Emerging drugs for endometriosis

Background: Endometriosis is a benign, common gynecological disorder affecting mostly women of reproductive age. It is associated with dysmenorrhea, pelvic pain, and subfertility. The current non-surgical medical treatment is not satisfactory and there is a pressing need for novel therapeutics with better efficacy, tolerability and safety profiles. Objective: To investigate the development of new therapies for endometriosis. Methods: The PubMed database has been extensively searched for all compounds tested preclinically and clinically. Results/conclusion: Besides the three main classes of drugs, i.e., GnRH agonists, progestins, and androgenic agents, there are several classes of compounds that have been tested preclinically and clinically. Surprisingly, a considerable proportion of officially registered Phase II/III clinical trials are listed as completed yet no information on their outcomes is available. Three completed and published Phase II trials found the tested compound disappointing. Another two Phase II clinical trials have been suspended. This apparent gap between the generally promising preclinical findings and the clinical trial outcomes reflects our current woefully inadequate understanding of the mechanisms underlying endometriosis-associated pain and subferitility and recurrence of endometriosis; questions the adequacy and value of animal models of endometriosis that are still in use; highlights the difficulty in developing new therapeutics for endometriosis; and calls for more research in the mechanisms underlying endometriosis-associated pain and subferitility and recurrence of endometriosis.     

Emerging drugs in endometriosis

Endometriosis is a common, estrogen-dependent, gynaecological disease, defined as the presence of endometrial-like tissue outside the uterus. Although several medications are used for treatment of the disease, they are associated with high recurrence rates, considerable side effects and limited duration of application. Due to these limitations and to the impact of endometriosis on the quality of life of affected women, their environment and the society, there is a great need for new drugs able to abolish endometriosis and its symptoms. Studies in recent years investigating the (patho)physiological mechanisms involved in disease aetiology have fostered the development of novel therapeutic concepts for endometriosis, by targeting the hypothalamic-pituitary-gonadal axis, by selective modulation of estrogenic and progestogenic pathways, by inhibiting angiogenesis or by interfering with inflammatory and immunological factors. This article presents a brief summary of the currently available medications and an overview regarding the development of some of the most interesting and/or most promising novel drug candidates for endometriosis.     

Emerging drugs in endometriosis

Endometriosis is a common, estrogen-dependent, gynaecological disease, defined as the presence of endometrial-like tissue outside the uterus. Although several medications are used for treatment of the disease, they are associated with high recurrence rates, considerable side effects and limited duration of application. Due to these limitations and to the impact of endometriosis on the quality of life of affected women, their environment and the society, there is a great need for new drugs able to abolish endometriosis and its symptoms. Studies in recent years investigating the (patho)physiological mechanisms involved in disease aetiology have fostered the development of novel therapeutic concepts for endometriosis, by targeting the hypothalamic–pituitary–gonadal axis, by selective modulation of estrogenic and progestogenic pathways, by inhibiting angiogenesis or by interfering with inflammatory and immunological factors. This article presents a brief summary of the currently available medications and an overview regarding the development of some of the most interesting and/or most promising novel drug candidates for endometriosis.     

Investigational drugs for endometriosis

Endometriosis is an enigmatic disease found in as many as 30% of reproductive age women. The symptoms for women who suffer from this malady vary but may include subfertility or chronic pelvic pain. Because endometriosis lesions rely on estradiol for growth, most of the existing drug regimens work by creating hypoestrogenism. Unfortunately, this leads to untoward side effects and alterations in ovulation and, subsequently, fertility potential. Newer drugs are currently under investigation that either create hypoestrogenemia more efficaciously or do not alter ovulation but still affect the growth of endometriosis. They target some of the pathophysiological pathways that are only now being elucidated, and include gonadotropin-releasing hormone antagonists, aromatase inhibitors, selective progesterone receptor modulators, angiogenesis inhibitors, matrix metalloprotease inhibitors, estrogen receptor beta-agonists and immune modulators.     

Emerging drugs for ichthyosis

The ichthyoses constitute a large and heterogeneous group of disorders characterised by varying degrees of skin scaling. Most forms are rare but between them, they affect tens of thousands of people worldwide. Treatment presently consists primarily of topical keratolytic agents, aimed at removing the ichthyotic scales, and emollients. If an ichthyosis cannot be controlled by topical therapy alone, retinoids can be used. Although effective in several forms of ichthyosis, side effects and teratogenicity severely limit their use. The recent development of retinoic acid metabolism blocking agents (RAMBAs) offers new possibilities. With these drugs, retinoid effects may be obtained with less side effects and a shorter post-treatment teratogenicity period. This review discusses the RAMBAs that are now in clinical trials and outlines possible future developments.     

Emerging drugs for epilepsy

Epilepsy affects < or = 1% of the world's population. Antiepileptic drugs (AEDs) are the mainstay of treatment, although more than a third of patients are not rendered seizure free with existing medications. Uncontrolled epilepsy is associated with increased mortality and physical injuries, and a range of psychosocial morbidities, posing a substantial economic burden on individuals and society. Limitations of the present AEDs include suboptimal efficacy and their association with a host of adverse reactions. Continued efforts are being made in drug development to overcome these shortcomings employing a range of strategies, including modification of the structure of existing drugs, targeting novel molecular substrates and non-mechanism-based drug screening of compounds in traditional and newer animal models. This article reviews the need for new treatments and discusses some of the emerging compounds that have entered clinical development. The ultimate goal is to develop novel agents that can prevent the occurrence of seizures and the progression of epilepsy in at risk individuals.     

Emerging drugs for narcolepsy

Narcolepsy is characterised by excessive daytime sleepiness, usually associated with cataplexy, hypnagogic hallucinations, sleep paralysis and fragmented nocturnal sleep. Although uncommon, it results in significant disability. Most cases occur sporadically, but genetic factors probably form a susceptibility background on which unknown environmental triggers act. The hypocretin system is strongly implicated in the development of narcolepsy. Cerebrospinal fluid levels of hypocretin-1 are significantly reduced in narcoleptic subjects with cataplexy. Despite the advances in our understanding of narcolepsy, current therapy is primarily symptomatic. Stimulants (standard and novel) combat excessive daytime sleepiness. Antidepressants (tricyclics, dual-action or selective serotonin re-uptake inhibitors) and sodium oxybate are anticataplexy agents. Hypnagogic hallucinations and sleep paralysis respond to antidepressants. Sodium oxybate consolidates sleep. Novel and experimental treatments include histamine antagonists, hypocretin agonists, slow-wave sleep enhancers, intravenous gamma-globulin, tramadol and corticosteroids.     

Emerging drugs for psoriasis

Psoriasis is a chronic immune-mediated inflammatory skin disease characterised by abnormal keratinocyte differentiation and proliferation. The immunopathogenesis is complex and novel evidence shows the involvement of both innate and adaptive immune response. Type 1 T cells and their effector cytokines play a pivotal role. Several drugs under preclinical and clinical development for psoriasis are directed against the immune response, targeting activation or proliferation of T cells, their trafficking and skin-homing, or effector cytokines. Among these, great attention has been given to TNF-α, following the demonstration of effectiveness of anti-TNF-α biologicals, and to IFN-γ inducers. Another appealing approach concerns drugs capable of inducing immunological tolerance. Progress made in the recognition of intracellular events has prompted the development of small molecules and oligonucleotides that can inhibit specific molecular targets. There is, however, a plethora of other emerging drugs, clearly suggestive of the current interest for psoriasis, which are briefly described in this paper.     

Emerging drugs for ichthyosis

The ichthyoses constitute a large and heterogeneous group of disorders characterised by varying degrees of skin scaling. Most forms are rare but between them, they affect tens of thousands of people worldwide. Treatment presently consists primarily of topical keratolytic agents, aimed at removing the ichthyotic scales, and emollients. If an ichthyosis cannot be controlled by topical therapy alone, retinoids can be used. Although effective in several forms of ichthyosis, side effects and teratogenicity severely limit their use. The recent development of retinoic acid metabolism blocking agents (RAMBAs) offers new possibilities. With these drugs, retinoid effects may be obtained with less side effects and a shorter post-treatment teratogenicity period. This review discusses the RAMBAs that are now in clinical trials and outlines possible future developments.     

Emerging drugs for osteoporosis

Introduction: Osteoporotic fracture is a cause of pain, loss of autonomy and excess mortality. Current drugs however, do not allow for a satisfactory non vertebral fracture risk reduction and the compliance is suboptimal.

Areas covered: Current treatments consist of mainly bisphosphonates, denosumabs, selective estrogen receptor modulators and teriparatides. All drugs currently in development will target some aspect of bone remodeling by using the recent advances in our knowledge of bone biology: cathepsin-K inhibitors (odanacatib) are antiresorptive, antisclerostin monoclonal antibodies (romosozumab and blosozumab) are anabolic agents and PTHrp 1-34 (abaloparatide) is an anabolic agent.

Expert opinion: New drugs with better tolerance and ideally with intermittent administration may improve their compliance. New drugs will have to provide higher efficiency levels with regards to reducing the risk of fractures. They may be second-line options, targeted at patients who are poor responders, or those who display contraindications to the older drugs, as a result of cost issues. In addition, some of these new drugs with potent anabolic effect may be confined to niches, for those patients at high risk of refracture after an initial severe fracture such as a hip fracture or a clinical vertebral fracture.     

Emerging drugs for malaria

Introduction: Malaria remains one of the most important infectious diseases, causing around 655 000 deaths annually, mostly among children in Sub-Saharan Africa. Plasmodium falciparum, the parasite responsible for the most severe form of malaria, has developed resistance against almost all drugs in clinical use. Development of new drugs, preferably acting by mechanisms distinct from those of established treatment, is thus urgently needed. Areas covered: Non-artemisinin drug candidates currently in pre-registration clinical trials are reviewed covering published data available until December 2011. Expert opinion: Although promising compounds are presently undergoing clinical evaluation, the lack of new treatments for severe malaria and the predominance of artemisinin-based combination therapy for uncomplicated malaria is concerning. Future research should be directed towards the discovery of new therapeutic principles.     

Emerging drugs for asthma

INTRODUCTION: Current drug treatments for asthma relieve bronchospasm and airway inflammation but do not offer a cure, and symptoms return when treatment is stopped. Asthma management guidelines emphasize the importance of effective asthma treatment to achieve and maintain asthma control. However, despite widely available and effective treatments, achieving asthma control is still an unmet need for many patients. AREAS COVERED: Remarkable efforts have been made to identify the characteristic features of difficult-to-control (usually severe) asthma that are different from those described for mild-to-moderate asthma, setting the stage for the development of new and even individualized therapies. The most fascinating options of the new asthma treatments are biologic therapies, in particular monoclonal antibodies. In addition, some novel once-daily combinations of long-acting β(2)-agonist and inhaled corticosteroids are under development. EXPERT OPINION: Asthma is a complex syndrome made up of a number of disease variants or asthma phenotypes, with different underlying pathophysiology. As different drugs target different pathways, it is necessary to determine the individual profile of pathophysiological abnormalities for each patient. Several cytokines have been implicated in the inflammatory cascades leading to the different asthma phenotypes, and the most relevant ones are discussed. The challenge in treating asthma resides precisely in its heterogeneity.     

Emerging drugs for uveitis

INTRODUCTION: Uveitis is a challenging disease covering both infectious and noninfectious conditions. The current treatment strategies are hampered by the paucity of randomized controlled trials and trials comparing the efficacy of different agents. AREAS COVERED: This review describes the current and future treatments of uveitis. A literature search was performed in PUBMED from 1965 to 2010 on drugs treating ocular inflammation with emphasis placed on more recent, larger studies. Readers should gain a basic understanding of current treatment strategies beginning with corticosteroids and transitioning to steroid sparing agents. Steroid sparing agents include antimetabolites such as methotrexate, azathioprine and mycophenolate mofetil; calcineurin inhibitors which include cyclosporine, tacrolimus; alkylating agents which include cyclophosphamide and chlorambucil; and biologics which include the TNF-α inhibitors infliximab, adalimumab and etanercept and daclizumab, IFN-α(2a) and rituximab. EXPERT OPINION: Newer agents are typically formulated from existing drugs or developed based on new advances in immunology. Future treatment will require a better understanding of the mechanisms involved in autoimmune diseases and better delivery systems in order to provide targeted treatment with minimal side effects.     

Emerging drugs for psoriasis

Psoriasis is a chronic immune-mediated inflammatory skin disease characterised by abnormal keratinocyte differentiation and proliferation. The immunopathogenesis is complex and novel evidence shows the involvement of both innate and adaptive immune response. Type 1 T cells and their effector cytokines play a pivotal role. Several drugs under preclinical and clinical development for psoriasis are directed against the immune response, targeting activation or proliferation of T cells, their trafficking and skin-homing, or effector cytokines. Among these, great attention has been given to TNF-alpha, following the demonstration of effectiveness of anti-TNF-alpha biologicals, and to IFN-gamma inducers. Another appealing approach concerns drugs capable of inducing immunological tolerance. Progress made in the recognition of intracellular events has prompted the development of small molecules and oligonucleotides that can inhibit specific molecular targets. There is, however, a plethora of other emerging drugs, clearly suggestive of the current interest for psoriasis, which are briefly described in this paper.     

Emerging drugs for schizophrenia

INTRODUCTION: Since the development of clozapine, scores of antipsychotics have been introduced. These are, with one exception (aripiprazole), based on the pharmacological principle of 5-HT(2)/dopamine antagonism. Research on other treatment targets, which, in part, influence dopaminergic pathways directly or indirectly, is mounting. Managing psychotic symptoms is only one facet of successful treatment of schizophrenia. Effective remedies against negative symptoms and cognitive deficits are still an unmet clinical need. AREAS COVERED: With the focus on the topics mentioned above, the authors briefly review the latest clinical research organized on the basis of receptor systems and other drug targets, which are discussed to be involved in the pathophysiology of schizophrenia. EXPERT OPINION: In conclusion, although clinicians will have to have considerable patience before truly novel anti-schizophrenia treatments become obtainable, a number of interesting leads with considerable theoretical potential are being explored. As yet, it is difficult to predict which of these mechanisms will effectively augment the currently available treatments.     

Emerging drugs for bronchiectasis

Introduction: The global burden of disease due to bronchiectasis is high, disproportionately impacting developing countries and disadvantaged populations. Bronchiectasis, the destruction and dilation of airways, is due to a variety of causes and is characterized by a self-perpetuating cycle of airway inflammation, infection and obstruction that results in substantial morbidity and mortality. Although many therapies have been tested that address each of these three components, as well as the diseases that both cause and result from bronchiectasis, there have been few randomized, placebo-controlled trials.

Areas covered: In this review, current knowledge of the clinical features, pathophysiology and epidemiology of bronchiectasis among both adults and children is summarized. We discuss the quality and extent of evidence supporting current treatment strategies, focusing on therapies for which the strongest evidence of efficacy exists. We then identify key goals for future research on the causes and treatments of a variety of types of bronchiectasis.

Expert opinion: Significant advances in the prevention and treatment of bronchiectasis will require substantially improved understanding of the pathogenesis of this orphan disease. A concerted, global effort to coordinate studies of both the pathophysiology and potential treatments of bronchiectasis, in its many forms, could lead to substantial improvements in outcomes.     

Emerging drugs for asthma

Background: Current therapies for asthma are aimed at controlling disease symptoms and for the majority of asthmatics inhaled corticosteroid anti-inflammatory therapy is effective. However, this approach requires life-time therapy while a subset of patients remains symptomatic despite optimal treatment creating a clear unmet medical need. Objectives: It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches may identify new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach may provide disease-modifying treatments. Results: Significant areas of drug development include humanised monoclonal antibodies (mAb) for asthma therapy including those against IgE, IL-4 and IL-5. Asthma-relevant cytokines or chemokines have been targeted in a number of other ways. These include the use of humanised receptor blocking mAb or the removal of cytokines or chemokines via their binding to soluble receptor constructs. Small-molecule receptor antagonists also target receptors or the cellular signal transduction pathways that are activated following cytokine or chemokine receptor ligation. Another approach is to target asthma relevant mediators or the pathways controlling pro-inflammatory leukocyte accumulation within the asthmatic lung. Conclusions: This review will discuss the current status, therapeutic potential and potential problems of these novel drug developments in asthma therapy. Current therapies for asthma are aimed at controlling disease symptoms, and for the majority of asthmatics inhaled corticosteroid anti-inflammatory therapy is effective. However, this approach requires lifetime therapy; and a subset of patients remains symptomatic despite optimal treatment, creating a clear unmet medical need. It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches may identify new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach may provide disease-modifying treatments. Significant areas of drug development include humanised mAb for asthma therapy, including those against IgE, IL-4 and IL-5. Asthma-relevant cytokines or chemokines have been targeted in a number of other ways. These include the use of humanised receptor blocking mAb or the removal of cytokines or chemokines via their binding to soluble receptor constructs. Small-molecule receptor antagonists also target receptors or the cellular signal transduction pathways that are activated following cytokine or chemokine receptor ligation. Another approach is to target asthma-relevant mediators, or the pathways controlling pro-inflammatory leukocyte accumulation within the asthmatic lung. This review will discuss the current status, therapeutic potential and potential problems of these novel drug developments in asthma therapy.     

Emerging drugs for conjunctivitis

Background: Conjunctivitis is a highly prevalent ocular condition with potential complications that include visual impairment. Infectious causes include bacterial, viral, parasitic and fungal etiologies, while noninfectious conjunctivitis is typically owing to allergy, tear film dysfunction or chemical trauma. Treatment requires frequent dosing and often lacks complete efficacy. Objective: The goal of this review is to investigate therapies for conjunctivitis that are undergoing clinical study and development. These data are presented in light of currently available treatment options to provide an understanding of the present and future direction of conjunctivitis management. Methods: The Pharmaprojects database was searched for conjunctivitis therapies currently in development around the world. Current treatment guidelines for infectious and noninfectious conjunctivitis were researched through PUBMED and OVID databases. Results: Several new compounds, including antimicrobial, antihistamine, anti-inflammatory and immunomodulating drugs, along with a novel thiazolidinedione, are currently undergoing investigation for their potential use in conjunctivitis management. These ophthalmic agents show promise in improving clinical outcomes for infectious and noninfectious conjunctivitis.