Vasovagal syncope: an update on the latest pharmacological therapies

Introduction: Syncope is an abrupt loss of consciousness in response to reduced perfusion to the brain. Neurocardiogenic or vasovagal syncope results from a complex neurologic reflex, and treatments to prevent recurrence attempt to modulate aspects of that reflex.

Areas covered: Pharmacologic treatments for vasovagal syncope address the syncope reflex in multiple ways. Fludrocortisone and sodium chloride increase systemic fluid volume. Midodrine, β blockers and norepinephrine transport inhibitors modulate the sympathetic nervous system. Other treatments for syncope modulate other neurotransmitters or affect heart rate. The most recent trials evaluating established and novel therapies are reviewed.

Expert opinion: To reduce recurrence of vasovagal syncope, conservative measures are first line. If these fail to prevent recurrence, the most promising medical therapy includes midodrine. Randomized placebo-controlled data evaluating fludrocortisone, midodrine and β blockers in older patients are awaited. Because of the significance of the placebo effect in this condition, any treatment must be evaluated in a randomized double-blind placebo-controlled trial before being accepted as effective.     

Neurocardiogenic syncope: aetiology and management

Neurocardiogenic syncope is the most common cause of syncope presenting in the outpatient setting. It is usually encountered among individuals without an underlying heart disease, but not uncommonly participates in the syncope mechanism of patients with an obstructive or an arrhythmic cardiac cause for syncope as well. The vasovagal event is caused by a transient profound hypotensive reaction most commonly associated with inappropriate bradycardia resulting from activation of a complex autonomic reflex. The pathophysiology of neurocardiogenic syncope has been elucidated by tilt table testing, a noninvasive and well-tolerated method for reproducing the event in susceptible individuals. Although the majority of people with vasovagal fainting need no specific treatment, treatment is required for those presenting with problematic features such as frequent events accompanied by trauma or accidents, and occasionally by a severe cardioinhibitory pattern response. A number of different drugs have been proposed to favourably act on different aspects of the neurocardiogenic reflex but only a few randomised, placebo-controlled, drug-specific trials are currently available. Alternatively, cardiac pacing has also been introduced for patients who have symptoms that are drug-refractory or for those with a severe cardioinhibitory hypotensive response. The selection of the appropriate treatment plan should be individualised after consideration of patient history, clinical characteristics and preference, results of the baseline tilting study, and the existing evidence from the few randomised, controlled studies performed so far.     

Neurocardiogenic syncope in children : current concepts in diagnosis and management

A wide variety of pharmacologic agents are currently used for the prevention of recurrent neurocardiogenic syncope in children and adolescents. Significant advances in the understanding of this syncopal disorder have occurred in the past decade, and the list of medications recommended has changed, reflecting the evolving understanding of the pathophysiology and development of agents with enhanced efficacy and fewer adverse effects. Clinicians have few randomized controlled trials available to guide their decisions about treating neurocardiogenic syncope, and even fewer when it comes to medications targeting the pediatric population. At the present time, beta-adrenergic receptor blockers, fludrocortisone, and also specific serotonin reuptake inhibitors and midodrine, appear to be favored treatment options. Ideally, specific therapy would be tailored to specific pathophysiologic mechanisms. Unfortunately, at present, specific treatments based on those abnormalities have not been identified.     

Rheumatoid arthritis: developing pharmacological therapies

Rheumatoid arthritis (RA) is a chronic inflammatory disease that often results in significant morbidity, mortality and disability. Over the past 20 years a better understanding of the pathogenesis of RA has led to the development of new approaches to disease treatment. The recent introduction of biological agents has changed the treatment paradigm for RA. The success of early biological therapies including TNF-α and IL-1 antagonists has spurred interest in the development of additional novel targets in the treatment of RA. Biological therapies approved for other indications, such as rituximab, are now being evaluated for the treatment of rheumatic diseases such as RA. A co-stimulatory blocker, abatacept, is also in pivotal Phase III trials. This article reviews evolving pharmacological therapies in RA with an emphasis on the newer approaches to treatment including inhibition of cognate signalling and T- and B-cell targets.     

Rheumatoid arthritis: developing pharmacological therapies

Rheumatoid arthritis (RA) is a chronic inflammatory disease that, despite recent advances in therapy, still results in significant morbidity, mortality and disability. The aetiology remains unknown and past therapies, although helpful for the majority of patients, have been suboptimal. The recent introduction of newer agents has changed the treatment paradigm of RA. COX-2 inhibitors, anti-TNF agents and interleukin-1 antagonists have allowed us to treat RA more effectively with relatively low risk of side effects. Investigations of other possible treatment pathways, such as inhibition of angiogenesis, may produce still better treatment and rapid unraveling of the immune system and how it relates to RA greatly enhances the opportunities for improved therapeutics in RA.     

Rheumatoid arthritis: developing pharmacological therapies

Rheumatoid arthritis (RA) is a chronic inflammatory disease that often results in significant morbidity, mortality and disability. Over the past 20 years a better understanding of the pathogenesis of RA has led to the development of new approaches to disease treatment. The recent introduction of biological agents has changed the treatment paradigm for RA. The success of early biological therapies including TNF-alpha and IL-1 antagonists has spurred interest in the development of additional novel targets in the treatment of RA. Biological therapies approved for other indications, such as rituximab, are now being evaluated for the treatment of rheumatic diseases such as RA. A co-stimulatory blocker, abatacept, is also in pivotal Phase III trials. This article reviews evolving pharmacological therapies in RA with an emphasis on the newer approaches to treatment including inhibition of cognate signalling and T- and B-cell targets.     

Rheumatoid arthritis: developing pharmacological therapies

Rheumatoid arthritis (RA) is a chronic inflammatory disease that, despite recent advances in therapy, still results in significant morbidity, mortality and disability. The aetiology remains unknown and past therapies, although helpful for the majority of patients, have been suboptimal. The recent introduction of newer agents has changed the treatment paradigm of RA. COX-2 inhibitors, anti-TNF agents and interleukin-1 antagonists have allowed us to treat RA more effectively with relatively low risk of side effects. Investigations of other possible treatment pathways, such as inhibition of angiogenesis, may produce still better treatment and rapid unraveling of the immune system and how it relates to RA greatly enhances the opportunities for improved therapeutics in RA.     

Antioxidant pharmacological therapies for COPD

Increased oxidative stress occurs in the lungs and systemically in COPD, which plays a role in many of the pathogenic mechanisms in COPD. Hence, targeting local lung and systemic oxidative stress with agents that modulate the antioxidants/redox system or boost endogenous antioxidants would be a useful therapeutic approach in COPD. Thiol antioxidants (N-acetyl-l-cysteine [NAC] and N-acystelyn, carbocysteine, erdosteine, and fudosteine) have been used to increase lung thiol content. Modulation of cigarette smoke (CS) induced oxidative stress and its consequent cellular changes have also been reported to be effected by synthetic molecules, such as spin traps (α-phenyl-N-tert-butyl nitrone), catalytic antioxidants (superoxide dismutase [ECSOD] mimetics), porphyrins, and lipid peroxidation and protein carbonylation blockers/inhibitors (edaravone and lazaroids/tirilazad). Preclinical and clinical trials have shown that these antioxidants can reduce oxidative stress, affect redox and glutathione biosynthesis genes, and proinflammatory gene expression. In this review the approaches to enhance lung antioxidants in COPD and the potential beneficial effects of antioxidant therapy on the course of the disease are discussed.     

Emerging pharmacological therapies for fibromyalgia

Fibromyalgia is a chronic pain disorder for which pathophysiological mechanisms are difficult to identify and current drug therapies demonstrate limited effectiveness and significant tolerability. To date, no drugs have been officially approved for the indication of fibromyalgia, and randomized, controlled clinical trials with fibromyalgia patients are taking place to identify potential therapeutic approaches. Although emerging therapies, such as the antidepressants duloxetine and milnacipran and the antiepileptic pregabalin, offer certain efficacy, randomized controlled trials are generally difficult due to factors such as a lack of understanding of the pathophysiology and a heterogenous fibromyalgia patient population. For a significant advance in the drug treatment of fibromyalgia, novel clues are still awaited that may offer an effective therapeutic approach.     

Emerging pharmacological therapies for erectile dysfunction

There are new and novel therapies emerging in the field of erectile dysfunction, both centrally acting and peripherally acting agents delivered orally, intracavernosally or topically. Pharmacological targets include the enzyme phosphodiesterase Type 5 (PDE5), adrenergic receptors, prostaglandin receptors and guanyl cyclase.     

Cutting back on pro-protein convertases: the latest approaches to pharmacological inhibition

The secretory pathway in cells possesses an elaborate set of endoproteolytic enzymes that carry out a crucial step in protein precursor maturation. This step is proteolytic activation by cleavage at specific pairs of basic residues. These enzymes, named pro-protein convertases (PCs), are responsible for generating bioactive peptides and activating several enzymes and growth factors that are implicated in many important physiological events. PCs have roles in several pathologies including viral infections and cancers and, thus, are promising targets for therapeutic applications. Recent structural and homology-modeling studies demonstrate more similarity than expected at the catalytic site of the seven PCs, which makes the development of selective drugs to target individual PCs frustrating. Based on this information, we review the latest strategies to inhibit PCs, which might lead to the development of specific compounds.     

Impaired decision-making in opiate-dependent subjects: effect of pharmacological therapies

Cognitive dysfunction is a major feature of drug addiction. In the present paper, we compared the decision-making ability using the Iowa gambling task of methadone- and buprenorphine-maintained individuals to non opiate-dependent drug-free controls. Buprenorphine-maintained individuals performed better than methadone-maintained individuals, and not differently than non opiate-dependent controls. In addition, methadone-maintained individuals had more perseverative errors on the Wisconsin card sorting task (WCST) as compared with non opiate-dependent drug-free controls whereas buprenorphine-maintained individuals had intermediate scores. Scores on Weschler adult intelligence scale (WAIS-R) were similar for methadone- and buprenorphine-maintained individuals whereas drug-free controls had significantly higher scores. In addition, both opiate-dependent groups performed more poorly than drug-free controls on the Benton visual retention test (BVRT). The results suggest that buprenorphine in contrast to methadone improves decision-making, and thus may be more effective in rehabilitation programs of opiate-dependent subjects and this improvement may be related to its distinct pharmacological action as a k antagonist.     

Investigational therapies for the pharmacological treatment of alcoholism

Introduction: Alcohol dependence is one of the most important psychiatric disorders leading to enormous harm in individuals and indeed within society. Yet, although alcohol dependence is a disease of significant importance, the availability of efficacious pharmacological treatment is still limited.

Areas covered: The current review focuses on neurobiological pathways that are the rationale for recent preclinical and clinical studies testing novel compounds that could be used as treatments for alcohol dependence. These neurobiological mechanisms include the: glutamatergic, dopaminergic and GABA mediated pathways as well as neuroendocrine systems. There is also an interest in the approaches for influencing chromatin structure.

Expert opinion: There are several compounds in Phase I and Phase II clinical studies that have produced potentially useful results for the treating alcoholism. Further evaluation is still necessary, and the implementation of Phase III studies will help to elucidate the usefulness of these compounds. It is important that personalized approaches (e.g., pharmacogenomics) are investigated in these later studies, as the efficacy of different compounds may vary substantially between subgroups of patients.     

Non-insulin pharmacological therapies for treating type 1 diabetes

Introduction: Despite intensified insulin treatment, many persons with type 1 diabetes (T1D) do not achieve glycemic and metabolic targets. Consequently, non-insulin chemical therapies that improve glycemic control and metabolic parameters without increasing the risk of adverse events (including hypoglycemia) are of interest as adjunct therapies to insulin.

Areas covered: In this review, the authors discuss the efficacy and safety of non-insulin therapies, including pramlintide, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP-4), sodium-glucose cotransporter (SGLT1 and SGLT2) inhibitors, metformin, sulfonylureas, and thiazolidinediones as add-on therapies to insulin in T1D.

Expert opinion: The current evidence shows that the efficacy of non-insulin therapies as add-on therapies to insulin is minimal or modest with an average HbA1c reduction of 0.2–0.5% (2–6 mmol/mol). Indeed, the current focus is on the development of SGLT inhibitors as adjuncts to insulin in type 1 diabetes. Studies of subgroups with obesity, residual beta-cell function (including newly diagnosed patients) and patients prone to hypoglycemia could be areas of future research.     

Available therapies and current management of fibromyalgia: focusing on pharmacological agents

Fibromyalgia (FM) is a chronic medical condition characterized by physical, psychiatric and psychological symptoms. Widespread pain, fatigue, sleep disturbances, heightened sensitivity, morning stiffness, decreased volition, depressed mood and a history of early abuse are frequently reported by patients with FM. Treatment of fibromyalgia is multidisciplinary, with an emphasis on active patient participation, medications, cognitive-behavioral therapy and physical modalities. No single medication has yet been found to sufficiently control all the symptoms of FM; currently available medication classes include antidepressants, nonsteroidal anti-inflammatory drugs, opioids, sedatives, muscle relaxants, analgesics, hypnotic agents and anticonvulsants. Hence, treatment for patients with FM, including pharmacological and non-pharmacological approaches, should be individualized based on each patient's clinical history, target symptoms and functional impairments. Although nonpharmacological modalities are also frequently used, recent research has focused on identifying more effective pharmacological treatments, particularly antidepressants and anticonvulsants. Furthermore, several new pharmacological agents have been now officially approved for the treatment of patients with FM. Thus, the purpose of this review is to help healthcare professionals make informed decisions about the appropriate use of a number of pharmacological treatments for patients with FM.     

Emerging therapies in the pharmacological treatment of Parkinson's disease

The pharmacological management of Parkinson's disease is a complex and dynamic task; there is no one 'right' strategy indicating which drugs should be used at a particular stage of the disease. There are now many different drugs belonging to several classes that may be effective, and there are still differences of opinion among leading clinicians about the best course of treatment. This review focuses on drug therapy for the motor impairment in Parkinson's disease. Current and future research directions are summarised by taking inventory of recent and innovative areas of development in the field, representing each category with at least one of its featured treatments. The main research efforts are being directed towards delaying the use of levodopa or finding therapies to be used as adjunct to it, in order to postpone motor complications and, in particular, dyskinesias. One of the recent trends is early employment of dopamine agonists. Additional efforts are being directed towards protecting and restoring dopamine neurons. Novel therapies acting on non-dopaminergic systems are also being researched.     

A risk-benefit assessment of pharmacological therapies for hirsutism.

In recent years, many new therapeutic regimens for hirsutism have been introduced. This has considerably enlarged the different choices of the physician but at the same time has produced considerable confusion and uncertainty as to what is the best possible therapy for the single patient or for the different pathologies of this condition. This review presents data on the characteristics, adverse effects and effective dosage for the more commonly used drugs for hirsutism. In most patients, low doses of antiandrogens (cyproterone acetate, flutamide or spironolactone) are used with few adverse effects and good results in terms of improvement of the hirsutism. Patients with severe hyperandrogenic hirsutism may require larger doses of antiandrogens. In only a few patients, therapy with agents that primarily reduce androgen secretion (mostly a gonadotropin releasing hormone agonist) is needed. In responsive patients, dexamethasone may be used at low doses (associated with an antiandrogen) to prolong the length of the remission. Finally, agents that inhibit 5alpha-reductase activity (finasteride) may be used as alternative to low dose antiandrogen therapy but the results are often less satisfactory.