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1.  Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy 
BMC Physiology  2002;2:1.
Iron deficiency (ID) results in ventricular hypertrophy, believed to involve sympathetic stimulation. We hypothesized that with ID 1) intravenous norepinephrine would alter heart rate (HR) and contractility, 2) abdominal aorta would be larger and more distensible, and 3) the beta-blocker propanolol would reduce hypertrophy.
1) 30 CD rats were fed an ID or replete diet for 1 week or 1 month. Norepinephrine was infused via jugular vein; pressure was monitored at carotid artery. Saline infusions were used as a control. The pressure trace was analyzed for HR, contractility, systolic and diastolic pressures. 2) Abdominal aorta catheters inflated the aorta, while digital microscopic images were recorded at stepwise pressures to measure arterial diameter and distensibility. 3) An additional 10 rats (5 ID, 5 control) were given a daily injection of propanolol or saline. After 1 month, the hearts were excised and weighed.
Enhanced contractility, but not HR, was associated with ID hypertrophic hearts. Systolic and diastolic blood pressures were consistent with an increase in arterial diameter associated with ID. Aortic diameter at 100 mmHg and distensibility were increased with ID. Propanolol was associated with an increase in heart to body mass ratio.
ID cardiac hypertrophy results in an increased inotropic, but not chronotropic response to the sympathetic neurotransmitter, norepinephrine. Increased aortic diameter is consistent with a flow-dependent vascular remodeling; increased distensibility may reflect decreased vascular collagen content. The failure of propanolol to prevent hypertrophy suggests that ID hypertrophy is not mediated via beta-adrenergic neurotransmission.
PMCID: PMC65049  PMID: 11818034
2.  Catecholamine effects upon rat hypothalamic corticotropin-releasing hormone secretion in vitro. 
Journal of Clinical Investigation  1988;82(3):839-846.
To further our understanding of the functional role of catecholaminergic systems in regulating hypothalamic corticotropin-releasing hormone (CRH) secretion, we assessed the direct effects of a multiplicity of catecholamine agonists and antagonists on hypothalamic CRH secretion. To accomplish this, we used an in vitro rat hypothalamic organ culture system in which CRH secretion from single explants was evaluated by a specific RIA (IR-rCRH). Norepinephrine (NE) stimulated IR-rCRH secretion dose dependently, with peak effects in the nanomolar range. The effect of NE was antagonized by the mixed alpha antagonist phentolamine, the alpha 1 antagonist prazosin, and the alpha 2 antagonist yohimbine, but not by the beta blocker, L-propanolol. Compatible with these data were the findings that the alpha 1 agonist phenylephrine and the alpha 2 agonist clonidine both stimulated IR-rCRH secretion in a dose-dependent fashion. On the other hand, whereas the beta agonist, isoproterenol, caused a weak, non-dose-dependent increase in IR-rCRH secretion, this effect could not be antagonized by L-propanolol. Despite pretreatment with serotonin and acetylcholine antagonists, the effect of NE upon IR-rCRH secretion was undiminished, suggesting that NE-induced CRH secretion is not mediated by either neurotransmitter. On the other hand, pretreatment with gamma-aminobutyric acid (GABA) attenuated NE-induced IR-rCRH secretion. Whereas epinephrine (E) stimulated IR-rCRH secretion, this occurred only at higher concentrations, and was antagonized by phentolamine, but not by L-propanolol. Dopamine (DA) had a weak stimulatory effect that could be antagonized by the DA1 receptor antagonist, SCH 23390, but not by phentolamine. We conclude that NE and E stimulate hypothalamic IR-rCRH secretion via alpha 1 and alpha 2 receptors. The effect of NE upon IR-rCRH secretion is not apparently mediated by serotonergic or cholinergic interneurons, but is modulated by the inhibitory neurotransmitter, GABA. These data support the idea that the central catecholaminergic systems are excitatory rather than inhibitory upon CRH secretion when acting directly at the hypothalamic level.
PMCID: PMC303591  PMID: 2901433
3.  Oral Propranolol for Circumscribed Choroidal Hemangioma 
Case Reports in Ophthalmology  2011;2(1):84-90.
Several therapeutic approaches have been developed to treat choroidal hemangioma. However, all these therapies are associated with a potential risk of damaging the overlying retina.
Case Report
We report a case of circumscribed choroidal hemangioma (CCH) in a 59-year-old man refractory to laser treatment. Visual acuity was 20/200 and a serous macular detachment was present. The CCH was treated with oral propanolol, whereupon visual acuity improved to 20/20 and the macular detachment resolved without systemic or local adverse effects.
Propanolol is a β-blocker commonly used in cardiology that may induce endothelium vasoconstriction and inhibit endothelial proliferation. It has been shown to be effective in infantile facial hemangiomas, and proved safe and effective for the CCH in our patient. Further studies are needed to confirm our observation.
PMCID: PMC3072177  PMID: 21475606
Circumscribed choroidal hemangioma; Propanolol; β-Blocker
4.  β2 adrenergic agonist, clenbuterol, enhances working memory performance in aging animals 
Neurobiology of aging  2007;29(7):1060-1069.
Previous studies using a mixed β1 and β2 adrenergic antagonist, propanolol, have indicated that β adrenoceptors have little effect on the cognitive functioning of the prefrontal cortex. However, recent studies have suggested that endogenous stimulation of β1 adrenoceptors impairs working memory in both rats and monkeys. Since propanolol has no effect on cognition, we hypothesized that activation of β2 adrenoceptors might improve performance in a working memory task. We tested this hypothesis by observing the effects of the β2 agonist, clenbuterol, on spatial working memory performance. Clenbuterol was either infused directly into the prefrontal cortex (rats) or administered systemically (monkeys). Results demonstrated that clenbuterol improved performance in many young and aged rats and monkeys who performed poorly under control conditions. Actions at β2 adrenoceptors were confirmed by challenging the clenbuterol response with the β2 adrenergic antagonist, ICI 118,551. The effects of clenbuterol were not universal and depended on the cognitive status of the animal: the drug moderately improved only a subset of animals with working memory impairment.
PMCID: PMC3154024  PMID: 17363115
Clenbuterol; ICI 118,551; Beta-2; Norepinephrine; Working memory; Aging; Prefrontal cortex
5.  Different Cardiovascular Responses to a Resistance Training Session in Hypertensive Women Receiving Propanolol Compared with Normotensive Controls 
The Scientific World Journal  2012;2012:913271.
The aim of the present study was to compare the responses of blood pressure, heart rate, and rate-pressure product of hypertensive women using beta-blockers with healthy controls during resistance exercise (by the end of the concentric phase of the contractions) and in the postexercise period (5 and 30 minutes after). Ten untrained normotensive women (N) and 10 mildly hypertensive females receiving 40 mg/day of propanolol (H) were selected. Three sets of 10 repetitions at 80% of 10 repetitions maximum with 30 s rest interval were performed on the leg press exercise. The H group exhibited lower systolic blood pressure after the second set compared with N. Heart rate and rate-pressure product were lower in H in all analyzed periods compared with N. Propanolol attenuates the cardiovascular response to a leg press resistance exercise in mildly hypertensive women.
PMCID: PMC3354718  PMID: 22645465
6.  Does exercise alter anaerobic threshold in coronary artery disease during beta blockade? 
The effect of propranolol on cardiac patients undergoing exercise training is reported to increase exercise tolerance and maximum oxygen uptake (VO2 max) but its effect on anaerobic threshold (AT) is unknown. It was the purpose of this study to determine the role of exercise training with propranolol on AT in patients with coronary artery disease (CAD). Eight men and one woman with significant (CAD) were selected for this study. Each patient completed a maximum treadmill stress test (MTST) following the Bruce protocol on propranolol 40-160 mg/day as a control study. Cardiorespiratory variables were measured at rest and at each stage of the treadmill test. These patients underwent an exercise training programme for 12-16 weeks on the same dose of propranolol. Training sessions were for a minimum of 30-40 minutes, 3 times a week, with training heart rate of 75%-85% of the pretraining peak heart rate. Training heart rate ranged from 98 to 128 beats/min. They were retested with a MTST after the training programme, on the same dose of propranolol. AT was calculated noninvasively by measuring respiratory variables every 30 seconds in relation to work increment. AT was identified by measuring the time course of VE, VCO2, VE/VO2, etc. in relation to incremental work. The mean values of VO2, O2P and % VO2 max at AT before and after training on propanolol were as follows: VO2 = 1.43 L/min +/- .25 and 1.86 L/min +/- .44, O2P = 14.35 +/- 2.40 and 18.73 +/- 4.00 ml/beat, % of VO2 max = 68.20 +/- 6.31 and 73.59 +/- 5.84. The mean changes of VO2 O2P, and % of VO2 max were + 0.43 L/min +/- 0.20 (P < .003), + 4.38 +/- 2.55 (P < .003) and +/- 5.07% +/- 4.84 (P < .001). After exercise training on propanolol, the mean peak exercise tolerance time and absolute VO2 max increased by 2.8 min (from 9.0 to 11.8 min) (P < .001) and 22.7% (P < .007), respectively. We conclude that the increase in anaerobic threshold in patients with coronary artery disease may be due to improvement in VO2 max, increased stroke volume, and peripheral O2 extraction.
PMCID: PMC1478518  PMID: 4027493
7.  Diminished Polymorphonuclear Leukocyte Adherence 
Journal of Clinical Investigation  1980;66(2):268-274.
To investigate the biochemical and cellular basis for the rise in polymorphonuclear leukocyte (PMN) count during epinephrine administration, PMN from subjects receiving epinephrine were studied for their capacity to adhere to nylon wool fibers and endothelial cell monolayers. After administration of epinephrine, the PMN count increased by 80% at 5 min, and isolated PMN adherence to nylon fibers fell from a base line of 44±2-18±3%. In contrast, when subjects were infused with the β-antagonist propanolol before receiving epinephrine, the PMN count failed to rise and PMN adherence was normal. Exposure of PMN endothelial cell monolayers to 0.1 μM epinephrine led to diminished PMN adherence that could be blocked by 10 μM propanolol but not by 10 μM phentolamine. Sera obtained from subjects 5 min after receiving epinephrine or from supernates derived from endothelial cell monolayers exposed to 90 nM epinephrine inhibited PMN adherence to nylon fibers. Addition of anticyclic AMP antisera but not anticyclic guanosine monophosphate antisera to the postepinephrine sera or to the postepinephrine supernate derived from the endothelial cell monolayers abolished their inhibitory effect of PMN adherence to nylon fibers. In contrast, direct exposure of PMN to epinephrine failed to affect their adherent properties. Because it has been previously shown that endothelial cells contain β-receptors and respond to catecholamines by raising their intracellular concentrations of cyclic AMP, and that PMN adherence is attenuated by cyclic AMP, it would appear that diminished PMN adherence after epinephrine administration is mediated through endothelial cell β-receptor activity, which in turn impairs PMN margination in vivo and could account for the rise in circulating PMN.
PMCID: PMC371707  PMID: 6249848
8.  Alkalinizing the intralysosomal pH inhibits degranulation of human neutrophils. 
Journal of Clinical Investigation  1983;72(5):1793-1800.
Degranulation of lysosomes is one of the consequences of neutrophil activation. Regulatory mechanisms of lysosomal secretion are thought to be localized largely in the plasma membrane and cytosol, with the lysosome playing a passive role in secretion. Recent evidence indicates that the intralysosomal pH is highly acidic (pH congruent to 5.5) and is maintained by active transport of H+. We investigated whether changes in the intralysosomal pH altered the availability of lysosomes for exocytosis. Intralysosomal pH in intact neutrophils was monitored with the weakly basic fluorescent probe, 9-aminoacridine (9AA). The weak bases, methylamine, chloroquine, clindamycin, propanolol, and ammonium chloride (0.1-50 mM), caused an alkalinization of the intralysosomal pH as determined by reversal of quenching of 9AA fluorescence. Similarly, each of the weak bases, including ammonium chloride, methylamine, chloroquine, ethylamine, propylamine, propanolol, clindamycin, and dansylcadaverine, inhibited neutrophil degranulation in response to the calcium ionophore A23187, phorbol myristate acetate, or the chemotactic peptide, formyl-methionine-leucine-phenylalanine plus cytochalasin B. These studies indicate that an acid intralysosomal pH is important to the neutrophil secretory response and suggest that the lysosome may play an active part in control of degranulation.
PMCID: PMC370468  PMID: 6415117
9.  KCNQ1 and KCNH2 Mutations Associated with Long QT Syndrome in a Chinese Population 
Human mutation  2002;20(6):475-476.
The long QT syndrome (LQTS) is a cardiac disorder characterized by prolongation of the QT interval on electrocardiograms (ECGs), syncope and sudden death caused by a specific ventricular tachyarrhythmia known as torsade de pointes. LQTS is caused by mutations in ion channel genes including the cardiac sodium channel gene SCN5A, and potassium channel subunit genes KCNQ1, KCNH2, KCNE1, and KCNE2. Little information is available about LQTS mutations in the Chinese population. In this study, we characterized 42 Chinese LQTS families for mutations in the two most common LQTS genes, KCNQ1 and KCNH2. We report here the identification of four novel KCNQ1 mutations and three novel KCNH2 mutations. The KCNQ1 mutations include L191P in the S2–S3 cytoplasmic loop, F275S and S277L in the S5 transmembrane domain, and G306V in the channel pore. The KCNH2 mutations include L413P in transmembrane domain S1, E444D in the extracellular loop between S1 and S2, and L559H in domain S5. The location and character of these mutations expand the spectrum of KCNQ1 and KCNH2 mutations causing LQTS. Excitement, exercises, and stress appear to be the triggers for developing cardiac events (syncope, sudden death) for LQTS patients with KCNQ1 mutations F275S, S277L, and G306V, and all three KCNH2 mutations L413P, E444D and L559H. In contrast, cardiac events for an LQTS patient with KCNQ1 mutation L191P occurred during sleep or awakening from sleep. KCNH2 mutations L413P and L559H are associated with the bifid T waves on ECGs. Inderal or propanolol (a beta blocker) appears to be effective in preventing arrhythmias and syncope for an LQTS patient with the KCNQ1 L191P mutation.
PMCID: PMC1679868  PMID: 12442276
Long QT Syndrome; LQTS; cardiac arrhythmia; KCNQ1; KVLQT1; KCNH2; HERG; potassium channel; mutation; torsade de pointes; sudden death; ion channel; IKs, IKr
The influence of the autonomic nervous system on the pathogenesis of complex fractionated atrial electrograms (CFAE) during atrial fibrillation (AF) is incompletely understood. This study evaluated the impact of pharmacological autonomic blockade on CFAE characteristics.
Autonomic blockade was achieved with propanolol and atropine in 29 patients during AF. Three-dimensional maps of the fractionation degree were made before and after autonomic blockade using the Ensite Navx® system. In 2 patients, AF terminated following autonomic blockade. In the remaining 27 patients, 20113 electrogram samples of 5 seconds duration were collected randomly throughout the left atrium (10054 at baseline and 10059 after autonomic blockade). The impact of autonomic blockade on fractionation was assessed by blinded investigators and related to the type of AF and AF cycle length.
Globally, CFAE as a proportion of all atrial electrogram samples were reduced after autonomic blockade: 61.6±20.3% vs. 57.9±23.7%, p=0.027. This was true/significant for paroxysmal AF (47±23% vs. 40±22%, p=0.003), but not for persistent AF (65±22% vs. 62±25% respectively, p=0.166). Left atrial AF cycle length prolonged with autonomic blockade from 170±33 ms to. 180±40 ms (p=0.001). Fractionation decreases only in the 14/27 patients with a significant (>6ms) prolongation of the AF cycle length (64±20% vs. 59±24%, p=0.027), while fractionation did not reduce when autonomic blockade did not affect the AF cycle length (58±21% vs. 56±25%, p=0.419).
Pharmacological autonomic blockade reduces CFAE in paroxysmal AF, but not persistent AF. This effect appears to be mediated by prolongation of the AF cycle length.
PMCID: PMC2910241  PMID: 20132382
Complex fractionated atrial electrograms; autonomic nervous system; ganglionated plexus; atrial fibrillation; catheter ablation; cycle length
11.  Management of vestibular migraine 
Vestibular migraine is considered to be the second most common cause of vertigo and the most common cause of spontaneous episodic vertigo. The duration of attacks varies from seconds to days, usually lasting minutes to hours, and they mostly occur independently of headaches. Long-lasting individual attacks are treated with generic antivertiginous and antiemetic drugs. Specific antimigraine drugs are unlikely to be very effective for rescue. The mainstay of the management of vestibular migraine is prophylactic medication. To date, there are no controlled trials available; the body of knowledge builds on case series and retrospective or observational studies. Most drugs are also used for the prevention of migraine headaches. The choice of medication should be guided by its side effect profile and the comorbidities of patients. Betablockers such as propanolol or metoprolol are preferred in patients with hypertension but in the absence of asthma. Anticonvulsants include topiramate when patients are obese, valproic acid and lamotrigine. Lamotrigine is preferred if vertigo is more frequent than headaches. Calcium antagonists include verapamil and flunarizine. If patients have anxiety, tricyclic antidepressants such as amitryptiline or nortryptiline or SSRIs and benzodiazepines such as clonazepam are recommended. Acetazolamide is effective in rare genetic disorders related to migraine-like episodic ataxia; however, its place in vestibular migraine is still to be established. Nonpharmacological measures such as diet, sleep, hygiene and avoidance of triggers are recommended as they are for migraine. Vestibular rehabilitation might be useful when there are complications such as loss of confidence in balance or visual dependence.
PMCID: PMC3105632  PMID: 21694818
migraine; vestibular; prophylaxis; beta-blockers; anti-convulsants
12.  Unusual cause of weight loss in a patient with HIV–hepatitis C virus coinfection 
Recombinant interferon α (IFN α), alone or in combination, is used extensively in the treatment of hepatitis C infection. IFN therapy is not free of side-effects and autoimmune thyroiditis is one of its rare side-effects. We present here a case of a patient with hepatitis C virus–human immunodeficiency virus coinfection on interferon therapy who presented with significant weight loss. He was found to have IFN-related autoimmune thyrotoxicosis and responded to antithyroid drugs and propanolol. Therefore, this case highlights that IFN-induced thyroiditis is an unusual side-effect and that during treatment, a thyroid-stimulating hormone assay should be performed at regular intervals (every 8–12 weeks).
PMCID: PMC3122597  PMID: 21716798
HIV; interferon α; thyroiditis; weight loss
13.  Stress Hormone – Mediated Invasion of Ovarian Cancer Cells 
There is growing evidence that stress and other behavioral factors may affect cancer progression and patient survival. The underlying mechanisms for this association are poorly understood. The purpose of this study is to determine the effects of stress-associated hormones norepinephrine, epinephrine, and cortisol on the invasive potential of ovarian cancer cells.
Experimental Design
The ovarian cancer cells EG, SKOV3, and 222 were exposed to increasing levels of either norepinephrine, epinephrine, or cortisol, and the in vitro invasive potential was determined using the membrane invasion culture system. Additionally, the effects of these stress hormones on matrix metalloproteinase-2 (MMP-2) and MMP-9 were determined by ELISA. The effects of the β-adrenergic agonist isoproterenol on in vivo tumor growth were determined using nude mice.
Stress levels of norepinephrine increased the in vitro invasiveness of ovarian cancer cells by 89% to 198%. Epinephrine also induced significant increases in invasion in all three cell lines ranging from 64% to 76%. Cortisol did not significantly affect invasiveness of the EG and 222 cell lines but increased invasion in the SKOV3 cell line (P = 0.01). We have previously shown that ovarian cancer cells express β-adrenergic receptors. The β-adrenergic antagonist propanolol (1 µmol/L) completely blocked the norepinephrine-induced increase in invasiveness. Norepinephrine also increased tumor cell expression of MMP-2 (P = 0.02 for both SKOV3 and EG cells) and MMP-9 (P = 0.01 and 0.04, respectively), and pharmacologic blockade of MMPs abrogated the effects of norepinephrine on tumor cell invasive potential. Isoproterenol treatment resulted in a significant increase in tumor volume and infiltration in the SKOV3ip1 in vivo model, which was blocked by propranolol.
These findings provide direct experimental evidence that stress hormones can enhance the invasive potential of ovarian cancer cells. These effects are most likely mediated by stimulation of MMPs.
PMCID: PMC3141061  PMID: 16428474
14.  Drug interaction as cause of spontaneously resolving epidural spinal hematoma on warfarin therapy 
We present a case of a 42-year-old male, an old case of deep vein thrombosis on warfarin and other drugs like quetiapine, aspirin, diclofenac sodium, fenofibrate, atorvastatin, propanolol and citalopram for concurrent illnesses, who presented with widespread mucocutaneous bleeding and epidural spinal hematoma. The epidural bleed presented clinically as a nontraumatic, rapidly improving myeloradiculopathy. Magnetic resonance imaging (MRI) of the spine revealed an epidural hematoma at D12-L1 level. The case was managed conservatively due lack of neurosurgical facilities. The patient gained full neurological recovery on conservative management alone. This case highlights the problem of drug interaction on warfarin therapy and also an unusual spontaneous recovery of spinal hematoma. Our case was anticoagulated in the recommended therapeutic INR range of 2.2 to 2.4. Most of the similar cases reported in literature were also anticoagulated in the therapeutic range. Thus intraspinal hemorrhage is a rare but dangerous complication of anticoagulant therapy. It must be suspected in any patient on anticoagulant agents who complains of local or referred spinal pain associated with neurological deficits. Drug interactions with warfarin are common. High suspicion and immediate intervention are essential to prevent complications from intraspinal hemorrhage.
PMCID: PMC3137834  PMID: 21799620
Anticoagulant; spinal epidural hematoma; warfarin
15.  Exposure of the Main Italian River Basin to Pharmaceuticals 
Journal of Toxicology  2011;2011:989270.
This study give a preliminary survey of pharmaceutical contamination and accumulation in surface waters and sediments along the river Po basin (74,000 km2, the largest in Italy), a strategic region for the Italian economy: it collects sewage from a vast industrialized area of Italy (Autorità di Baciono del fiume Po, 2006, 2009). 10 pharmaceuticals (atenolol, propanolol, metoprolol, nimesulide, furosemide, carbamazepine, ranitidine, metronidazole, paracetamol, and atorvastatin) from several therapeutic classes were searched in 54 sampling points along the river Po from the source to the delta, and at the mouth of its major effluents. In water samples were found pharmaceuticals in the range of 0.38–0.001 μg/L, except for furosemide (max conc. 0.605 μg/L), paracetamol (max conc. 3.59 μg/L), metoprolol (never detected) and for atenolol (not analysed). In sediment samples, only paracetamol was not detected, while the others were generally found in the range of 0.4–0.02 μg/kg ww with high concentrations for atenolol (max conc. 284 μg/kg ww) and furosemide (max conc. 98.4 μg/kg ww). The findings confirm also STPs as point sources of contamination. Despite of the much evidence for the adverse effects of pharmaceuticals in the aquatic environment, the observed low levels cannot be considered to pose a serious risk to human health; further studies are necessary for a comprehensive risk assessment.
PMCID: PMC3175726  PMID: 21941542
16.  Ulcerated Infantile Haemangioma of Leg Successfully Treated with Propranolol 
Infantile haemangioma (IH) frequently requires no intervention. Eighty percent of IHs are focal and solitary. Fifteen percent of cutaneous haemangiomas occur on the extremities. A large size or a specific location or both may carry complications such as ulceration which is one of the main complications, and active treatment is usually required to manage pain, potential scarring, and occasionally, bleeding and infection. Oral propanolol is used in the treatment of IH and is found to be an effective treatment for complicated IH, replacing systemic corticosteroids as first-line therapy. Recommendations for instituting treatment with propranolol in infants differ among different specialties and academic centres. We report an infant with ulcerated IH of leg who responded dramatically to treatment with propranolol in 4 months.
PMCID: PMC3263136  PMID: 22279391
Haemangioma; infancy; propranolol; ulcerated infantile haemangioma
17.  Pharmacological interventions in the treatment of the acute effects of cannabis: a systematic review of literature 
Cannabis intoxication is related to a number of physical and mental health risks with ensuing social costs. However, little attention has been given to the investigation of possible pharmacological interactions in this condition.
To review the available scientific literature concerning pharmacological interventions for the treatment of the acute effects of cannabis.
A search was performed on the Pubmed, Lilacs, and Scielo online databases by combining the terms cannabis, intoxication, psychosis, anxiety, and treatment. The articles selected from this search had their reference lists checked for additional publications related to the topic of the review.
The reviewed articles consisted of case reports and controlled clinical trials and are presented according to interventions targeting the physiological, psychiatric, and cognitive symptoms provoked by cannabis. The pharmacological interventions reported in these studies include: beta-blockers, antiarrhythmic agents, antagonists of CB-1 and GABA-benzodiazepine receptors, antipsychotics, and cannabidiol.
Although scarce, the evidence on pharmacological interventions for the management of cannabis intoxication suggests that propanolol and rimonabant are the most effective compounds currently available to treat the physiological and subjective effects of the drug. Further studies are necessary to establish the real effectiveness of these two medications, as well as the effectiveness of other candidate compounds to counteract the effects of cannabis intoxication, such as cannabidiol and flumazenil.
PMCID: PMC3294246  PMID: 22273390
cannabis; intoxication; acute effects; psychosis; anxiety; pharmacological treatment
18.  Metabolomic profiles of myocardial ischemia under treatment with salvianolic acid B 
Chinese Medicine  2012;7:6.
Radix Salvia miltiorrhiza (Danshen) has been used as a principal herb in treating cardiovascular diseases in Chinese medicine. Salvianolic acid B (SA-B), a water-soluble active component of Danshen, was found to have anti-myocardial ischemia (anti-MI) effect. This study aims to investigate mechanisms of SA-B on MI.
Five conventional Western medicines (isosorbide dinitrate, verapamil, propranolol, captopril and trimethazine) with different mechanisms for treating cardiovascular diseases were selected as positive references to compare with SA-B in changing of the metabolomic profiles in MI rats under treatment. Potential mechanisms of SA-B were further investigated in H9C2 cell line.
The metabolomic profiles between SA-B- and propranolol-treated MI rats were similar, since there was a big overlap between the two groups in the PLS-DA score plot. Finally, it was demonstrated that SA-B exhibited a protective effect on MI mainly by decreasing the concentration of cyclic adenosine monophosphate (cAMP) and Ca2+ and inhibiting protein kinase A (PKA).
SA-B and propanolol exhibited similar metabolomic profiles, indicating that the two drugs might have a similar mechanism.
PMCID: PMC3317850  PMID: 22409910
19.  Preparation and evaluation of sustained release microballoons of propranolol 
Background and the purpose of the study
The purpose of the present investigation was to characterize, optimize and evaluate microballoons of Propranolol hydrochloride and to increase its boioavailability by increasing the retention time of the drug in the gastrointestinal tract.
Propranolol hydrochloride-loaded microballoons were prepared by the non-aqueous O/O emulsion solvent diffusion evaporation method using Eudragit RSPO as polymer. It was found that preparation temperature determined the formation of cavity inside the microballoon and this in turn determined the buoyancy. Microballoons were subjected to particle size determination, micromeritic properties, buoyancy, entrapment efficiency, drug loading, in vitro drug release and IR study. The correlation between the buoyancy, bulk density and porosity of microballoons were elucidated. The release rate was determined in simulated gastric fluid (SGF) of pH 1.2 at 37±0.5°C.
The microballoons presented spherical and smooth morphologies (SEM) and were porous due to presence of hollow cavity. Microballoons remained buoyant for >12 hrs for the optimized formulation. The formulation demonstrated favorable in vitro floating and release characteristics. The encapsulation efficiency was high. In vitro dissolution kinetics followed the Higuchi model. The drug release from microballoons was mainly controlled by diffusion and showed a biphasic pattern with an initial burst release, followed by sustained release for 12 hrs. The amount of the drug which released up to 12 hrs was 82.05±0.64%. Statistical analysis (ANOVA) showed significant difference (p<0.05) in the cumulative amount of drug released after 30 min, and up to 12 hrs from optimized formulations.
The designed system for propanolol would possibly be advantageous in terms of increased bioavailability and patient compliance.
PMCID: PMC3232109  PMID: 22615657
Floating drug delivery system; O/O emulsion Solvent diffusion/evaporation method; Eudragit RS PO; Buoyancy
20.  Potassium channel openers and prostacyclin play a crucial role in mediating the vasorelaxant activity of Gynura procumbens 
Previous studies of Gynura procumbens (G. procumbens) have shown that partially purified fractions of the leaves are capable of lowering the blood pressure of rats by inhibiting angiotensin-converting enzymic activity and causing vasodilatation. The objectives of this study were therefore to further purify the active compounds that exhibited selective effects on blood vessels, determine the mechanism of actions, and to qualitatively analyse the putative compounds present.
The butanolic fraction (BU) of the crude ethanolic extract was purified using column chromatography to obtain several sub-fractions of different polarities. The in vitro effects of BU and the sub-fractions on vascular tension were subsequently determined using isolated rat thoracic aortic rings. The most potent sub-fraction (F1) alone was then investigated for its mechanisms of the vasorelaxant activity. In another experiment, thin-layer chromatography was used to qualitatively analyse the active compounds found in F1.
The BU and the sub-fractions ranging from 10-7 to 10-2 g/ml significantly (p < 0.05) inhibited the sustained tonic contractions induced by phenylephrine and potassium chloride in a concentration-dependent manner with various degree of potency. The most potent sub-fraction (F1) antagonised the calcium-induced vasocontractions (1 x 10-4 – 1 x 10-2 M) in calcium-free with high concentration of potassium as well as in calcium- and potassium-free Krebs-Henseleit solutions. Contractions induced by noradrenaline and caffeine were not affected by F1. The vasorelaxing effect caused by F1 was significantly attenuated with preincubation of potassium channel blockers (glibenclamide and 4-aminopyridine) and prostacyclin inhibitor (indomethacin) while it was not affected by preincubation with tetraethylammonium, l-nitro-arginine methyl esther, propanolol, atropine, oxadiazolo quinoxalin one and methylene blue. The qualitative phytochemical analysis of F1 indicated the presence of flavonoids.
These results confirm previous findings that G. procumbens causes vasodilatory effects by blocking calcium channels. In addition, the present study further demonstrates that the vasodilatory effect of G. procumbens may also be due to the opening of potassium channels and the stimulation of prostacyclin production. The putative compounds are probably flavonoids in nature.
PMCID: PMC3729661  PMID: 23879679
Gynura procumbens; Vasodilation; Calcium channel; Potassium channel; Prostacylin
21.  Evaluation of Potential Ionizing Irradiation Protectors and Mitigators Using Clonogenic Survival of Human Umbilical Cord Blood Hematopoietic Progenitor Cells 
Experimental hematology  2013;41(11):10.1016/j.exphem.2013.08.001.
We evaluated the use of colony formation (CFU-GM, BFU-E, and CFU-GEMM) by human umbilical cord blood (CB) hematopoietic progenitor cells for testing novel small molecule ionizing irradiation protectors and mitigators. Each of 11 compounds was added before (protection) or after (mitigation) ionizing irradiation including: GS-nitroxides (JP4-039 and XJB-5-131), the bifunctional sulfoxide MMS-350, the phosphoinositol-3-kinase inhibitor (LY294002), TPP-imidazole fatty acid, (TPP-IOA), the nitric oxide synthase inhibitor (MCF-201-89), the p53/mdm2/mdm4 inhibitor (BEB55), methoxamine, isoproterenol, propanolol, and the ATP sensitive potassium channel blocker (glyburide). The drugs XJB-5-131, JP4-039, and MMS-350 were radiation protectors for CFU-GM. JP4-039 was also a radiation protector for CFU-GEMM. The drugs, XJB-5-131, JP4-039, and MMS-350 were radiation mitigators for BFU-E, MMS-350 and JP4-039 were mitigators for CFU-GM, and MMS350 was a mitigator for CFU-GEMM. In contrast, other drugs that were effective in murine assays: TTP-IOA, LY294002, MCF201-89, BEB55, propranolol, isoproterenol, methoxamine, and glyburide showed no significant protection or mitigation in human CB assays. These data support testing of new candidate clinical radiation protectors and mitigators using human CB clonogenic assays early in the drug discovery process, reducing the need for animal experiments.
PMCID: PMC3834150  PMID: 23933481
cord blood; radiosensitivity; radiation mitigation; therapeutics
22.  Can somatostatin control acute bleeding from oesophageal varices in Schistosoma mansoni patients?[ISRCTN63456799] 
Management of patients with bleeding oesophageal varices comprises of mainly diagnostic endoscopy, sclerotherapy and band ligation. One of the major problems to do any of the above is the active bleeding which makes any intervention difficult. The neuropeptide hormone somatostatin administered exogenously has caused a reduction in portal hypertension and variceal bleeding in patients suffering from liver cirrhosis. We believe that the symptomatic use of somatostatin for variceal bleeding in Schistosoma mansoni infected subjects can reduce bleeding, thereby alleviating the pathology caused by schistosomiasis.
We herein present a study protocol for establishing this neuropeptide as a potential therapeutic agent in schistosomiasis. Adolescent subjects, age range varying from 12–17 years will be selected, based on several inclusion criteria, most important being infection with Schistosoma mansoni with bleeding from oesophageal varices in the last 24 hours. One group of schistosomiasis patients will be treated with somatostatin and praziquantel, the other with propanolol and praziquantel. Survival graphs will be set up to correlate somatostatin administration with survival time. A two part questionnaire will be set up to control treatment outcomes. The pre-treatment part of the clinical questionnaire will identify inclusion criteria questions, the post-treatment part of the questionnaire will identify treatment outcomes.
We expect that the administration of somatostatin as a bolus followed by a 24 hour long infusion, will stop bleeding immediately, delay rebleeding as compared to the control study group and delay mortality in the somatostatin treated subjects.
PMCID: PMC539281  PMID: 15596012
23.  Treating exposure to chemical warfare agents: implications for health care providers and community emergency planning. 
Current treatment protocols for exposure to nerve and vesicant agents found in the U.S. stockpile of unitary chemical weapons are summarized, and the toxicities of available antidotes are evaluated. The status of the most promising of the new nerve agent antidotes is reviewed. In the U.S. atropine and pralidoxime compose the only approved antidote regimen for organophosphate nerve agent poisoning. Diazepam may also be used if necessary to control convulsions. To avoid death, administration must occur within minutes of substantial exposure together with immediate decontamination. Continuous observation and repeated administration of antidotes are necessary as symptoms warrant. Available antidotes do not necessarily prevent respiratory failure or incapacitation. The toxicity of the antidotes themselves and the individualized nature of medical care preclude recommending that autoinjectors be distributed to the general public. In addition, precautionary administration of protective drugs to the general population would not be feasible or desirable. No antidote exists for poisoning by the vesicant sulfur mustard (H, HD, HT); effective intervention can only be accomplished by rapid decontamination followed by palliative treatment of symptoms. British anti-Lewisite (BAL) (2,3-dimercapto-1-propanolol) is the antidote of choice for treatment of exposure to Lewisite, another potent vesicant. Experimental water-soluble BAL analogues have been developed that are less toxic than BAL. Treatment protocols for each antidote are summarized in tabular form for use by health care providers.
PMCID: PMC1567777  PMID: 2088748
24.  Human endurance--mind or muscle? 
Two investigations have been carried out. The first studied the effects of autonomic blockade on the cardiovascular response to a step test, a 50% maximum isometric grip test and a Valsalva manoeuvre: the step test was of 5 minutes duration and the other two for as long as possible. beta adrenergic blockade by propanolol diminished the blood pressure and pulse rate response to both the step test and isometric grip. The pulse rate response to the step test was also affected by cholinergic blockade with atropine. The response to the Valsalva test showed a cholinergic blockade effect of pulse rate alone and a blood pressure response alone on alpha adrenergic blockade by phenoxybenzamine. The second studied psychological stressing on physical and mental ability. A potential 'punishment' situation increased the blood pressure and pulse rate response to isometric grip while decreasing the time for which it could be maintained. A potential 'reward' situation increased both the maximum grip and the time for which 50% grip could be maintained. It is concluded that psychological factors can affect performance dependant on whether the situation is perceived as one of 'reward' or 'punishment'. A factor in the mediation of the adverse response is an inappropriate response of the autonomic nervous system.
PMCID: PMC1859774  PMID: 444804
25.  An eighteen months' study of the clinical response to metoprolol, a selective beta1-receptor blocking agent, in patients with angina pectoris. 
Postgraduate Medical Journal  1976;52(610):481-486.
Following an initial dose response study, metoprolol, a selective beta1-receptor blocking agent, was compared with equipotent dosages of propanolol in a double blind cross-over study, including exercise tolerance tests, on fourteen patients with angina pectoris. Long term therapy with metoprolol then followed until the seventy-second week. Patients performed 8% more total work on metoprolol with 15% more work recorded up to the onset of S-T depression, in comparison with propranolol. In the long term, ther was no significant difference in work performed when the daily dosage of metoprolol was changed from a q.i.d. to a b.d. regime. Metoprolol was shown to be an effective anti-anginal compound with good tolerance and safety, with gradual improvement in underlying myocardial ischaemia during long term treatment.
PMCID: PMC2496449  PMID: 10564

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