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Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema

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Background: Diabetic retinopathy (DR) and diabetic macular edema (DME) are potentially blinding, microvascular retinal diseases in people with diabetes mellitus. Preclinical studies support a protective role of the hormone prolactin due to its ocular incorporation and conversion to vasoinhibins, a family of prolactin fragments that inhibit ischemia-induced retinal angiogenesis and diabetes-derived retinal vasopermeability. Here, we describe the protocol of an ongoing clinical trial investigating a new therapy for DR and DME based on elevating the circulating levels of prolactin with the prokinetic, dopamine D2 receptor blocker, levosulpiride. Methods: It is a prospective, randomized, double blind, placebo-controlled trial enrolling male and female patients with type 2 diabetes having DME, non-proliferative DR (NPDR), proliferative DR (PDR) requiring vitrectomy, and DME plus standard intravitreal therapy with the antiangiogenic agent, ranibizumab. Patients are randomized to receive placebo (lactose pill, orally TID) or levosulpiride (75 mg/day orally TID) for 8 weeks (DME and NPDR), 1 week (the period before vitrectomy in PDR), or 12 weeks (DME plus ranibizumab). In all cases the study medication is taken on top of standard therapy for diabetes, blood pressure control, or other medical conditions. Primary endpoints in groups 1 and 2 (DME: placebo and levosulpiride), groups 3 and 4 (NPDR: placebo and levosulpiride), and groups 7 and 8 (DME plus ranibizumab: placebo and levosulpiride) are changes from baseline in visual acuity, retinal thickness assessed by optical coherence tomography, and retinal microvascular abnormalities evaluated by fundus biomicroscopy and fluorescein angiography. Changes in serum prolactin levels and of prolactin and vasoinhibins levels in the vitreous between groups 5 and 6 (PDR undergoing vitrectomy: placebo and levosulpiride) serve as proof of principle that prolactin enters the eye to counteract disease progression. Secondary endpoints are changes during the follow-up of health and metabolic parameters (blood pressure, glycated hemoglobin, and serum levels of glucose and creatinine). A total of 120 patients is being recruited. Discussion: This trial will provide important knowledge on the potential benefits and safety of elevating circulating and intraocular prolactin levels with levosulpiride in patients with DR and DME.
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... Vasoinhibin is a peptide hormone with a diverse array of endocrine, paracrine, and autocrine effects, ranging from the regulation of blood vessel growth, permeability, and dilation (Clapp et al., 2015) to non-vascular effects, which include the stimulation of vasopressin release (Mejia et al., 2003), the stimulation of anxiety-and depression-related behavior (Zamorano et al., 2014), and thrombolytic effects (Bajou et al., 2014). Vasoinhibin has been investigated in the context of several human diseases, and pathophysiological roles emerged in vasoproliferative retinopathies (Arnold et al., 2010;Triebel et al., 2009Triebel et al., , 2011 and pregnancy-associated diseases (Hilfiker-Kleiner et al., 2007;Nakajima et al., 2015;Gonzalez et al., 2007;Leanos-Miranda et al., 2008), including its evaluation in clinical interventional studies (Hilfiker-Kleiner et al., 2017;Robles-Osorio et al., 2018). ...
... Vi-isoformEnzyme/Subst. Amino acid position/P-position/Amino acid/number of observed cleavages(MEROPS) cardiac vasoinhibin levels in diabetic macular edema and peripartum cardiomyopathy, respectively(Robles-Osorio et al., 2018) (Hilfi ...
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Vasoinhibin is an antiangiogenic, profibrinolytic peptide generated by the proteolytic cleavage of the pituitary hormone prolactin by cathepsin D, matrix metalloproteinases, and bone morphogenetic protein-1. Vasoinhibin can also be generated when placental lactogen or growth hormone are enzymatically cleaved. Here, it is investigated whether plasmin cleaves human prolactin and placental lactogen to generate vasoinhibin-like peptides. Co-incubation of prolactin and placental lactogen with plasmin was performed and analyzed by gel electrophoresis and Western blotting. Mass spectrometric analyses were carried out for sequence validation and precise cleavage site identification. The cleavage sites responsible for the generation of the vasoinhibin-like peptides were located at K170-E171 in prolactin and R160-T161 in placental lactogen. Various genetic variants of the human prolactin and placental lactogen genes are projected to affect proteolytic generation of the vasoinhibin-like peptides. The endogenous counterparts of the vasoinhibin-like peptides generated by plasmin may represent vasoinhibin-isoforms with inhibitory effects on vasculature and coagulation.
... [15][16][17] These observations have led to the hypothesis that medications causing hyperprolactinaemia, resulting in higher levels of vasoinhibin, could be beneficial in DME and DR. 18 One such medication is levosulpiride, a prokinetic frequently used to treat diabetic gastroparesis, 19 that is highly effective for inducing hyperprolactinaemia as it blocks dopamine D2 receptors in the anterior pituitary gland. 20 The ongoing clinical trial supported the potential beneficial outcome of levosulpiride by showing that this compound elevates PRL and vasoinhibin levels in the vitreous of patients with proliferative DR undergoing elective pars plana vitrectomy. ...
... 35 Elevating circulating PRL and, therefore, ocular vasoinhibin is the basis of an ongoing clinical trial investigating levosulpiride for the treatment of DME and DR. 18 Levosulpiride elicits hyperprolactinaemia through blockage of dopaminergic D2 receptors at the anterior pituitary level. 20 The clinical trial has demonstrated that levosulpiride increases PRL and its conversion to bioactive vasoinhibin in the vitreous of patients with proliferative DR. ...
Article
Excessive vasopermeability and angiogenesis compromise vision in diabetic macular edema (DME) and diabetic retinopathy (DR). Vasoinhibin is a fragment of the hormone prolactin (PRL) that inhibits diabetes-induced retinal hyper-vasopermeability and ischemia-induced retinal angiogenesis in rodents. Hyperprolactinemia generated by the dopamine D2 receptor antagonist, levosulpiride, associates with higher levels of vasoinhibin in the vitreous of patients with DR, implying a beneficial outcome due to vasoinhibin-mediated inhibition of retinal vascular alterations. Here, we tested whether hyperprolactinemia induced by racemic sulpiride increases intraocular vasoinhibin levels and inhibits retinal hyper-vasopermeability in diabetic rats. Diabetes was generated with streptozotocin and, four weeks later, rats were treated for two weeks with sulpiride or osmotic minipumps delivering PRL. ELISA, Western blot, and the Evans blue assay evaluated serum PRL, retinal vasoinhibin, and retinal vasopermeability, respectively. Hyperprolactinemia in response to sulpiride or exogenous PRL associated with increased levels of vasoinhibin in the retina and reduced retinal hyper-vasopermeability. Furthermore, sulpiride decreased retinal hemorrhages in response to the intravitreal administration of vascular endothelial growth factor (VEGF). Neither sulpiride nor exogenous PRL modified blood glucose levels or body weight. We conclude that sulpiride-induced hyperprolactinemia inhibits the diabetes- and VEGF-mediated increase in retinal vasopermeability by promoting the intraocular conversion of endogenous PRL to vasoinhibin. These findings support the therapeutic potential of sulpiride and its levorotatory enantiomer, levosulpiride, against DME and DR.
... However, for the latter two, clinical studies were conducted or are underway, in which the generation of vasoinhibin is pharmacologically stimulated or inhibited. For the treatment of diabetic retinopathy and diabetic macular edema, an ongoing clinical study is investigating the effect of levosulpiride, a selective dopamine D2 receptor antagonist, on retinal alterations [30]. The rationale behind this trial is that the levosulpiride-induced hyperprolactinemia promotes MMP-mediated conversion to vasoinhibin, which could lead to beneficiary outcomes in terms of vasoinhibin-mediated antagonization of diabetes-induced retinal alterations [31] (NCT03161652 i ). ...
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Proteolysis of protein hormones is primarily acknowledged in the context of breakdown and metabolic clearance by hepatorenal elimination. However, less explored is the specific proteolytic processing of large protein hormones, for which canonical signaling pathways were already established [e.g., prolactin (PRL)], to generate unique messengers that impact cellular functions via pathways unrelated to the receptors of their precursor molecules. Yet, the proteolysis of PRL to generate new messengers evolved under positive selection, and cleaved protein hormones regulate essential functions to maintain homeostasis at the organismal, tissue, or organ levels. The cleavage sites at which proteolysis occurs and the proteases with their determinants define a hormone-metabolism junction at which specific proteolytic cleavage, pathological alteration, and hepatorenal elimination occur.
... NCT03161652). These trials used dopamine D2 receptor agonist-or antagonist-medications causing hypoprolactinemia or hyperprolactinemia to indirectly downregulate [58] or upregulate [59] vasoinhibin levels, respectively. The current study introduces a potent vasoinhibin analog that is small, stable, orally effective, and easy to produce for the direct clinical treatment of the above diseases and other angiogenesis-related disorders. ...
Article
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The hormone prolactin acquires antiangiogenic and antivasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, an endogenous prolactin fragment of 123 or more amino acids that inhibits the action of multiple proangiogenic factors. Preclinical and clinical evidence supports the therapeutic potential of vasoinhibin against angiogenesis-related diseases including diabetic retinopathy, peripartum cardiomyopathy, rheumatoid arthritis, and cancer. However, the use of vasoinhibin in the clinic has been limited by difficulties in its production. Here, we removed this barrier to using vasoinhibin as a therapeutic agent by showing that a short linear motif of just three residues (His46-Gly47-Arg48) (HGR) is the functional determinant of vasoinhibin. The HGR motif is conserved throughout evolution, its mutation led to vasoinhibin loss of function, and oligopeptides containing this sequence inhibited angiogenesis and vasopermeability with the same potency as whole vasoinhibin. Furthermore, the oral administration of an optimized cyclic retro-inverse vasoinhibin heptapeptide containing HGR inhibited melanoma tumor growth and vascularization in mice and exhibited equal or higher antiangiogenic potency than other antiangiogenic molecules currently used as anti-cancer drugs in the clinic. Finally, by unveiling the mechanism that obscures the HGR motif in prolactin, we anticipate the development of vasoinhibin-specific antibodies to solve the on-going challenge of measuring endogenous vasoinhibin levels for diagnostic and interventional purposes, the design of vasoinhibin antagonists for managing insufficient angiogenesis, and the identification of putative therapeutic proteins containing HGR.
... The discovery of a dysregulation of vasoinhibin generation in diabetic retinopathy and peripartum cardiomyopathy led to the development of new pharmacological treatments to increase or decrease vasoinhibin generation and their evaluation in clinical interventional trials (ClinicalTrials.gov Identifier: NCT03161652 and NCT00998556) (14)(15)(16). ...
Article
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Vasoinhibin is a protein hormone with antiangiogenic, antivasodilatatory, and antivasopermeability effects generated by the proteolytic cleavage of prolactin. The discovery of its role in diabetic retinopathy and peripartum cardiomyopathy led to the evaluation of new pharmacological treatments in clinical interventional trials. However, the quantitative evaluation of vasoinhibin in biological samples from patients has not been possible due to the lack of vasoinhibin-specific antibodies. Recently, loop 1 of vasoinhibin was identified to have a different three-dimensional structure compared to PRL, and thus to contain vasoinhibin-specific epitopes. Here, we report the development of two sets of vasoinhibin-specific monoclonal antibodies against two neighboring regions of the vasoinhibin loop 1. An experimental sandwich ELISA with two monoclonal anti-vasoinhibin antibodies was developed, which had no cross-reactivity to recombinant human full-length prolactin. The ELISA had a quantitation limit of 100 ng/ml, and intra-assay- and inter-assay coefficients of variation of 12.5% and 14%, respectively. The evaluation of 15 human serum samples demonstrated concentrations of below limit of detection (n=3), below limit of quantitation (n=1) and between 0.23 µg/ml (230 ng/ml) to 605 µg/ml (n=12) in the quantifiable range. Despite the high specificity of the monoclonal-monoclonal antibody sandwiches which discriminate vasoinhibin from PRL, there might be cross-reactivities by serum proteins other than vasoinhibin. A fully established vasoinhibin ELISA may support diagnostic and therapeutic measures in vascular diseases.
... While PRL is pro-angiogenic 25 , the vasoinhibins have antiangiogenic effects in ocular tissue including the neuroretina 10,25-27 . They have been shown to be protective against diabetic macular edema caused by blood-retinal barrier breakdown 28 , and are being investigated for their protective effect in diabetic retinopathy in an ongoing clinical trial (NCT03161652) 29 . PRL is also produced by a number of extra-pituitary tissues 30,31 , including the retina 10,32 , and its mRNA was found in all three retinal cellular layers in normal rat retina using RT-PCR and in situ hybridization (ISH) 10,32 . ...
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Prolactin (PRL) hormone functions as a pleiotropic cytokine with a protective role in the retina. We recently identified by transcriptome profiling that PRL is one of the most highly upregulated mRNAs in the retinas of mutant rcd1 (PDE6B) and xlpra2 (RPGR) dogs at advanced stages of photoreceptor disease. In the present study, we have identified the expression of a short PRL isoform that lacks exon 1 in canine retinas and analyzed the time-course of expression and localization of this isoform in the retinas of these two models. Using laser capture microdissection to isolate RNA from each of the retinal cellular layers, we found by qPCR that this short PRL isoform is expressed in photoreceptors of degenerating retinas. We confirmed by in situ hybridization that its expression is localized to the outer nuclear layer and begins shortly after the onset of disease at the time of peak photoreceptor cell death in both models. PRL protein was also detected only in mutant dog retinas. Our results call for further investigations into the role of this novel PRL isoform in retinal degeneration.
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The role of prolactin (PRL) favoring metabolic homeostasis is supported by multiple preclinical and clinical studies. PRL levels are key to explaining the direction of its actions. In contrast with the negative outcomes associated with very high (>100 μg/L) and very low (<7 μg/L) PRL levels, moderately high PRL levels, both within but also above the classically considered physiological range are beneficial for metabolism and have been defined as HomeoFIT-PRL. In animal models, HomeoFIT-PRL levels counteract insulin resistance, glucose intolerance, adipose tissue hypertrophy and fatty liver; and in humans associate with reduced prevalence of insulin resistance, fatty liver, glucose intolerance, metabolic syndrome, reduced adipocyte hypertrophy, and protection from type 2 diabetes development. The beneficial actions of PRL can be explained by its positive effects on main metabolic organs including the pancreas, liver, adipose tissue, and hypothalamus. Here, we briefly review work supporting PRL as a promoter of metabolic homeostasis in rodents and humans, the PRL levels associated with metabolic protection, and the proposed mechanisms involved. Finally, we discuss the possibility of using drugs elevating PRL for the treatment of metabolic diseases.
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Diabetic retinopathy (DR) and diabetic macular edema (DME) are major causes for visual loss in adults. Nearly half of the world's population with diabetes has some degree of DR, and DME is a major cause of visual impairment in these patients. Severe vision loss occurs because of tractional retinal detachment due to retinal neovascularization, but the most common cause of moderate vision loss occurs in DME where excessive vascular permeability leads to the exudation and accumulation of extracellular fluid and proteins in the macula. Metabolic control stands as an effective mean for controlling retinal vascular alterations in some but not all patients with diabetes, and the search of other modifiable factors affecting the risk for diabetic microvascular complications is warranted. Prolactin (PRL) and its proteolytic fragment, vasoinhibin, have emerged as endogenous regulators of retinal blood vessels. PRL acquires antiangiogenic and anti-vasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, which helps restrict the vascularization of ocular organs and, upon disruption, promotes retinal vascular alterations characteristic of DR and DME. Evidence is linking PRL (and other pituitary hormones) and vasoinhibin to DR and recent preclinical and clinical evidence supports their translation into novel therapeutic approaches.
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Diabetic retinopathy is the most common microvascular complication of diabetes. It remains a major cause of new-onset visual loss in the United States and other industrialized nations. In Diabetic Retinopathy, Elia Duh and a panel of internationally recognized experts comprehensively assess the current state of knowledge regarding the clinical management of DR as well as its underlying mechanisms. The authors outline the current understanding of diabetic retinopathy from the perspective of clinical practice, while reviewing the multi-factorial pathogenesis and pathophysiology of DR from the standpoint of biomedical research. Also included is a discussion of emerging concepts relating to the management and treatment of DR. Informative and highly-practical, Diabetic Retinopathy provides ophthalmologists, diabetologists, endocrinologists, and internists with a highly readable guide not only to understanding diabetic retinopathy, but also to its optimal clinical management.
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