Repeated exposure to laboratory stressors often results in behavioral changes that are commonly referred to as depressive-like behaviors. Here, we examined the contribution fear conditioning may play in altering an animals' behavior in a repeated stress paradigm. Fischer rats were exposed daily to different stressors in a complex environment (context A). After four days of stressor exposure, exploratory behavior (10 min in new cage) and social interaction (5 min with juvenile) were tested on day 5 in either the same environment or a new environment (context B). Rats showed decreased exploration and social interaction when tested in context A compared to control rats or rats tested in context B. Additionally, chronic infusion of propranolol (beta-adrenergic receptor antagonist that crosses the blood-brain barrier), but not nadolol (beta-adrenergic receptor antagonist that does not readily cross the blood-brain barrier), prevented the behavioral changes following repeated stressor exposure. Propranolol treatment did not affect the acute or chronic elevation of corticosterone, the decrease in body weight gain, or adrenal hypertrophy observed in animals exposed to stress. These data demonstrate that conditioned fear responses can contribute to behavioral changes in a repeated stress paradigm. Additional studies revealed, Sprague-Dawley rats do not demonstrate decreased exploration or social interaction when testing occurs in the same context as repeated stressor exposure suggesting Fischer rats may have a greater propensity to associate distal cues with aversive events in a complex environment. This may be due to greater stress responses in Fischer animals that are known to enhance consolidation of emotionally arousing events.
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These studies suggest that the active ingredient of A. hypogaea such as resveratrol can act as a sympathomimetic compound and induce aggregation of melanophores of tadpole B. melanostictus via the induction of beta type of the adrenoceptors. The present study opens new vistas for the use of A. hypogaea and its active ingredient, resveratrol for its clinical application as a nontoxic melanolytic compound for the treatment of hyperpigmentation.
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Propylthiouracil is a drug used in the treatment of hyperthyroidism for more than 60 years. Adverse side effects are seen in 1-5% of patients. Renal complications of the drug including glomerulonephritis and vasculitis are rarely seen. Cases of propylthiouracil-induced rapidly progressive glomerulonephritis and vasculitis are reported in association with antineutrophil cytoplasmic autoantibodies. Here we report a case of positive antineutrophil cytoplasmic autoantibodies rapidly progressive glomerulonephritis (RPGN) associated with propylthiouracil treatment.
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Anaesthesia for resection of a phaeochromocytoma in early pregnancy can be successfully managed with preoperative alpha and beta sympathetic blockade and a balanced anaesthetic technique using magnesium as the main intraoperative hypotensive agent.
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Of the 777 patients, 64 (8.2%) developed atrial tachycardia. The independent risk factors for developing atrial tachycardia included surgical age 6 months or younger (odds ratio, 4.4; 95% confidence interval, 1.1-19.15), use of 3 or more inotropes (odds ratio, 2.9; 95% confidence interval, 1.4-6.2), and heterotaxy syndrome (odds ratio, 2.9; 95% confidence interval, 1.1-7.4). All-cause mortality in the atrial tachycardia group was increased (21.9% vs 7.2%, P<.001) during a median follow-up period of 14.6 months (interquartile range, 6.8-24.6), and atrial tachycardia was independently associated with decreased survival (hazard ratio, 1.9; 95% confidence interval, 1.1-3.8). Infants with perioperative atrial tachycardia had a longer hospital length of stay (32 vs 17 days, P<.001) and duration of inotrope use (10.5 vs 3.0 days, P<.001). A total of 57 patients received antiarrhythmic therapy, with propranolol the most common (n=31). Among the survivors, 48 patients received outpatient antiarrhythmic therapy, which was successfully discontinued in 23 patients at a median duration of 14 months (interquartile range, 5.7-18.6) without recurrence.
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A 22year old man with mild von Willebrand disease presented with two occipital CCM, one of them with acute hemorrhage. Genetic testing for CCM1-3 did not reveal a mutation. Over a period of 54months, the patient suffered 26 new CCM hemorrhages despite multiple treatment attempts including thalidomide, simvastatin and hemostatic factors. Only after initiation of propranolol, which has already been successfully used in three children with giant cerebral cavernoma, the occurrence of new CCM with hemorrhages was completely stopped already at dose of 30mg daily - now for a period of 26months and without any other medications.
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Twelve (60%) haemangiomas were located on the upper eyelid, five in the lower eyelid (25%) and three in the medial cantus (15%). The tumour resolved completely in 10 children (50%) and in 10 children (50%) partial resolution was documented. Seven (35%) patients underwent treatment (intralesional or oral steroids or propranolol). Grey-scale US depicted a solid-tissue mass with low internal echogenicity. Mean haemangioma volume was 1.33 cm(3) . Colour Doppler imaging demonstrated intralesional flow with a mean peak systolic velocity of 15.2 cm per second and a mean resistance index of 0.51. All US and CDI examinations were carried out on alert children and no sedation or general anaesthesia was needed. During mean follow-up time of 23 months, no child required any additional imaging or diagnostic procedures to confirm the diagnosis.
ISP suppressed induction of VF and the increase of DF with time. PRO aggravated VF and accelerated DF.
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Akrinor (AKR), a mixture of theodrenaline (TDR) and cafedrine (CDR), is a sympathomimetic agent used to counter transitory hypotension. Although some cases of vascular complications associated with AKR have been reported there are no experimental data about its direct effects on coronary arteries. The effects of AKR, TDR, CDR, and ephedrine (EDR) were studied on the isometric contraction of the ring preparations of pig coronary arteries precontracted with KCl. The influence of endothelium removal and preincubation with nonselective beta-adrenoreceptor antagonist propranolol (PROP), alpha(1)-adrenoreceptor antagonist prazosin, dopamine receptor antagonist SCH 23390, and adenosine receptor antagonist CGS 15943 were also tested. AKR, TDR, and CDR produced relaxation of the preparations. Preparations without endothelium were more sensitive to AKR relaxing effects. EDR produced an increase of vascular ring tonus. AKR, TDR, and EDR produced contraction in preparations pretreated with PROP. Higher concentrations of AKR relaxed PROP-pretreated preparations. AKR-induced contraction could be prevented by pretreatment with prazosin. Dopamine and adenosine receptor antagonists did not influence relaxing effects of AKR. In conclusion, AKR and its constituents induce the relaxation of pig coronary artery preparations precontracted with KCl. The observed contraction in the preparations pretreated with PROP was probably due to stimulation of unmasked alpha(1)-adrenoreceptors.
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In heart failure, protein kinase A-mediated hyperphosphorylation of ryanodine receptors (RyRs) in sarcoplasmic reticulum (SR) causes dissociation of FKBP12.6 from RyRs. This results in an abnormal Ca2+ leak through RyRs, possibly leading to cardiac dysfunction. In the present study, we assess whether beta-blockers can correct this defect in RyR in tachycardia-induced heart failure and thereby improve cardiac function.
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Trauma-induced hypercatecholaminemia negatively impacts bone marrow (BM) function by suppressing BM hematopoietic progenitor cell (HPC) growth and increasing HPC egress to injured tissue. Beta blockade (BB) given before tissue injury alone has been shown to reduce both HPC mobilization and restore HPC colony growth within the BM. In a clinically relevant model, this study examines the effect of BB given after both tissue injury and hemorrhagic shock (HS).
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We recently demonstrated that adipocyte lactate production depends on alpha-1 adrenergic control and that adipocytes can produce lactate even when insulin-stimulated glucose uptake is markedly impaired. This prompted us to investigate the glucose uptake in response to an alpha-1 adrenergic stimulation. We measured the adrenergic regulation of glucose uptake by adipocytes isolated from epididymal white adipose tissue using agonists (norepinephrine, phenylephrine and isoproterenol) and antagonists (prazosin and propranolol) of alpha-1 and beta adrenoceptor subtypes. Our results show that the maximal glucose uptake obtained in the presence of 10(-8) M norepinephrine is partially inhibited by prazosin (10(-6) M, 57%) or propranolol (10(-6) M, 52%) suggesting that glucose uptake is subjected to both alpha-1 and beta regulation. Indeed, our findings show that glucose uptake is dose-dependently increased by phenylephrine. This stimulation is totally inhibited by prazosin (10(-6) M). Isoproterenol stimulated glucose uptake. The stimulation of glucose uptake by isoproterenol is totally inhibited in the presence of propranolol (10(-6) M) in the incubation medium. Our results demonstrate for the first time that alpha-1 adrenergic subtype is involved in the regulation of glucose uptake by white adipocytes.
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Timolol has recently been reported to be an effective and safe treatment for small and superficial infantile hemangiomas (IH). However, it is controversial to choose it as an alternative to oral propranolol for large superficial IH. In this study, we generated a new modified timolol agent as the base of an ointment. To evaluate the efficacy and safety of this new agent, we recruited 20 patients with large superficial IH. The average age was 4 months old. The average area of the IH was 28.8 cm(2) . The treatment was continued for 2-6 months. Three assessors were asked to judge the changes in both the treated and untreated parts separately by comparing photographs. After an average of 3.25 months of treatment, the average visual analog scale scores were 5.5 and 4.3 for those with and without the medication, respectively. The treated parts regressed significantly more than the untreated parts (P < 0.05). There were no side-effects observed during treatment. High performance liquid chromatography was used to detect the serum concentration of timolol, and no timolol was detected in any of the blood samples (<0.02 μg/mL). Our new modified timolol agent is proven to be an effective therapy option for IH. Prospective studies with high-precision serum timolol concentrations, with heart rate or blood pressure monitoring during treatment, are needed to evaluate potential systemic absorption when using timolol on large IH.
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Parasympathetic neurons were isolated from human tracheas and grown in serum-free medium for one week. Cells were incubated with either (R)-albuterol (the active isomer), (S)-albuterol (the inactive isomer) or (R,S)-albuterol for 90 minutes before adding 2 ng/ml TNF-alpha for another 4 hours (for mRNA) or 24 hours (for protein).
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Pathology showed a Zellballen pattern, negative tumor margins and benign para-aortic lymph nodes. Mutation analysis of the succinate dehydrogenase type B (SDHB) gene revealed a heterozygous change of C to T at position 640 in exon 6 (Q214X) predicting an amino acid change to a stop codon.
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At the heart of every migraine treatment concept is the management of the acute attack with effective medication. Here, the triptans have been progressively replacing the ergot alkaloids with their unsatisfactory relationship between effect and side effects. Prophylactic medication is indicated when, despite every non-pharmaceutic measure, migraine attacks occur on seven or more days in a month. The beta receptor blockers metoprolol and propranolol have so far been considered the substances of first choice, but in practice there is now a trend towards substances with a lower potential for side effects. The article provides an up-to-date overview of the efficacy and tolerability of the various migraine prophylactics.
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Propranolol appears to be a safe and effective treatment in the management of periorbital proliferating phase infantile hemangioma.
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Rapamycin and SDZ-RAD showed a distinct preference for transport in the basolateral to apical direction of Caco-2 monolayers as efflux was >20 times greater than apical to basolateral transport. Efflux of SDZ-RAD was completely inhibited by verapamil while efflux of rapamycin was mostly inhibited by verapamil and partially inhibited by probenecid. Passive permeability was shown to be 20 x 10(-6) cm/sec for SDZ-RAD and 10 x 10(-6) cm/sec for rapamycin. In situ rat studies also showed the permeability of rapamycin to be half that of SDZ-RAD with permeabilities of 12.6 X 10(-6) for rapamycin and 24.8 x 10(-6) cm/sec for SDZ-RAD.
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The cardiogenic capacity of embryonic stem (ES) cells has been well-investigated. However, little is known about the development of adrenoceptor (AR) systems during the process of ES cell differentiation, which are critically important in cardiac physiology and pharmacology. In this present study, we investigated the expression profile of adrenoceptor subtypes, beta-adrenergic modulation of muscarinic receptors and adrenoceptor-related signaling in cardiomyocytes derived from ES cells (ESCMs). Reverse transcription-polymerase chain reaction revealed that undifferentiated mouse ES cells expressed alpha(1A)-, alpha(1B)-, alpha(1D)- and beta(2)-AR mRNA. However, beta(1)-AR was only expressed after vitamin C induction. The expressions of alpha(1A)-, alpha(1D)- and beta(1)-ARs increased significantly while alpha(1B)- and beta(2)-ARs showed no significant change during the differentiation process. Furthermore, we detected the expression of tyrosine hydroxylase. Both alpha(1)-AR and beta-AR could activate extracellular responsive kinase in ESCMs. Isoprenaline could inhibit the expression of M(2) muscarinic receptor protein. CGP20712A, a beta(1)-AR antagonist, up-regulated the expression of M(2) muscarinic receptor while ICI118551, a beta(2)-AR antagonist, showed no effect. These results indicated that functional adrenoceptors and tyrosine hydroxylase, a critical enzyme in catecholamine biosynthesis, were differentially expressed in ESCMs. Adrenoceptor-related signaling pathways and beta-adrenergic modulation of muscarinic receptors were established during differentiation.
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Recent data suggest that propranolol is an effective treatment for infantile hemangiomas (IHs). Data on the optimal dose, duration of therapy, and predictors of response are currently lacking.
Worldwide, contamination of aquatic systems with micropollutants, including pharmaceuticals, is one of the challenges for sustainable management of water resources. Although micropollutants are present at low concentrations, many of them raise considerable toxicological concerns, particularly when present as components of complex mixtures. Recent research has shown that this problem cannot be sustainably solved with advanced effluent treatment. Therefore, an alternative that might overcome these environmental problems is the design of new pharmaceutical molecules or the redesign of existing pharmaceutical molecules that present the functionality needed for their application and have improved environmental biodegradability. Such redesigning can be performed by small molecular changes in the drug molecule with intact drug moiety which could incorporate the additional attribute such as biodegradability while retaining its pharmacological potency. This proof of concept study provides an approach for the rational redesign of a given pharmaceutical (Propranolol as an example). New derivatives with small molecular changes as compared to propranolol molecule were generated by a nontargeted photolysis process. Generated derivatives with intact drug moieties (an aromatic ring and a β-ethanolamine moiety) were further screened for aerobic biodegradability and pharmacological potency. The feasibility of the approach of redesigning an existing pharmaceutical through nontargeted generation of new derivatives with intact drug moiety and through subsequent screening was demonstrated in this study. Application of such approaches in turn might contribute to the protection of water resources in a truly sustainable manner.
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To review the clinical experience on pheochromocytoma in Indian subset of patients.
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Male Wistar rats were divided into four groups: sedentary rats (SR); sedentary rats treated with N(omega)-nitro-l-arginine methyl ester (L-NAME) for one week (SRL); rats trained for eight weeks (TR); and rats trained for eight weeks and treated with L-NAME in the last week (TRL).