in intensive care.Conclusion Expectant management of early onset, severe pre-eclampsia and careful neonatal care led to high perinatal and neonatal survival rates. It also allowed the judicious use of neonatal intensive care facilities. Neonatal sepsis remains a cause for concern.

To determine the clinical effectiveness and safety of alpha,-blockade therapy versus placebo in the treatment of men with moderate to severe symptoms of prostatism in a community-based population under usual care conditions.The Hytrin Community Assessment Trial is a prospective, placebo-controlled, randomized, double-blinded, 1-year clinical trial, conducted at 15 academic medical centers (regional sites) and 141 private urology practices (satellite sites). A total of 2084 men at least 55 years old with moderate to severe symptoms of benign prostatic hyperplasia (BPH) as determined by an American Urological Association (AUA) Symptom Score (AUA-SS) of 13 or more points and a bother score (AUA-BS) of 8 or more were enrolled. Randomized patients at regional sites were required to have a peak urinary flow rate less than 15 mL/s with a voided volume of at least 150 mL. Treatment with terazosin was initiated with 1 mg daily for 3 days, followed by 2 mg daily for 25 days. Thereafter, patients were titrated stepwise to 5 or 10 mg if they failed to achieve a 35% or greater improvement in the AUA-SS. Primary outcome measures were AUA-SS, AUA-BS, BPH Impact Index (Bll), disease-specific quality of life (QOL) score, and treatment failure as defined as discontinuation due to persistent or worsening symptoms or need for surgical intervention for BPH. Secondary outcome measures were peak urinary flow rate and postvoid residual urine volume.AUA-SS (0 to 35 point scale) improved from a baseline mean of 20.1 points by 37.8% during terazosin (n = 976) and by 18.4% during placebo (n = 973) treatment (P < 0.001). Similarly, statistically superior improvements were observed in regard to the AUA-BS, Bll, and the QOL score in the terazosin-treated patients. Peak urinary flow rate improved from a baseline of 9.6 mL/s (both regional treatment groups) by 2.2 mL/s in the terazosin group (n = 137) and by 0.7 mL/s in the placebo group (n = 140) (P ≤0.05). Treatment failure occurred in 11.2% of terazosin- and 25.4% of placebo-treated patients (P < 0.001 ; Kaplan-Meier adjusted withdrawal rates at 365 days). Withdrawal from study drug treatment due to adverse events occurred in 19.7% of terazosin- and 15.2% of placebo-treated patients (P < 0.001).Terazosin given once daily in a dose ranging from 2 to 10 mg in community-based urology practices under conditions simulating usual care is effective in reducing the symptoms, perception of bother, and the impairment of QOL due to urinary symptoms in men with moderate to severe symptoms of prostatism. This effect is superior to placebo and maintained over 12 months of follow-up. Clinical research outcome studies in BPH can be conducted in community-based practices, thus simulating as closely as possible “usual care” conditions.

Objective To identify and correlate various factors affecting the outcome of children with scorpion sting envenomation treated with prazosin in a tertiary care hospital. Methods The study included 90 children admitted with scorpion sting envenomation over a period of four and half year. Grading of severity was done on the basis of local or systemic involvement, and management protocol was followed as per hospital guidelines. All cases with envenomation were given prazosin at a dose of 30 μg/kg/dose;first repeat dose at 3 h followed by every 6 h till recovery. Patients with acute pulmonary edema (APE) were treated as per standard protocol. Results All patients had perspiration and cold extremities. Most of them had sting over extremities except two,having over the trunk. Shock was present in 48(53.3%), whereas myocarditis, encephalopathy, pulmonary edema and priapism were present in 38(42.2%), 32(35.5%), 34(37.8%), and 28(31.1%) children, respectively. Eight (8.9%) children had died. The mean value of blood pressure, sodium and potassium among survivors and non-survivors was insignificant. Mortality was significantly higher in children presented after 6 h of bite. Patients, who had metaboloic acidosis, tachpnea, myocarditis, APE, encephalopathy and priapism had significantly higher mortality (p < 0.05). Conclusions Symptoms of acidosis, tachypnea, myocarditis, APE, encephalopathy after 6 h of sting are major contributing factors affecting outcome in children with scorpion sting envenomation.

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bio...

Fluorescent ligands provide the means of studying receptors in whole tissues using confocal laser scanning microscopy and have advantages over antibody-or non-fluorescence-based method. Confocal microscopy provides large volumes of images to be measured. ...

Purpose To evaluate the effect of Terazosin (α1 adrenergic blocker) on bladder emptying in children with posterior urethral valves. Materials and methods Forty-two children with significant post void residual urine after valves ablation were placed on Terazosin ranging from 0.25 to 2 mg. Post void urine at the commencement and at follow up was monitored with abdominal ultrasound. Results Post void residual urine significantly reduced in 40 patients (95%) who were put on Terazosin. Mean pretreatment PVR was 15.7 ml and mean PVR at the last follow up was 2.4 ml (P = 0.000). This was a reduction of 85% in the pretreatment post void residual urine volume. All the patients had improvement in urinary stream. One patient reacted to Terazosin with hypotension necessitating its withdrawal. Mean follow up was 17 months. Conclusion Terazosin has proved to be safe and results in significant improvement in bladder emptying in our patients with posterior urethral valves. Randomized controlled trial and long-term follow up are necessary to further define the role of α1 adrenergic blocker therapy in children with posterior urethral valves. This study will become the justification for such a study.

Rationale Clozapine is an efficacious, symptom-ameliorating, atypical antipsychotic drug with few extrapyramidal side effects. Clozapine has been reported either not to affect or to increase d-amphetamine-induced stereotypy, a behavior that is blocked by typical antipsychotic drugs. Objectives This work used a high-resolution measurement system to reassess clozapine’s effects on d-amphetamine-induced focused stereotypy (FS) in rats. Materials and methods A force-plate actometer permitted the quantitation of the rhythm and vigor of movements during FS. Eight rats received a sensitizing series of doses of 5.0 mg/kg d-amphetamine sulfate, and this dosing regimen induced head movements with a rhythm near 10 Hz. Thirty minutes after d-amphetamine treatment, rats received acute clozapine (2.5–10.0 mg/kg), followed by eight, daily clozapine injections (5.0 mg/kg) given with d-amphetamine on days 2, 5, and 8. Effects of acute doses of the α1-noradrenergic antagonist prazosin (0.5–2.0 mg/kg) on the d-amphetamine response were also examined. Results Clozapine dose-dependently slowed the near 10-Hz rhythm and reduced the vigor of the d-amphetamine-induced FS. Clozapine significantly lengthened the duration of the FS phase, but the rhythm remained slowed. No evidence for tolerance to clozapine’s rhythm-slowing effects was seen in the subchronic phase. Prazosin dose-dependently reduced the near 10-Hz rhythm induced by d-amphetamine, but prazosin did not lengthen the FS phase. Conclusions The results show that clozapine diminished the rhythm and vigor of d-amphetamine-induced stereotyped head movements but, at the same time, lengthened the duration of the expression of the stereotypy. α1 antagonism is a likely contributor to the rhythm-modulating effects of clozapine.

Summary of Recommendations:Prazosin is recommended for treatment of Posttraumatic Stress Disorder (PTSD)-associated nightmares. Level AImage Rehearsal Therapy (IRT) is recommended for treatment of nightmare disorder. Level ASystematic Desensitization and Progressive Deep Muscle Relaxation training are suggested for treatment of idiopathic nightmares. Level BVenlafaxine is not suggested for treatment of PTSD-associated nightmares. Level BClonidine may be considered for treatment of PTSD-associated nightmares. Level CThe following medications may be considered for treatment of PTSD-associated nightmares, but the data are low grade and sparse: trazodone, atypical antipsychotic medications, topiramate, low dose cortisol, fluvoxamine, triazolam and nitrazepam, phenelzine, gabapentin, cyproheptadine, and tricyclic antidepressants. Nefazodone is not recommended as first line therapy for nightmare disorder because of the increased risk of hepatotoxicity. Level CThe following behavioral therapies may be considered for treatment of PTSD-associated nightmares based on low-grade evidence: Exposure, Relaxation, and Rescripting Therapy (ERRT); Sleep Dynamic Therapy; Hypnosis; Eye-Movement Desensitization and Reprocessing (EMDR); and the Testimony Method. Level CThe following behavioral therapies may be considered for treatment of nightmare disorder based on low-grade evidence: Lucid Dreaming Therapy and Self-Exposure Therapy. Level CNo recommendation is made regarding clonazepam and individual psychotherapy because of sparse data.Citation:Aurora RN; Zak RS; Auerbach SH; Casey KR; Chowduri S; Krippot A; Maganti RK; Ramar K; Kristo DA; Bista SR; Lamm CI; Morgenthaler TI. Best practice guide for the treatment of nightmare disorder in adults. J Clin Sleep Med 2010;6(4):389-401.

Antihypertensive effect, platelet aggregation, and plasma lipid profile were studied in a group of 14 hypertensive patients with diastolic blood pressure between 96 and 116 mm Hg during placebo and terazosin phases. Terazosin, an alpha 1-adrenergic blocking agent, was given initially at the dosage of 1 mg daily. Then it was continued at a dosage of 2 mg daily and 5 mg daily respectively, each dosage for 4 weeks. Blood pressure was taken every 2 weeks. Ex vivo platelet aggregation induced by epinephrine, collagen, and adenosine diphosphate (ADP) were carried out twice during the first placebo phase, once at the end of each terazosin dosage, and once in the second placebo phase. Total cholesterol, HDL cholesterol, and triglycerides were measured at the end of first placebo and terazosin phases. Blood from eight patients was taken during the second placebo phase to carry out in vitro response of platelet aggregation induced by ADP, collagen, and epinephrine before and after incubation ...

Rationale Central α1- and α2-adrenoceptors in a number of different brain regions are known to have opposing actions on gross behavioral activity, with the former stimulating and the latter inhibiting activity. Therefore, blockade of α1-receptors may induce inactivity by leading to unopposed α2 activity. Objective The aim of this study was to test if central blockade of α2-receptor function restores behavioral activity in α1-receptor-blocked mice. Methods Dose-response studies were undertaken on the effects of α1- and α2-agonists and antagonists microinjected into the dorsal pons on gross behavioral activity in a novel cage test. Results The behavioral inactivity resulting from blockade of α1-receptors in the pons with the antagonist, terazosin, was reversed by either a low dose of an α2-antagonist, atipamezole, or a low dose of an α2-agonist, dexmedetomidine, but was exacerbated by a high dose of the α2-agonist. Conclusion The results support the hypothesis that blockade of α1-receptors in the dorsal pons of mice produces inactivity by causing unopposed activity of α2-receptors. This condition may be relevant to inactive states seen after stress or during depressive illness.

Redox active proteins in plant mitochondria were examined using 2-D oxidant/reductant diagonal-SDS-PAGE to separate and identify proteins with intermolecular or intramolecular disulphide bonds using diamide in the first dimension and DTT in the second dimension. Eighteen proteins spots were resolved either above or below the diagonal and these were in-gel digested and identified by MS/MS. This analysis revealed intermolecular disulphide bonds in alternative oxidase, O-acetylserine (thiol) lyase, citrate synthase and between subunits of the ATP synthase. Intramolecular disulphide bonds were observed in a range of mitochondrial dehydrogenases, elongation factor Tu, adenylate kinase and the phosphate translocator. Many of the soluble proteins found were known glutaredoxin/thioredoxin targets in other plants, but the membrane proteins were not found by these methods nor were the nature of the disulphides able to be investigated. The accessibility of thiols involved in disulphide bonds to modification by a lipid derived aldehyde gave an insight into the potential impact of Cys modification on redox-functions in mitochondria during lipid peroxidation. Comparison of the protein sequences of the identified proteins with homologs from other species has identified specific Cys residues that may be responsible for plant-specific redox modulations of mitochondrial proteins.

The aim of performing this work is to study and evaluate Genotoxicity and Cytotoxicity of Prazosin HCL in mice. The animals were treated with Prazosin (PZ) at the doses of 5, 15, 25 mg/kg/body weight intraperitoneal (IP) for single dose (14 days) toxicity studies. Different methods were used to perform the study like Measurement of body weight, organ weight and food intake, Estimation of Malondialdehyde (MDA) level, Estimation of Reduced Glutathione (GSH) level, For evaluation of Genotoxicity following parameters has been evaluated: Micronucleus assay in bone marrow, Micronucleus assay in peripheral blood, Determination of DNA damage: Metaphase chromosome analysis, Determination of DNA damage: DNA fragmentation assay, Determination of Cytotoxicity: Histological examination.The results obtained clearly demonstrate that PZ produced toxic responses at the higher dose in the hepatocytes as evident from increased MDA level, decreased GSH level, DNA damage, increased DNA fragmentation in mice. Also, it is interesting that in bone marrow cells, PZ induced structural chromosomal aberrations, and significantly DNA strand breakage observed. So it is considered as Genotoxicity toward the bone marrow cells and to the hepatocytes of mice. The present study provided evidence that Prazosin induced significant genotoxic effects in mice at its equivalent hepatotoxic dose level.

In vitro assays on a series of cis- and trans-octahydrobenzo[g]quinolines indicated an unusual trend of affinities at the dopaminergic receptors and alpha adrenoceptors. The trans N-benzyl analogues exhibited affinity at the alpha2 as well as the D1-like receptors whereas their N-unsubstituted congeners showed a distinct preference for the alpha2 adrenoceptor. Enhanced activity for the alpha2 receptors was also exhibited by the cis N-benzylated isomers. These observations are interpreted by theoretical calculations.

Central neural networks operate continuously throughout life to control respiration, yet mechanisms regulating ventilatory frequency are poorly understood. Inspiration is generated by the pre-Bötzinger complex of the ventrolateral medulla, where it is thought that excitation increases inspiratory frequency and inhibition causes apnea. To test this model, we used an in vitro optogenetic approach to stimulate select populations of hindbrain neurons and characterize how they modulate frequency. Unexpectedly, we found that inhibition was required for increases in frequency caused by stimulation of Phox2b-lineage, putative CO-chemosensitive neurons. As a mechanistic explanation for inhibition-dependent increases in frequency, we found that phasic stimulation of inhibitory neurons can increase inspiratory frequency via postinhibitory rebound. We present evidence that Phox2b-mediated increases in frequency are caused by rebound excitation following an inhibitory synaptic volley relayed by ...

In PTSD, sleep disorders represent an important symptoms dimension which is associated with more severe PTSD and increased risk of relapse. The basic treatment for PTSD is not always associated to an improvement of sleep disturbances and nightmares. Alpha-blockers, and more specifically Prazosin, have shown a specific action on sleep disorders in PTSD. We report the clinical case of a young women with PTSD, who was suffering from severe sleep disorder and distressing nightmare. The patient was treated with Terazosin, a conger of Prazosin, and has shown symptom remission. Further studies on the use of alpha-blokers might reveal new therapeutic options in PTSD.