Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 12, Number 21, 2006

Contents

Anti-Angiogenesis Agents
Executive Editor: Cezary Marcinkiewicz


Editorial Pp. 2597-2598


Regulation of Angiogenesis by the Kallikrein-Kinin System Pp. 2599-2607
R.W. Colman
[Abstract]


Cross Talk between the Cardiovascular and Nervous Systems: Neurotrophic Effects of Vascular Endothelial Growth Factor (VEGF) and Angiogenic Effects of Nerve Growth Factor (NGF) Implications in Drug Development Pp. 2609-2622
P. Lazarovici, C. Marcinkiewicz and P.I. Lelkes
[Abstract]


Angiogenesis Inhibitors: Perspectives in Medical, Surgical and Radiation Oncology Pp. 2623-2630
C. Verhoef, J.H.W. de Wilt and H.M.W. Verheul
[Abstract]


Angiogenesis as a Therapeutic Target in Arthritis: Lessons from Oncology Pp. 2631-2644
J. Bainbridge, B. Sivakumar and E. Paleolog
[Abstract]


Antineovascular Agents in the Treatment of Eye Diseases Pp. 2645-2660
W. Eichler, Y. Yafai, P. Wiedemann and D. Fengler
[Abstract]


Imaging of Tumor Angiogenesis: Current Approaches and Future Prospects Pp. 2661-2672
H.E. Daldrup-Link, G.H. Simon and R.C. Brasch
[Abstract]


Natural Product-Derived Small Molecule Activators of Hypoxia-Inducible Factor-1 (HIF-1) Pp. 2673-2688
D.G. Nagle and Y-D. Zhou
[Abstract]


General Articles


Hematopoietic Colony Stimulating Factors in Cardiovascular and Pulmonary Remodeling: Promoters or Inhibitors? Pp. 2689-2699
J. Parissis, G. Filippatos, S. Adamopoulos, X. Li, D.T. Kremastinos and B.D. Uhal
[Abstract]


Pharmacological Management of Huntington’s Disease: An Evidence-Based Review Pp. 2701-2720
R.M. Bonelli and G.K. Wenning
[Abstract]




Abstracts
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Editorial

Anti-Angiogenesis Agents

Angiogenesis is a process of new vessels formation from preexisting vasculature. This process is important in organ development during embryogenesis and less significant for the physiology of adult organisms. However, pathological angiogenesis has been observed in many diseases and is starting to be considered as a pharmaceutical target for therapy. A major effort has been initiated in developing angiostatic drugs for inhibition of cancer progression, but in other disorders including inflammatory and eye diseases, clinical trials testing angiogenesis inhibitors have also been initiated. The new pharmaceuticals have been designed based on the structure of endogenous regulators of angiogenesis as well as natural products isolated from plants and animals. The review papers presented in this issue of the journal summarize approaches that are currently focusing on clinical application of angiogenesis modulators and also provide a general overview of the mechanisms that could be important in angiogenesis related complications during therapy.

In the first two papers the authors discuss the modulation of angiogenesis by endogenous factors and how this event may affect pathological angiogenesis. The article provided by Colman [1] summarized the efforts that have been undertaken to characterize the relationship between angiogenesis and the kallikrein-kinin system. The major component of this system bradykinin (BK) participates in positive regulation of angiogenesis, whereas the kinin-free derivative of high molecular weight kininogen (HKa) has been characterized as an angiogenesis inhibitor. The active domain (D5) of HKa and the antibody that blocks binding of high molecular weight kininogen (HK) to endothelial cells inhibited experimental tumor growth as well as inflammatory arthritis and bowel diseases. The targeting of kallikrein-kinin system in inhibition of angiogenesis seems to be a very exciting new paradigm in cancer and inflammatory diseases therapy. Further studies are required to explain the mechanisms underlying this approach.

A very interesting paper is presented by Lazarovici and his colleagues [2]. The authors broadly discuss the importance of vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) in cardiovascular and nervous systems, focusing on the seemingly independent, yet interrelated problems of angiogenesis and neurogenesis. The observation that VEGF may directly affect neuronal outgrowth and provide neuroprotection, while NGF may regulate angiogenesis, suggests the existence of an effective cross-talk between the vascular and the nervous system. These growth factors bind to specific receptors that have been found on both neurons and endothelial cells. Thus, they may act as complementary elements which might be essential for the protection and functioning of both the vascular and nervous systems. In this light, the use of selective blockers of VEGF and NGF receptors that are currently in clinical trials may be re-considered in a new realm, a paradigm shift. For example, the synthetic small compound K252a that binds to the NGF-specific receptor trkA, may be applied as an angiostatic drug in cancer therapy. As a caveat, pharmacological modulation of one system may have harmful side effects on the other system. Thus, blocking of angiogenesis in cancer therapy may initiate and develop neurodegradative processes, while neuroprotective therapy in Alzheimer’ and Parkinson’s diseases may induce pathological angiogenesis resulting in development of cancer. Based on this, the clinical trials involving blockade of VEGF and NGF function should carefully monitor side effects of the nervous and vascular systems, respectively.

The general overview of inhibitors of angiogenesis that are currently in clinical trials are provided by Verhoef et al. [3]. Special attention of the authors is focused on the application of anti-angiogenic compounds in clinical oncology. For this reason, the multimodality treatment in clinical practice, involving the cooperative activity of surgeons, radiotherapist and medical oncologists, is raised as an attractive strategy for fighting cancer. All possible difficulties that may occur during angiostatic therapy are emphasized and discussed, as well as benefits of this cooperative approach are broadly described.

Although the majority of anti-angiogenesis agents are developed for treatment in oncology, the angiostatic therapy may be significant for other diseases. The next two review articles discuss possible applications of angiostatic pharmaceuticals in autoimmune disease such as arthritis [4], and eye diseases such as diabetic retinopathy or age-related macular degeneration [5]. Bainbridge et al. [4] presented the bulk of anti-neovascularization compound in clinical and pre-clinical trials with respect to use in therapy of rheumatoid arthritis (RA). This kind of therapy may be an alternative approach to anti-cytokine treatment in RA. The authors discuss in depth all possible directions of blocking of neovascularization process in RA based on the strategy and experience previously achieved by the oncologist. Moreover, the perspectives of development of the original RA-related angiostatic therapy are also analyzed in this article.

The possible application of angiostatic therapy is also considered in eye diseases. It is very well established that retinal pathological neovascularization is one of the serious processes can result in blindness. Eichler et al. [5] summarize this problem in this excellent review article, giving a perspective view of molecular therapy, targeting angiogenesis. Similar to the previous chapter, the authors support anti-angiogenic treatment for eye diseases based on the experience established by the oncologist. The major focus of the review describes angiostatic compounds that interrupt intermolecular signaling pathways.

Anti-angiogenic therapy requires frequent and lifelong monitoring. The optical imaging may be the most useable method to fulfill this approach. Dandrup-Link at al [6] summarized the current status of application of available imagining techniques in visualization of angiogenesis. The techniques including ultrasound, CT, MR, SPEC and PET are currently under consideration to monitor angiostatic therapy. The authors attention is particularly focused on tumor-related angiogenesis, emphasizing the role of imaging of the vascularization process prior to cancer treatment, and during and after anti-angiogenic therapy. This kind of strategy may be important for planning and correlating clinical cancer treatment.

The opposite approach, related to angiogenesis-dependent therapy, is presented by Nagle and Zhou [7]. In this article, the authors focused on the promotion of angiogenesis in the pathology of atherosclerotic coronary diseases. The therapeutical strategy for patients is induction of new collateral blood vessels formation as a replacement for the occluded vessels. The beneficial, stimulatory effect in this process may involve hypoxia-inducible factor-1 (HIF-1) activation. In the presented chapter, the authors overviewed the natural products-derived compounds that were characterized as activators of HIF-1. These low molecular weight organic compounds may have a valuable therapeutic implication for the treatment of ischemia and other ischemia/hypoxia-related disorders.

References

[1] Colman RW. Regulation of Angiogenesis by the Kallikrein-Kinin System. Curr Pharm Design 2006; 12(21): 2599-2607.

[2] Lazarovici P, Marcinkiewicz C, Lelkes PI. Cross Talk between the Cardiovascular and Nervous Systems: Neurotrophic Effects of Vascular Endothelial Growth Factor (VEGF) and Angiogenic Effects of Nerve Growth Factor (NGF)-Implications in Drug Development. Curr Pharm Design 2006; 12(21): 2609-2622.

[3] Verhoef C, de Wilt JHW, Verheul HMW. Angiogenesis Inhibitors: Perspectives in Medical, Surgical and Radiation Oncology. Curr Pharm Design 2006; 12(21): 2623-2630.

[4] Bainbridge J, Sivakumar B, Paleolog E. Angiogenesis as a Therapeutic Target in Arthritis: Lessons from Oncology. Curr Pharm Design 2006; 12(21): 2631-2644.

[5] Eichler W, Yafai Y, Wiedemann P, Fengler D. Antineovascular Agents in the Treatment of Eye Diseases. Curr Pharm Design 2006; 12(21): 2645-2660.

[6] Daldrup-Link HE, Simon GH, Brasch RC. Imaging of Tumor Angiogenesis: Current Approaches and Future Prospects. Curr Pharm Design 2006; 12(21): 2661-2672.

[7] Nagle DG, Zhou Y-D. Natural Product-Derived Small Molecule Activators of Hypoxia-Inducible Factor-1 (HIF-1). Curr Pharm Design 2006; 12(21): 2688.

Cezary Marcinkiewicz Ph.D.
Temple University, School of Medicine
Department of Neuroscience
1900 N. 12th Street
Philadelphia, PA 19122
USA
E-mail: cmarcink@temple.edu


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Regulation of Angiogenesis by the Kallikrein-Kinin System
R.W. Colman

High molecular weight kininogen (HK) is a plasma protein that is cleaved by plasma kallikrein in the clinical settings of sepsis and chronic inflammatory diseases such as rheumatoid arthritis and Crohn’s disease. This proteolytic event results in a nonapeptide, bradykinin (BK), and a kinin-free derivative of HK, namely HKa. BK promotes angiogenesis by upregulation of bFGF through the B1 receptor or by stimulation of VEGF formation via the B2 receptor. Kininogen-deficient rats show diminished angiogenesis when neovascularization is stimulated. The formation of HKa results in exposure of domain 5 (D5). HKa or D5 inhibit endothelial cell migration and proliferation, both of which are needed for angiogenesis. In the chicken chorioallantoic membrane assay when neovascularization is stimulated by bFGF or VEGF, HKa or D5 inhibit angiogenesis. Monoclonal antibody C11C1, which prevents binding of HK to endothelial cells, also limits its conversion to BK thus downregulating angiogenesis. In vivo, mAb C11C1 inhibits tumor angiogenesis in mice as well as in experimental inflammatory arthritis and inflammatory bowel disease in Lewis rats. In vitro HKa or D5 inhibits endothelial cell adhesion to vitronectin and fibrinogen, resulting in anokis and apoptosis. The HKa receptor, uPAR, forms a signaling complex containing the integrin αvβ3 or α5β1, caveolin, Src kinase Yes, focal adhesion kinase and paxcillin. HKa physically disrupts the complex by interfering with the binding of vitronectin to uPAR. Both mAb C11C1 and D5 have potential applications for controlling unwanted angiogenesis in inflammation and cancer.


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Cross Talk between the Cardiovascular and Nervous Systems: Neurotrophic Effects of Vascular Endothelial Growth Factor (VEGF) and Angiogenic Effects of Nerve Growth Factor (NGF) Implications in Drug Development
P. Lazarovici, C. Marcinkiewicz and P.I. Lelkes

Both blood vessels and nerves are guided to their tissue targets by “specific” growth factors such as vascular endothelial growth factor (VEGF) and nerve growth factor (NGF), originally discovered as growth factors specific for endothelial and neuronal cells, respectively. While the eminent role of VEGF in the formation of new blood vessels (angiogenesis) is unquestioned, recent studies indicate that VEGF also has direct effects on the nervous system in terms of neuronal growth, survival (neurotrophic), axonal outgrowth (neurotropic), and neuroprotection. Conversely, NGF, a neurotrophin that plays a crucial role in promoting neurotrophic and neurotropic effects in sympathetic neurons, has recently been identified as a novel angiogenic molecule exerting a variety of effects on endothelial cells and in the cardiovascular system in general. VEGF and NGF have also been implicated in both neurodegenerative and vascular diseases. The pleiotropic effects of these growth factors have raised interest in assessing their therapeutic potential. The challenge for the future is to unravel to what extent the effects of these growth factors are interrelated with regards to their angiogenic, and neurotrophic effects and how to design selective drugs interfering with their respective actions. Most biological actions of NGF and VEGF are mediated by their cognate receptor protein tyrosine kinases, tropomyosin related kinase (trkA for NGF) and kinase insert domain-containing receptor (KDR, VEGFR-2, flk-1 for VEGF), which activate a complex and integrated network of signaling pathways in neurons and endothelial cells. Two small molecules, K252a and SU-5416, which are antagonists of trkA and VEGFR-2, respectively, may serve as key tools in dissecting the role of NGF and VEGF in angiogenesis and neurogenesis. Development of selective drugs specific for the trkA and VEGFR-2 subtypes of receptors will provide new tools for the treatment of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, as well as of numerous angiogenesis-dependent diseases, such as cancer, diabetes, and arthritis.


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Angiogenesis Inhibitors: Perspectives in Medical, Surgical and Radiation Oncology
C. Verhoef, J.H.W. de Wilt and H.M.W. Verheul

In the past decade, many angiogenesis inhibitors have been developed for clinical use in oncology. Surgeons, radiotherapists as well as medical oncologists have been investigating with much effort and enthusiasm the translation of these agents from the preclinical setting into treatment strategies of patients. Recently, for the first time in history, the angiogenesis inhibitor bevacizumab (avastin), a humanized anti-vascular endothelial growth factor (VEGF) antibody, showed a survival benefit of 4.7 months in a phase III clinical trial in patients with advanced colorectal cancer when this agent was given in combination with chemotherapy. At the annual meeting of the American Association of Clinical Oncology 2005, similar results of bevacizumab in lung, breast and ovarian cancer clinical trials have been shown.

These landmark studies proofed for the first time in the clinical setting that Dr. Folkman back in 1971 was right by proposing: “in order to stop tumor growth, one should attack its blood supply”. Nowadays it seems trivial to propose such a hypothesis, at that time it was a very provocative hypothesis and it took more than 30 years to proof this hypothesis in the clinic.

Although one may be excited about this major finding, there is no time to relax. The survival benefit of bevacizumab is only about 4 months. Therefore more potent antiangiogenic agents and more active treatment strategies are urgently warranted.

Newer angiogenesis inhibitors that are currently in preclinical or early clinical development have shown in preclinical experiments improved antitumor activities. In addition, combinations of biological agents that interfere in multiple biological pathways in cancer growth including chemotherapy, are of major clinical interest as well. The multimodality approach in which surgeons, radiotherapists and medical oncologists collaborate needs to be explored as well. In a variety of cancer types, like breast colon and lung cancer, these specialists should design multimodality strategies based on current standard treatment in which they incorporate angiogenesis inhibitors in the right time frame of surgery and radiotherapy. In this review we will bring you up to date on the clinical development of angiogenesis inhibitors and we will summarize the multimodality strategies that are under development.


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Angiogenesis as a Therapeutic Target in Arthritis: Lessons from Oncology
J. Bainbridge, B. Sivakumar and E. Paleolog

Rheumatoid arthritis (RA) is a chronic disabling autoimmune inflammatory disease of unknown aetiology with a prevalence of about 1% in most parts of the world. As a result of the debilitating nature of the disease, sufferers struggle with the simple activities of daily living and frequently fail to remain in full time employment. Furthermore, the mortality associated with the disease is equivalent to that seen in triple vessel coronary artery disease. Over the 10-15 years, advances in understanding the mechanisms of RA pathogenesis based on studies of human cells and animal models of arthritis have led to the identification of new targets for therapeutic intervention. Despite these advances, a significant proportion of patients continue to exhibit disease which is refractory to such therapy. As an alternative to anti-cytokine therapy, formation of new blood vessels (‘angiogenesis’) represents a potentially attractive target for therapy in RA. Angiogenesis has been a putative target in cancer since it was first linked to tumour growth and metastases in the 1970s. A number of significant advances have been made in the development of anti-cancer therapy using such an approach. This review focuses on the potential for targeting angiogenesis in RA, building upon the experience of angiogenesis inhibition in the oncological setting. Through this we hope to emphasise the potential value of anti-angiogenic therapy in RA and identify future directions for optimising treatment of this disabling disease.


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Antineovascular Agents in the Treatment of Eye Diseases
W. Eichler, Y. Yafai, P. Wiedemann and D. Fengler

Neovascularization is a common and potentially visually threatening complication of eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). An antiangiogenic therapy is aimed at inhibiting the growth of new blood vessels and should prevent onset or progression of neovascularization. Accumulated evidence indicates that growth factors, endothelial cell surface receptors, and extracellular matrix (ECM) proteins are major mediators of neovascularization and appealing targets for pharmacotherapeutical intervention. Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of retinal neovascularization (in linking tissue ischemia to angiogenesis), and is likely to contribute also significantly to choroidal neovascularization (CNV). Several antineovascular agents antagonize the function of VEGF, by blocking its proangiogenic activity. Indeed, VEGF targeting or disruption of VEGF signalling is the most effective strategy known so far in the pharmacological treatment of ocular neovascularization. Other compounds such as pigment epithelium-derived factor (PEDF) either aim at balancing the levels of pro-angiogenic and angiostatic molecules, target inflammation (cyclooxygenase inhibitors, steroids) or comprise modifiers of the ECM such as inhibitors of matrix metalloproteinases (MMPs) and agents that block the action of integrins. Vascular targeting agents (combretastatin) promote removal of newly formed vessels. This review provides an update on recent investigations directed at the pharmacotherapeutical management of ocular neovascular diseases, placing special emphasis on the underlying target molecules and relevant intracellular signalling pathways.


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Imaging of Tumor Angiogenesis: Current Approaches and Future Prospects
H.E. Daldrup-Link, G.H. Simon and R.C. Brasch

Tumor angiogenesis imaging should provide non-invasive assays of tumor vascular characteristics to supplement the now conventional diagnostic imaging goals of depicting tumor location, size, and morphology. This article will review the current status of angiogenesis imaging approaches, considering ultrasound, CT, MR, SPECT, PET and optical techniques with attention to their respective capabilities and limitations. As a group, these imaging methods have some potential to depict and quantify tumor microvascular features, including those considered to be functionally associated with tumor angiogenesis. Additionally, new molecule-specific imaging techniques may serve to depict those biochemical pathways and regulatory events that control blood vessel growth and proliferation. Non-invasive monitoring of anti-angiogenic therapies has great appeal and should find wide application for defining tumor microvascular and metabolic changes, because treatment-related changes in tumor morphology tend to occur rather late and are non-specific. Future developments are likely to include “fusion” or “hybrid” imaging methods. Superimposed data from MR imaging with spectroscopy, PET with CT, and PET with MR should be able to integrate advantages of different modalities yielding comprehensive information about tumor structure, function and microenvironment.


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Natural Product-Derived Small Molecule Activators of Hypoxia-Inducible Factor-1 (HIF-1)
D.G. Nagle and Y-D. Zhou

Hypoxia-inducible factor-1 (HIF-1) is a key mediator of oxygen homeostasis that was first identified as a transcription factor that is induced and activated by decreased oxygen tension. Upon activation, HIF-1 upregulates the transcription of genes that promote adaptation and survival under hypoxic conditions. HIF-1 is a heterodimer composed of an oxygen-regulated subunit known as HIF-1α and a constitutively expressed HIF-1β subunit. In general, the availability and activity of the HIF-1α subunit determines the activity of HIF-1. Subsequent studies have revealed that HIF-1 is also activated by environmental and physiological stimuli that range from iron chelators to hormones. Preclinical studies suggest that HIF-1 activation may be a valuable therapeutic approach to treat tissue ischemia and other ischemia/hypoxia-related disorders.

The focus of this review is natural product-derived small molecule HIF-1 activators. Natural products, relatively low molecular weight organic compounds produced by plants, animals, and microbes, have been and continue to be a major source of new drugs and molecular probes. The majority of known natural product-derived HIF-1 activators were discovered through the pharmacological evaluation of specifically selected individual compounds. On the other hand, the combination of natural products chemistry with appropriate high-throughput screening bioassays may yield novel natural product-derived HIF-1 activators. Potent natural product-derived HIF-1 activators that exhibit a low level of toxicity and side effects hold promise as new treatment options for diseases such as myocardial and peripheral ischemia, and as che-mopreventative agents that could be used to reduce the level of ischemia/reperfusion injury following heart attack and stroke.


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Hematopoietic Colony Stimulating Factors in Cardiovascular and Pulmonary Remodeling: Promoters or Inhibitors?
J. Parissis, G. Filippatos, S. Adamopoulos, X. Li, D.T. Kremastinos and B.D. Uhal

Hemopoietic colony stimulating factors (HCSFs) are naturally occurred substances that are released in response to infection or inflammation and regulate the proliferation and differentiation of hemopoietic progenitor cells. Some representative members of this peptide family induce atherogenesis through the mediation of monocyte-endothelial cell adhesive interaction and promotion of angiogenesis within the atherosclerotic plaques. HCSFs, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), also promote post-infarction cardiac remodeling though the enhanced activation and infiltration of monocytes into injured myocardial tissue and through altered equilibrium of collagen deposition/degradation. On the other hand, exogenous administration of granulocyte colony-stimulating factor (G-CSF) or eythropoietin (EPO) in patients with chronic ischemic disease or recent myocardial infarction have lead to beneficial arteriogenesis or myocardial cell regeneration, thus preventing adverse cardiac remodeling. While GM-CSF may hold therapeutic potential as an inhibitor of lung fibrogenesis, G-CSF appears to promote fibrosis in the lungs. The pathophysiological role of HCSFs also depends on the timing of their action on cardiovascular remodeling, as well as on the target progenitor hematopoietic cell. This article summarizes current knowledge about the clinical and therapeutic implications of these factors in chronic artery disease, post-infarction cardiac remodeling, chronic heart failure and in pulmonary fibrosis.


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Pharmacological Management of Huntington’s Disease: An Evidence-Based Review
R.M. Bonelli and G.K. Wenning

Introduction: Despite the increasing body of published reports on pharmacological interventions in Huntington’s disease (HD), an evidence based review (EBR) of treatment studies has not yet been published.

Method: Systematic literature searches were done using Medline (1965 – August 2005), the central database in the Coch-rane Library (1969 – August 2005), and reference lists published in review articles and other clinical reports. Randomized controlled trials (RCTs) were classified as level-I-studies in this paper. Level-II evidence was assigned to non-randomized, controlled clinical studies. Level-III-studies comprised open label trials excluding case reports. Measures of efficacy as well as safety and tolerability were considered for each compound.

Results: We identified 218 publications on pharmacological interventions in HD since 1965. Among them were 20 level-I, 55 level-II, 54 level-III trials, and 89 case reports. All these papers are listed and analyzed. Chorea was the primary end point in all level-I and level-II symptomatic intervention trials. There is some evidence for treating chorea with haloperidol or fluphenazine, and less evidence for olanzapine. These three drugs have been considered “possibly useful” for the treatment of chorea in this analysis. Other substances (e.g. amantadine, riluzole, and tetrabenazine) are considered “investigational” for chorea. There is very low evidence for the treatment of other problems: “possibly useful” drugs are L-dopa and pramipexole for rigidity; amitryptiline and mirtazapine for depression; risperidone for psychosis; and olanzapine, haloperidol, and buspirone for behavioral symptoms in HD. Three substances are considered “investigational” for possible neuroprotection: coenzyme Q10, minocycline, and unsaturated fatty acids.

Conclusion: There is poor evidence in management of HD today. The analysis of the twenty level-I studies fails to result in any treatment recommendation of clinical relevance. High-quality RCT are highly warranted to advance HD treatment in clinical practice.