Repurposing Ophthalmologic Timolol for Dermatologic Use: Caveats and Historical Review of Adverse Events.

Ophthalmic timolol solution is increasingly being repurposed as a topical therapeutic for a variety of dermatologic diseases, including pyogenic granulomas, infantile hemangiomas, and chronic wounds. There are no published guidelines or protocols for use in these indications in adults, and the dermatologic community may not be familiar with adverse events that have been extensively documented relating to its ophthalmic use. We review the evidence available relating to adverse events to topical timolol use to evaluate its safety in dermatologic applications and to alert clinicians to screening and monitoring that is needed when repurposing this drug for dermatologic use. The majority of serious adverse events associated with ophthalmic timolol were reported in the first 7 years of use, between 1978 and 1985, of which most common were cardiovascular and respiratory events, but also included 32 deaths. The available evidence suggests that ophthalmic timolol safety profiling may have been incomplete prior to widespread use. Recent clinical trials for dermatologic indications have focused on documenting efficacy and have not had rigorous monitoring for potential adverse events. Topical timolol may be safe and effective for the treatment of various dermatologic conditions in patients whose medical histories have been carefully reviewed for evidence of pre-existing cardiac or pulmonary disease and are monitored for potential adverse events. Despite the wide use of timolol in ophthalmologic practice, safe dermatologic repurposing requires recognition of the potential for facilitated systemic absorption though the skin and appreciation of its history of adverse events.

Bloqueadores beta: perspectiva histórica y mecanismos de acción / Beta-blockers: historical perspective and mechanisms of action

Los bloqueadores beta son moléculas ampliamente utilizadas y capaces de antagonizar los receptores adrenérgicos (RA) beta, pertenecen a la familia de receptores acoplados a proteínas G y reciben el estímulo de las catecolaminas endógenas. Tras su estimulación, se activan cascadas intracelulares que en última instancia originan la contracción cardiaca o la dilatación vascular, según el subtipo y su ubicación. Se han descrito 3 subtipos, que se expresan de manera diferenciada en el organismo (RA-ß1, ß2 y ß3), y el subtipo ß1 es el más abundante en el corazón. Desde su descubrimiento, los RA-ß se han convertido en diana para combatir las enfermedades cardiovasculares. Desde su invención por James Black a finales de los años cincuenta, los bloqueadores beta han supuesto una revolución en la terapia cardiovascular. Hasta ahora se dispone de 3 generaciones: los bloqueadores beta no selectivos, los bloqueadores beta cardioselectivos (antagonista selectivo de ß1) y los bloqueadores beta vasodilatadores. Estos constituyen la tercera generación y son capaces de bloquear los ß1 además de tener actividad vasodilatadora, bien bloqueando los RA-alfa1 o activando los RA-ß3. Los bloqueadores beta todavía se utilizan ampliamente en la clínica tras más de 50 años desde la introducción del propranolol en el mercado por su capacidad para reducir la frecuencia cardiaca y, por lo tanto, la demanda miocárdica de oxígeno en el caso de una angina

Beta-blockers are widely used molecules that are able to antagonize ß-adrenergic receptors (ARs), which belong to the G protein-coupled receptor family and receive their stimulus from endogenous catecholamines. Upon ß-AR stimulation, numerous intracellular cascades are activated, ultimately leading to cardiac contraction or vascular dilation, depending on the relevant subtype and their location. Three subtypes have been described that are differentially expressed in the body (ß1-, ß2- and ß3-ARs), ß1 being the most abundant subtype in the heart. Since their discovery, ß-ARs have become an important target to fight cardiovascular disease. In fact, since their discovery by James Black in the late 1950s, ß-blockers have revolutionized the field of cardiovascular therapies. To date, 3 generations of drugs have been released: nonselective ß-blockers, cardioselective ß-blockers (selective ß1-antagonists), and a third generation of these drugs able to block ß1 together with extra vasodilation activity (also called vasodilating ß-blockers) either by blocking alfa1- or by activating ß3-AR. More than 50 years after propranolol was introduced to the market due to its ability to reduce heart rate and consequently myocardial oxygen demand in the event of an angina attack, ß-blockers are still widely used in clinics

The Long Way to a Successful Medical Therapy of Heart Failure with Beta-blockers in Children with Heart Disease.

Heart failure remains the main cause of death in children with heart disease. In USA and Europe hospital mortality of children with heart failure is about 7% of children, nearly twice as high as in adults. In this review a group of authors report about their experience with beta-blockers in childhood heart failure. Most of them start to treat children with severe heart failure at a time - 20 years ago - when beta blockers seem to be contraindicated in this situation. The physicians and their patients and/or parents all are aware of the risk of this decision. However, unproven medical therapies for heart failure are the most important therapeutical dilemma in pediatric cardiology. The authors carefully observed a highly selected group of patients with the highest risk to die and had the patience to wait for the longtime follow up. Today - based upon this experience -we know that beta blockers are safe and may save the lives of many children with heart disease all over the world. Together with young colleagues who enthusiastically support this idea the authors now intend to break down the "wall of ignorance" for this promising therapy in pediatric cardiology.

The major impacts of James Black's drug discoveries on medicine and pharmacology.

James Black has many claims to pharmacological fame as the creator of two new classes of drugs (beta-blockers and H2 antihistamines) and as a tireless innovator in drug discovery strategies and analytical procedures. The latter attributes in particular assisted Black in the invention of the prototypes for the two major classes of drugs for which he is best known, propranolol and cimetidine. The clinical impact of these drugs on both morbidity and mortality has been profound. In addition, the application of his analytical approach to drug discovery and pharmacology led others in the field to create many other new classes of drugs. Shortly before he died in 2010, Black wrote a retrospective review of his research career that provides insight into his innovative thinking and career success. This overview affords readers a very personal picture of the man, his ideas and his contributions.

A history of glaucoma pharmacology.

The history of glaucoma pharmacology begins in 1862 with the isolation of physostigmine from the calabar bean. The discovery of epinephrine's intraocular pressure lowering capacity came along some 40 years later. During the 20th century, drug discovery and development accelerated, with the introduction of carbonic anhydrase inhibitors, beta blockers, and prostaglandin analogs. This survey of the history of glaucoma medications reviews some of the pivotal stories behind the development of the drugs that we use daily to manage our patients with glaucoma. In addition, some unmet needs that persist in glaucoma pharmacology are discussed.

From Bowditch to beta-blockers: evolution of the understanding of the importance of heart rate and myocardial energetics in cardiomyopathy - with reference to : a comparison of stimulation frequency and electro-augmentation on myocardial function, extensibility, coronary flow rate, oxygen consumption and glucose metabolism.

During the past three decades, every aspect of cardiomyopathy has undergone dramatic change. When examining the literature on the physiological aspects of the failing heart, one immediately recognises that South Africa has made a contribution: Brink, Bester and Lochner evaluated the possible therapeutic aspects of the Bowditch phenomenon and myocardial energetics in cardiomyopathy almost four decades ago, at a time when the condition even had another name, myocardiopathy.

The low-affinity site of the beta1-adrenoceptor and its relevance to cardiovascular pharmacology.

beta-Adrenoceptor blocking agents (beta-blockers) that at low concentrations antagonize cardiostimulant effects of catecholamines, but at high concentrations also cause cardiostimulation, have been appearing since the late 1960s. These cardiostimulant beta-blockers, coined non-conventional partial agonists, antagonize the effects of catecholamines through a high-affinity site (beta(1H)AR), but cause cardiostimulation mainly through a low-affinity site (beta(1L)AR) of the myocardial beta(1)-adrenoceptor. The experimental non-conventional partial agonist (-)-CGP12177 increases cardiac L-type Ca(2+) current density and Ca(2+) transients, shortens action potential duration but augments action potential plateau, increases heart rate and force, as well as causes arrhythmic Ca(2+) transients and arrhythmic cardiocyte contractions. Other beta-blockers, which do not cause cardiostimulation, consistently have lower affinity for beta(1L)AR than beta(1H)AR. These sites were verified and the cardiac pharmacology of non-conventional partial agonists confirmed on recombinant beta(1)-adrenoceptors and on beta(1)-adrenoceptors overexpressed into the heart. A targeted mutation of Asp138 to Glu138 virtually abolished the pharmacology of beta(1H)AR but left intact the pharmacology of beta(1L)AR. Non-conventional partial agonists may be beneficial for the treatment of peripheral autonomic neuropathy but probably due to their arrhythmic propensities, may be harmful for the treatment of chronic heart failure.

beta-Adrenergic blockers: a 50-year historical perspective.

The development and subsequent clinical application of the beta-adrenergic receptor blocking drugs over the past 50 years represent one of the major advances in human pharmacotherapy. No other class of synthetic drugs has demonstrated such widespread therapeutic utility for the treatment of so many cardiovascular and noncardiovascular diseases. In addition, these drugs have proven to be molecular probes that have contributed to our understanding of disease, and on the molecular level, both the structure and the function of the 7 transmembrane G protein receptors, which mediate the actions of many different hormones, neurotransmitters, and drugs. The evolution of beta-blocker drug development has led to refinements in their pharmacodynamic actions that include agents with relative beta1-selectivity, partial agonist activity, concomitant alpha-adrenergic blockers activity, and direct vasodilator activity. In addition, long-acting and ultra-short-acting formulations of beta-blockers have also demonstrated a remarkable record of clinical safety in patients of all ages. Indeed, the beta-adrenergic blockers have provided us with a great clinical legacy for now and in years to come.

[40 years beta-adrenoceptor blockers in psychiatry]. / 40 Jahre Beta-Blocker in der Psychiatrie.

Beta-adrenoceptor blockers belong to the most successful drug classes of medicine. Mainly they are used in internal medicine. 40 years ago beta-adrenoceptor blockers have occasionally been used in psychiatry for the treatment of anxiety disorders. Over the past four decades, the effects of beta-adrenoceptor blockers in the treatment of schizophrenic and manic psychoses, withdrawal syndromes and aggressive behaviour with temper outbursts has been investigated. Beta-adrenoceptor blockers are also used in the treatment of side-effects of psychopharmacological agents like neuroleptic or antidepressant-induced tachycardias, lithium-induced tremor, antipsychotic-induced akathisia or tardive dyskinesia as well. Since the mid-nineties it has been attempted to improve the efficacy of antidepressant agents by means of the 5-HT-(1a)-receptorantagonist pindolol. Presumedly memory consolidation of traumatic events can be enhanced by adrenergic activation. Therefore some open clinical trials investigated the effects of propranolol, a lipid soluble drug, which crosses the blood-brain barrier easily, to reduce the manifestation of PTSD. The present review presents the results of the literature with respect to the indications for beta-blockers in psychiatry. Considering evidence-based-medicine criteria beta-blockers are indicated to treat lithium-induced tremor, antipsychotic-induced akathisia and to reduce aggressive behavior of patients with brain-injuries.