Dry Form Of Age-related Macular Degeneration Research Articles

The influence of test illuminance on visual acuity in patients with primary open-angle glaucoma and age-related macular degeneration

PURPOSE. To study the influence of the illuminance level of test objects on the resolution of the visual analyzer in patients with primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD), and assess the possibility of using the obtained results for early diagnosis of these eye diseases.METHODS. Visual acuity (VA) under controlled illumination conditions (from 50 to 400 lx) of test objects was assessed using the developed device in three groups: in 50 healthy subjects aged 37.08±10.19 years without ophthalmic pathology (group A), in 50 patients with early (Ia and IIa) stages of POAG aged 47.16±8.28 years (group B) and 50 patients aged 46.08±4.56 years (group C) with dry form of AMD (initial stage).RESULTS. With an increase in the illumination of test objects (IT) from 50 to 400 lx, the VA of healthy individuals significantly increases on average by δ=0.32 (from 1.0±0.22 to 1.32±0.24, p<0.01), while in POAG the increase in VA with an increase in IT is much less pronounced, averaging δ=0.12 (from 0.9±0.20 to 1.02±0.26, p<0.05). At the same time, starting from IT 150 lx and above, the differences between the values of VA in the control group and in the group of patients with POAG of the initial stages become significant (p<0.05). VA of patients with AMD with increasing IT practically does not change, remaining at a stable level: δ=0.04 (from 0.76±0.20 to 0.80±0.26, t=0.66, p>0.5). At the same time, the VA values in this group of patients for each illumination level are significantly lower (p<0.05) than the corresponding VA values in the control group (group A).CONCLUSION. The revealed regularities can be used for early diagnosis of the pathological process: an increase in VA at the maximum level of IT relative to the initial value by less than δ≤0.2 indicates pathology of the optic nerve (POAG), and the absence of significant changes in VA with an increase in IT (minimum values of δ) is characteristic of the pathological process in the macula (AMD).

Dynamics of Structural and Functional Changes of Patients with Dry Form Age-related Macular Degeneration after Double Filtration Plasmapheresis

Actuality. One of the significant ophthalmic diseases is a dry form age-related macular degeneration (dAMD). The issues of etiology and pathogenesis are not completely cleared nowadays and they signify the subject of discussion. There are risk factors of dAMD (age, heredity, lifestyle etc.) which can cause metabolic disorders, changes hemorheological parameters which promote activation of druseogenesis and as a result an angiogenesis. Mostly an outcome of dAMD is geographical atrophy and decrease of central visual acuity. At the same time, it is known that similar metabolic and rheological disorders detected in other diseases are effectively corrected by extracorporeal rheoaferesis, in particular, using double filtration plasmapheresis. Thus, using of extracorporeal rheoaferesis with dAMD patients is pathogenetically well-reasoned, but in the available literature, a correct analysis of the effectiveness and safety of double filtration plasmapheresis in patients with intermediate stage of dAMD is presented poorly.Objective. To study along with data of OCT, OCT angiography, visometry, microperimetry and electroretinography structural and functional changes in the macular zone in patients with a dry form of age-related macular degeneration after the using of double filtration plasmapheresis.Patients and methods. The study included 63 patients (94 eyes) with an intermediate stage of dAMD. The patients were separated into two groups randomly. The first (main) group included 34 patients (52 eyes) who were performed double filtration plasmapheresis (DFPP) on an OctoNova device using a Plasmaflo plasma filter and a Cascadeflo EC40 fractionator in the amount of 4 procedures with a frequency of 1 time per week for 1 month. The second group (control) included 29 patients (42 eyes) who did not receive any specific treatment. In the main group of patients, OCT, OCT angiography, microperimetry and electroretinography were additionally performed in addition to standard ophthalmological examination before the DFPP course, after the DFPP course (1 month after the start of follow-up), 6 and 12 months later. Patients in the control group also underwent a similar examination at the specified time — 1, 6, 12 months after the start of follow-up.Results. In this study we found according to optical coherence tomography, optical coherence tomography-angiography, visometry, microperimetry and electroretinography, positive dynamics of structural and functional parameters of the macular retina is observed in patients with a dry form of age-related macular degeneration with using double filtration plasmapheresis. At the same time, a statistically significant difference between the two groups begins at 1 month and persists for 12 months of follow-up, which points to stabilization of the pathological process during the specified period.Conclusions. This study showed that after applying the double filtration plasmapheresis in patients with dry form of age-related macular degeneration, there is an improvement in structural and functional parameters of the macular zone, consisting in a decrease volume DOPES and stabilization of retinal light sensitivity.

An intelligent decision-making system for early diagnosis of macular pathology

Purpose: to develop a software technology based on artificial intelligence methods aimed at analyzing large volumes of optical coherent tomography (OCT) data in order to identify early symptoms of age-related macular degeneration (AMD) and the transition from dry AMD to neovascular AMD (nAMD).Material and methods. Patients with dry AMD (1125 eyes), wet nAMD (1200 eyes) and subjects without ophthalmic pathology (1205 eyes) underwent a standard ophthalmological examination and macular OCT (Cirrus HD-OCT 4000, Carl Zeiss Meditec AG, Germany) according to the MacularCube scanning protocol with a standard ETDRS macular map. The thickness of the retina from the inner limiting membrane to the retinal pigment epithelium and the presence and location of fovea configuration changes were determined.Results. Two ultra-precise artificial neural networks (ANN) were created: one intended to identify patients with early signs of dry AMD and the other to identify those with signs of nAMD. By the time when 1000 training images were processed, the image interpretation decision-making accuracy in the first ANN increased to reach 97.6%, in the second ANN, to 96.8%, which shows the high efficiency of this technology. The deep learning processes were run on an Amazon Web Service EC2 GPU. The trained ANN model was also tested on healthy eyes at each estimated probability value. The correspondence between the doctor's diagnosis and the decision taken by the ANN was assessed.Conclusions. A software technology based on artificial intelligence methods has been developed, which answered the need to process a large amount of OCT data. The technology proved effective in identifying early symptoms of dry and wet forms of AMD and in early diagnosis of the transition of the dry form of AMD into neovascular form, the latter requiring immediate treatment.

Protection of Aronia melanocarpa Fruit Extract from Sodium-Iodate-Induced Damages in Rat Retina.

Age-related macular degeneration (AMD) is one of the major causes of blindness in elderly populations. However, the dry form of AMD has lack of effective treatments. The fruits of Aronia melanocarpa are rich in anthocyanins. In this study, the protective effects of aronia fruit extract on rat retina were investigated using a NaIO3-induced dry AMD model. Full-field electroretinograms (ERGs) showed that b-wave amplitudes were significantly decreased and the retina structures were disordered in the model. The extract treatment alleviated the injuries. The b-wave amplitudes increased 61.5% in Scotopic 0.01ERG, 122.0% in Photopic 3.0ERG, and 106.8% in Photopic 3.0 flicker; the retina structure disorder was improved with the thickness of outer nuclear layer increasing by 44.1%; and the malonaldehyde level was significantly reduced in extract-treated rat retinas compared to the model. The proteomics analysis showed the expressions of five crystallin proteins, α-crystallin A chain, β-crystallin B2, β-crystallin A3, α-crystallin B chain, and γ-crystallin S, which protect retina ganglion cells, were increased by 7.38-, 7.74-, 15.30-, 4.86-, and 9.14-fold, respectively, in the extract treatment compared to the control, which was also confirmed by immunoblotting. The results suggest that aronia fruit extract, probably due to its anthocyanins, could protect the rat retina by alleviating oxidative damages and by upregulating the crystallin proteins to protect its nerve system.

The beneficial long-term effects of rheohaemapheresis in patients with the dry form of age-related macular degeneration are accompanied by lowering of LDL-C and PCSK9 and improvement of markers of endothelial dysfunction

Background and Aims: Age-related macular degeneration (AMD) is a progressive chronic disease with resulting visual impairment or even blindness with limited therapeutic options. Because hyperlipidemia is a significant risk factor for AMD development we investigated long-term effects of rheohaemapheresis in the dry form of AMD on the lipid related parameters including PCSK9.

Targeted therapy in age-related macular degeneration (AMD)

Introduction and purpose: Age-related macular degeneration (AMD) is a major cause of blindness in highly developed countries, with blindness frequency of 8.7%. This article is a review of the latest therapeutic options for AMD.A brief description of the state of knowledge: AMD is a multifactorial disease which etiology is not completely understood. Its development is affected by disorders at the cellular level, environmental and genetic factors. Intraocular injections of anti-VEGF agents are currently considered as the basis of AMD neovascular treatment. In the search for better and better therapeutic agents, the effects of administration of bevacizumab and ranizumab were tested. Many clinical studies confirm long-term and effective improvement in patients' vision after using the above-mentioned drugs, indicating that the initial response to treatment and the persistence of the therapeutic effect is individually variable and may be associated with genotypic difference. Another promising alternative to AMD treatment is the use of specific viral vectors that transfer substances slowing down the disease into the vitreous. Another method of gene therapy is the use of HIF transcription factors (hypoxia-induced factors), for now, the research is performed on animal models. Patients with dry AMD also have a chance for successful treatment. Examined gene therapy in dry form of AMD, including retinal surgery combined with viral vector injection, is in I/II phase study in Great Britain. Conclusions: Looking at the number of blindness cases in highly developed countries caused by AMD, every effort should be made to introduce effective treatment that at least inhibits disease progression. Undoubtedly, more research is needed to confirm the efficacy and long-term safety of AMD.

Pilot study of homeostatic alterations of mineral elements in serum of patients with age-related macular degeneration via elemental and isotopic analysis using ICP-mass spectrometry

Age-related macular degeneration (AMD), the main cause of irreversible blindness in people over 60 years of age, is an eye disease that evolves with loss of central vision. Although AMD manifests itself in the eye, blood is continuously flowing through the macular region, such that potential alterations in this region could be reflected in the composition of whole blood or plasma/serum. Therefore, the potential clinical relevance of analysis of serum samples was assessed because of the low degree of invasiveness of blood sampling. 40 initial samples (20 from controls and 20 from patients with the dry form of AMD) have been analysed in this work to investigate the possible occurrence of homeostatic alterations of essential mineral elements caused by the disease. Both major (Na, Mg, P and K) and trace (Fe, Cu and Zn) essential mineral elements were determined in blood serum using single-collector ICP-mass spectrometry. Also, the isotopic composition of Cu (an element proposed to be directly involved in the onset of AMD) was determined using multi-collector ICP-mass spectrometry. Unexpected light Cu isotopic compositions in three individuals assumed as controls, resulted in a re-evaluation of their clinical information and a later exclusion due to pathologies initially not accounted for. In this pilot study, a significant alteration in the δ65Cu value has been found between the two final cohorts (AMD patients: n = 20; controls n = 17), with lower δ65Cu values (i.e. an enrichment in the light 63Cu isotope) in the case of AMD. Also, higher serum concentrations of the elements P and Zn were established in AMD at a systemic level.

A Review of Pathogenic Drivers of Age-Related Macular Degeneration, Beyond Complement, with aFocus on Potential Endpoints for Testing Therapeutic Interventions in Preclinical Studies.

Age-related macular degeneration (AMD) continues to be the leading cause of visual impairment for the elderly in developed countries. It is a complex, multifactorial, progressive disease with diverse molecular pathways regulating its pathogenesis. One of the cardinal features of the early clinical subtype of AMD is the accumulation of lipid- and protein-rich deposits within Bruch's membrane, called drusen, which can be visualized by fundus imaging. Currently, multiple in vitro and in vivo model systems exist, which can be used to help tease out mechanisms associated with different molecular pathways driving disease initiation and progression. Given the lack of treatments for patients suffering from the dry form of AMD, it is imperative to appreciate the different known morphological endpoints associated with the various pathogenic pathways, in order to derive further insights, for the ultimate purpose of disease modeling and development of effective therapeutic interventions.

Daily zeaxanthin supplementation prevents atrophy of the retinal pigment epithelium (RPE) in a mouse model of mitochondrial oxidative stress.

Oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD). The dry form of AMD (geographic atrophy) is characterized by loss of RPE, photoreceptors, and macular pigments. The cumulative effects of oxidative stress impact mitochondrial function in RPE. In Sod2flox/floxVMD2-cre mice, the RPE specific deletion of Sod2, the gene for mitochondrial manganese superoxide dismutase (MnSOD), leads to elevated oxidative stress in retina and RPE, and causes changes in the RPE and underlying Bruch’s membrane that share some features of AMD. This study tested the hypothesis that zeaxanthin supplementation would reduce oxidative stress and preserve RPE structure and function in these mice. Zeaxanthin in retina/RPE/choroid and liver was quantified by LC/MS, retinal function and structure were evaluated by electroretinogram (ERG) and spectral domain optical coherence tomography (SD-OCT), and antioxidant gene expression was measured by RT-PCR. After one month of supplementation, zeaxanthin levels were 5-fold higher in the retina/RPE/choroid and 12-fold higher in liver than in unsupplemented control mice. After four months of supplementation, amplitudes of the ERG a-wave (function of rod photoreceptors) and b-wave (function of the inner retina) were not different in supplemented and control mice. In contrast, the c-wave amplitude (a measure of RPE function) was 28% higher in supplemented mice than in control mice. Higher RPE/choroid expression of antioxidant genes (Cat, Gstm1, Hmox1, Nqo1) and scaffolding protein Sqstm1 were found in supplemented mice than in unsupplemented controls. Reduced nitrotyrosine content in the RPE/choroid was demonstrated by ELISA. Preliminary assessment of retinal ultrastructure indicated that supplementation supported better preservation of RPE structure with more compact basal infoldings and intact mitochondria. We conclude that daily zeaxanthin supplementation protected RPE cells from mitochondrial oxidative stress associated with deficiency in the MnSOD and thereby improved RPE function early in the disease course.

Classical, Micropulse and NanoSecond Laser Therapy in Dry-Form (Non-Neovascular) Age-Related Macular Degeneration

Age-related macular degeneration (AMD), which is a multifactorial, degenerative disease of the retina, is the most common reason for legal blindness over 50 years of age. Dry-form (non-neovascular) AMD is the common type, and frequently non-progressive to total vision loss. Epidemiological, histopathological, and biochemical data demonstrate that AMD is associated with oxidative damage, lipofuscin accumulation, chronic inflammation, and mutations in the complement system. Drusen, hyperpigmentation/hypopigmentation in retinal pigment epithelium, and geographical atrophy can also be observed in dry-form AMD. Various treatment modalities can be used according to the stages of the disease. Antioxidants, visual cycle inhibitors, anti-inflammatory agents, neuroprotective treatment, conventional, micropulse, and nano-second laser applications are intended to regulate the various mechanisms involved in the pathogenesis of the disease.

Classical, Micropulse and NanoSecond Laser Therapy in Dry-Form (Non-Neovascular) Age-Related Macular Degeneration

Age-related macular degeneration (AMD), which is a multifactorial, degenerative disease of the retina, is the most common reason for legal blindness over 50 years of age. Dry-form (non-neovascular) AMD is the common type, and frequently non-progressive to total vision loss. Epidemiological, histopathological, and biochemical data demonstrate that AMD is associated with oxidative damage, lipofuscin accumulation, chronic inflammation, and mutations in the complement system. Drusen, hyperpigmentation/hypopigmentation in retinal pigment epithelium, and geographical atrophy can also be observed in dry-form AMD. Various treatment modalities can be used according to the stages of the disease. Antioxidants, visual cycle inhibitors, anti-inflammatory agents, neuroprotective treatment, conventional, micropulse, and nano-second laser applications are intended to regulate the various mechanisms involved in the pathogenesis of the disease.

Recent advances in the management of dry age-related macular degeneration: A review.

Age-related macular degeneration (AMD), the most important cause of vision loss in elderly people, is a degenerative disorder of the central retina with a multifactorial etiopathology. AMD is classified in dry AMD (d-AMD) or neovascular AMD depending on the presence of choroidal neovascularization. Currently, no therapy is approved for geographic atrophy, the late form of d-AMD, because no treatment can restore the damage of retinal pigment epithelium (RPE) or photoreceptors. For this reason, all treatment approaches in d-AMD are only likely to prevent and slow down the progression of existing atrophy. This review focuses on the management of d-AMD and especially on current data about potential targets for therapies evaluated in clinical trials. Numerous examinations are available in clinics to monitor morphological changes in the retina, RPE and choroid of d-AMD patients. Fundus autofluorescence and optical coherence tomography (OCT) are considered the most useful tools in the diagnosis and follow-up of d-AMD alterations, including the monitoring of atrophy area progression. Instead, OCT-angiography is a novel imaging tool that may add further information in patients affected by d-AMD. Several pathways, including oxidative stress, deposits of lipofuscin, chronic inflammation and choroidal blood flow insufficiency, seem to play an important role in the pathogenesis of d-AMD and represent possible targets for new therapies. A great number of treatments for d-AMD are under investigation with promising results in preliminary studies. However, only few of these drugs will enter the market, offering a therapeutic chance to patients affected by the dry form of AMD and help them to preserve a good visual acuity. Further studies with a long-term follow-up would be important to test the real safety and efficacy of drugs under investigation.

Validity of Oxygen-Ozone Therapy as Integrated Medication Form in Chronic Inflammatory Diseases.

The state-of-the-art of oxygen-ozone therapy is now clarified and all the mechanisms of action of medical ozone are within classical biochemistry and molecular biology. The outcomes of standard treatments in peripheral arterial occlusive disease (PAOD) and dry-form of age-related macular degeneration (AMD) have been compared with the documented therapeutic results achieved with ozonated autohemotherapy (O-AHT). On the other hand, the clinical data of O-AHT on stroke remain indicative. As the cost of O-AHT is almost irrelevant, its application in all public hospitals, especially those of poor Countries, would allow two advantages: the first is for the patient, who will improve her/his conditions, and the second is for Health Authorities burdened with increasing costs. The aim of this paper is to report to clinical scientists that O-AHT is a scientific-based therapeutic approach without side effects. The integration of O-AHT with effective approved drugs is likely to yield the best clinical results in several chronic inflammatory diseases.

Forms of age-related macular degeneration

Age-related macular degeneration (AMD) is the major reason for blindness affecting about 50 % of blind people in Germany. Early forms of AMD with drusen and pigment epithelium changes can be detected in 20 % of patients over 65 years old. The dry form of AMD causes slow deterioration of visual acuity, which cannot currently be adequately treated. In contrast development of a choroidal neovascularization (CNV) membrane results in rapid visual loss which will become permanent if treatment is not started immediately. Using anti-vascular endothelial growth factor (VEGF) agents stabilization and improvement of visual acuity is possible. Special types of AMD, such as retinal angiomatous proliferation and polypoidal choroidal vasculopathy are much less common. The natural course of the diseases can be very different, end stages often result in scarring and anti-VEGF agents are only weakly effective.

Serum MicroRNAs as Potential Biomarkers of AMD.

BackgroundAge-related macular degeneration (AMD) is a major cause of blindness worldwide. Circulating microRNAs (miRNAs) in serum have emerged as novel candidate biomarkers for many diseases. The aim of the present study was to identify a serum microRNA (miRNA) expression profile specific for dry and wet forms of AMD.Material/MethodsSerum miRNA expression was first screened using TaqMan® Human MicroRNA Array A (Applied Biosystems). An extensive, self-validated, individual, quantitative RT-PCR (qRT-PCR) study was then performed on a cohort of 300 AMD patients (150 wet form and 150 dry form) and 200 controls. The Mann-Whitney U test and nonparametric Spearman’s rank correlation coefficient were used for statistical analysis.ResultsmiRNA expression analysis revealed increased expression of miR661 and miR3121 in serum of patients with dry AMD and miR4258, miR889, and Let7 in patients with wet form. Expression of analyzed miRNA was not observed or remained at low level in controls.ConclusionsDifferences in miRNA serum profile exist between patients with wet and dry form of AMD, which indicates miRNAs as potential biomarkers of AMD. Further studies should be performed to confirm its significance in clinical practice.

Stem cell treatment for age related macular degeneration

Age Related Macular Degeneration (AMD) is the most common cause of blindness in the U.S,A. affecting more than two million people. It is expected that as the aging population grows the numbers will continue to increase. This number is expected to rise to over three million by the year 2020. AMD is characterized by the appearance of drusen, a protein complex, at the level of retina pigmented epithelium; and by atrophy of the retina pigmented epithelium. For patients with the dry form of AMD there are no current effective medications.

Cognitive dysfunction and age-related macular degeneration.

Several previous studies showed that age-related macular degeneration (AMD) and Alzheimer's disease (AD) share common risk factors and histopathology changes, and there is epidemiological evidence linking AMD to cognitive impairment. We tested this theory in 51 patients with late-stage AMD and 24 controls by analyzing their neuropsychological profiles. In this study, data showed that patients affected by late-stage AMD have a worse global cognitive function than those of the controls and, in particular, show worse performances in memory tasks. Moreover, patients affected by the dry form of AMD are significantly impaired in executive functions in addition to memory. Data support the hypothesis of a possible association between AMD and cognitive impairment. In particular, patients affected by the dry form of AMD may be at greater risk of developing subsequent dementia.

The effect of intravitreal administration of bevacizumab on macular edema and visual acuity in age-related macular degeneration with subfoveolar choroidal neovascularisation

Age-related macular degeneration (AMD) is a leading cause of the loss of central visual acuity in population older than 70 years. We can distinguish wet and dry form of AMD. The aim of the study was to present our early results in treatment of the wet (neovascular) form of AMD with intravitreal administration of bevacizumab. The study included 39 patients. Each patient underwent a complete ophthalmological examination, fluorescein angiography (FA) and optical coherence tomography (OCT). All the patients received 1.25 mg of intravitreal bevacizumab (0.05 mL of commercial phial of Avastin). The total of three doses was given with a one-month interval between doses. Among 39 patients, 24 were women and 15 men. The average best corrected visual acuity (BCVA) was improved from 0.09 before the therapy to 0.24 after the administration of all the three doses of bevacizumab (p < 0.001). The average central macular thickness (CMT) measured by OCT was improved from 474 microm in the beginning to 341 microm after the administration of all the three doses of the drug (p < 0.001). There were no side effects. Our short-term experience indicates that intravitreal administration of three doses of bevacizumab in one-month intervals between the doses leads to a significant reduction of macular edema and improvement of BCVA in patients with neovascular AMD.

Rheohaemapheresis in the treatment of nonvascular age-related macular degeneration

PurposeTo evaluate the experience with rheohaemapheresis (RH) in the treatment of age-related macular degeneration (AMD). MethodsThirty-eight patients were each treated with 8 procedures of RH (14 males, 24 females). The control group consisted of 34 random patients (30 females, 4 males) with the dry form of AMD but not treated by RH. Our modification of the cascade method (named rheohaemapheresis) was used for plasma separation. After plasma separation (blood cell separator, Cobe Spectra, Denver, CO, USA), the separated plasma was pumped through a rheofilter (Evaflux 4A, Kuraray, Osaka, Japan) to remove lipoproteins and other high-molecular-weight rheologic factors. ResultsIn treated patients, best-corrected visual acuity (BCVA) increased significantly from 0.61 (0.06–1.00) to 0.68 (0.35–1.00) after 2.5 years (p = 0.035). We found no significant changes or differences in scotopic activity, whereas cone response and paramacular activity in the more peripheral region between 14° and 22° of eccentricity were significantly higher in treated patients after 2.5 years. ConclusionRH therapy favourably influenced BCVA. During 2.5 years after the therapy, no progression of dry to wet AMD was observed in our patients. RH reduced the area of drusenoid retinal pigment epithelium detachment (which increased during the natural course of dry form AMD). RH influenced rheological markers and probably improved metabolism in the affected retinal areas which lead to the aforementioned positive results.

Current and future strategies for nonexudative age-related macular degeneration

Background: Age-related macular degeneration (AMD) is the leading cause of blindness in the industrialized world. Recently, the anti-VEGF strategy revolutionized the treatment of the exudative ‘wet’ form of the disease and improved therapeutic outcomes. However, the current strategy does not treat the causative and even more common neurodegenerative ‘dry’ process of the disease. Objectives: In this article we review the current approach and rationale for the present and developing therapeutic strategies that target the nonexudative dry form of AMD. Methods: A review of the literature and ongoing studies was undertaken. Results: Currently, there is no proven drug for the treatment of dry AMD. Cessation of smoking, and nutritional recommendations and supplements are supposed to slow disease progression. Different strategies targeting perfusion, inflammation, oxidative stress and degeneration, or interfering early in – or even prior to – the formation of subretinal pigmented epithelium deposits, may finally succeed in treating the causative processes of the disease. Conclusion: For the nonexudative form of AMD, no established treatment exists, except for the use of oral supplements with high-dose antioxidants that may delay progression. Therefore, a fundamental treatment approach for the neurodegenerative process is needed. Potential future drugs are under development.