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Trodusquemine is an aminosterol with a variety of biological and pharmacological functions, such as acting as an antimicrobial, stimulating body weight loss and interfering with the toxicity of proteins involved in the development of Alzheimer's and Parkinson's diseases. The mechanisms of interaction of aminosterols with cells are, however, still largely uncharacterized. Here, by using fluorescently labeled trodusquemine (TRO‐A594 and TRO‐ATTO565), we show that trodusquemine binds initially to the plasma membrane of living cells, that the binding affinity is dependent on cholesterol, and that trodusquemine is then internalized and mainly targeted to lysosomes after internalization. We also found that TRO‐A594 is able to strongly and selectively bind to myelinated fibers in fixed mouse brain slices, and that it is a marker compatible with tissue clearing and light‐sheet fluorescence microscopy or expansion microscopy. In conclusion, this work contributes to further characterize the biology of aminosterols and provides a new tool for nerve labeling suitable for the most advanced microscopy techniques. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) constitutes a major global health issue, characterized by progressive neurodegeneration and cognitive impairment, for which no curative treatment is currently available. Current therapeutic approaches are focused on symptom management, highlighting the critical need for disease-modifying therapy. The hallmark pathology of AD involves the aggregation and accumulation of amyloid-β (Aβ) peptides in the brain. Consequently, drug discovery efforts in recent decades have centered on the Aβ aggregation cascade, which includes the transition of monomeric Aβ peptides into toxic oligomers and, ultimately, mature fibrils. Historically, anti-Aβ strategies focused on the clearance of amyloid fibrils using monoclonal antibodies. However, substantial evidence has highlighted the critical role of Aβ oligomers (AβOs) in AD pathogenesis. Soluble AβOs are now recognized as more toxic than fibrils, directly contributing to synaptic impairment, neuronal damage, and the onset of AD. Targeting AβOs has emerged as a promising therapeutic approach to mitigate cognitive decline in AD. Natural products (NPs) have demonstrated promise against AβO neurotoxicity through various mechanisms, including preventing AβO formation, enhancing clearance mechanisms, or converting AβOs into non-toxic species. Understanding the mechanisms by which anti-AβO NPs operate is useful for developing disease-modifying treatments for AD. In this review, we explore the role of NPs in mitigating AβO neurotoxicity for AD drug discovery, summarizing key evidence from biophysical methods, cellular assays, and animal models. By discussing how NPs modulate AβO neurotoxicity across various experimental systems, we aim to provide valuable insights into novel therapeutic strategies targeting AβOs in AD. [Display omitted] • Increase evidence supports the use of natural products to suppress AβO neurotoxicity. • Natural products combat AβO-induced neurotoxicity by various mechanisms in vitro. • Animal studies confirm that natural products can target AβO in vivo as well. • Further research is needed to translate these findings to clinical applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the many ongoing advances in cancer prevention, diagnosis and clinical management, global mortality from human cancers remains at high levels. Notably, more effective treatment of many cancers is advancing due to introduction of novel biologic therapies targeted to tumor signaling and immunologic pathways. Tumor growth is dependent on a sustained blood supply of nutrients and oxygen, and this process termed tumor-associated angiogenesis (TAA) has prognostic and therapeutic importance in several human malignancies. This review addresses use of squalamines to stop tumor growth. This naturally occurring compound can inhibit angiogenesis in tumors thereby reducing malignant progression in preclinical studies and in early clinical trials. Mechanisms of action of squalamine in human vascular endothelial cells indicate that this compound attaches to cell membranes, potentially interacting with calmodulin, Na+/H+ exchanger isoform NHE3 and other signaling pathways involved in the angiogenic process. Thus, squalamine elicits blockade of VEGF-induced endothelial tube-like formation in vitro. Further, squalamine reduces growth of several preclinical models of human cancers in vivo and acts to stop metastatic tumor spread, actions due largely to blockade of angiogenesis induced by the tumor and tumor microenvironment. Squalamine in Phase I/II trials, alone or combined with standard care, shows promising antitumor activity with limited side-effects in patients with advanced solid cancers. Increased attention on squalamine regulation of signaling pathways with or without combination treatments in solid malignancies deserves further study. [ABSTRACT FROM AUTHOR]

Squalamine is a natural aminosterol that has been discovered in the tissues of the dogfish shark (Squalus acanthias). Studies have previously demonstrated that this promoter compound and its derivatives exhibit potent bactericidal activity against Gram-negative, Gram-positive bacteria, and multidrug-resistant bacteria. The antibacterial activity of squalamine was found to correlate with that of other antibiotics, such as colistin and polymyxins. Still, in the field of microbiology, evidence has shown that squalamine and its derivatives have antifungal activity, antiprotozoa effect against a limited list of protozoa, and could exhibit antiviral activity against both RNA- and DNA-enveloped viruses. Furthermore, squalamine and its derivatives have been identified as being antiangiogenic compounds in the case of several types of cancers and induce a potential positive effect in the case of other diseases such as experimental retinopathy and Parkinson's disease. Given the diverse effects of the squalamine and its derivatives, in this review we provide the different advances in our understanding of the various effects of these promising molecules and try to draw up a non-exhaustive list of the different mechanisms of actions of squalamine and its derivatives on the human organism and on different pathogens. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is associated with α-synuclein (αS) aggregation within the enteric nervous system (ENS) and constipation. Squalamine displaces proteins that are electrostatically bound to intracellular membranes and through this mechanism suppresses aggregation of αS monomers into neurotoxic oligomers. Objective: We sought to evaluate the safety of ENT-01 oral tablets (a synthetic squalamine salt), its pharmacokinetics, and its effect on bowel function in PD patients with constipation. Methods: In Stage 1, 10 patients received escalating single doses from 25 to 200 mg/day or maximum tolerated dose (MTD). In Stage 2, 34 patients received daily doses escalating from 75 to a maximum of 250 mg/day, a dose that induced change in bowel function or MTD, followed by a fixed dose for 7 days, and a 2-week washout. Primary efficacy endpoint was defined as an increase of 1 complete spontaneous bowel movement (CSBM)/week, or 3 CSBM/week over the baseline period, as defined by FDA guidelines for prokinetic agents. Safety was also assessed. Results: Over 80% of patients achieved the primary efficacy endpoint, with the mean number of CSBM/week increasing from 1.2 at baseline to 3.6 during fixed dosing (p = 1.2 × 10−7). Common adverse events included nausea in 21/44 (47%) and diarrhea in 18/44 (40%) patients. Systemic absorption was

Squalamine is a natural aminosterol that has been discovered in the tissues of the dogfish shark (Squalus acanthias). Studies have previously demonstrated that this promoter compound and its derivatives exhibit potent bactericidal activity against Gram-negative, Gram-positive bacteria, and multidrug-resistant bacteria. The antibacterial activity of squalamine was found to correlate with that of other antibiotics, such as colistin and polymyxins. Still, in the field of microbiology, evidence has shown that squalamine and its derivatives have antifungal activity, antiprotozoa effect against a limited list of protozoa, and could exhibit antiviral activity against both RNA- and DNA-enveloped viruses. Furthermore, squalamine and its derivatives have been identified as being antiangiogenic compounds in the case of several types of cancers and induce a potential positive effect in the case of other diseases such as experimental retinopathy and Parkinson’s disease. Given the diverse effects of the squalamine and its derivatives, in this review we provide the different advances in our understanding of the various effects of these promising molecules and try to draw up a non-exhaustive list of the different mechanisms of actions of squalamine and its derivatives on the human organism and on different pathogens.

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder thought to be caused by accumulation of α-synuclein (α-syn) within the brain, autonomic nerves, and the enteric nervous system (ENS). Involvement of the ENS in PD often precedes the onset of the classic motor signs of PD by many years at a time when severe constipation represents a major morbidity. Studies conducted in vitro and in vivo, have shown that squalamine, a zwitterionic amphipathic aminosterol, originally isolated from the liver of the dogfish shark, effectively displaces membrane-bound α-syn. Objective: Here we explore the electrophysiological effect of squalamine on the gastrointestinal (GI) tract of mouse models of PD engineered to express the highly aggregating A53T human α-syn mutant. Methods: GI motility and in vivo response to oral squalamine in PD model mice and controls were assessed using an in vitro tissue motility protocol and via fecal pellet output. Vagal afferent response to squalamine was measured using extracellular mesenteric nerve recordings from the jejunum. Whole cell patch clamp was performed to measure response to squalamine in the myenteric plexus. Results: Squalamine effectively restores disordered colonic motility in vivo and within minutes of local application to the bowel. We show that topical squalamine exposure to intrinsic primary afferent neurons (IPANs) of the ENS rapidly restores excitability. Conclusion: These observations may help to explain how squalamine may promote gut propulsive activity through local effects on IPANs in the ENS, and further support its possible utility in the treatment of constipation in patients with PD. [ABSTRACT FROM AUTHOR]

Synthesis of A-ring-modified lupane, oleanane and ursane type triterpenoid conjugates with spermidine through an aldimine linkage or diethylentriamine via an amide bond is described. These derivatives were evaluated for their in vitro antimicrobial properties against human pathogens. Except for derivatives 1 and 7, all compounds have moderate to weak minimum inhibitory concentrations (MICs) against Gram-positive Staphylococcus aureus bacteria, with MICs varying from 3.125 to 200 µM. Compound 11 is efficient against Escherichia coli and Pseudomonas aeruginosa, with MICs of 25 and 50 µM, respectively, while all other derivatives do not possess important antimicrobial activities against these Gram-negative bacteria.

There is a general decline in gastrointestinal function in old age including decreased intestinal motility, sensory signaling, and afferent sensitivity. There is also increased prevalence of significant constipation in aged populations. We hypothesized this may be linked to reduced colonic motility and alterations in vagal-gut-brain sensory signaling. Using in vitro preparations from young (3 months) and old (18–24 months) male CD1 mice we report functional age-related differences in colonic motility and jejunal mesenteric afferent firing. Furthermore, we tested the effect of the aminosterol squalamine on colonic motility and jejunal vagal firing rate. Old mice had significantly reduced velocity of colonic migrating motor complexes (MMC) by 27% compared to young mice (p = 0.0161). Intraluminal squalamine increased colonic MMC velocity by 31% in old mice (p = 0.0150), which also had significantly reduced mesenteric afferent single-unit firing rates from the jejunum by 51% (p < 0.0001). The jejunal vagal afferent firing rate was reduced in aged mice by 62% (p = 0.0004). While the time to peak response to squalamine was longer in old mice compared to young mice (18.82 ± 1.37 min vs. 12.95 ± 0.99 min; p = 0.0182), it significantly increased vagal afferent firing rate by 36 and 56% in young and old mice, respectively (p = 0.0006, p = 0.0013). Our results show for the first time that the jejunal vagal afferent firing rate is reduced in aged-mice. They also suggest that there is translational potential for the therapeutic use of squalamine in the treatment of age-related constipation and dysmotility.

There is a general decline in gastrointestinal function in old age including decreased intestinal motility, sensory signaling, and afferent sensitivity. There is also increased prevalence of significant constipation in aged populations. We hypothesized this may be linked to reduced colonic motility and alterations in vagal-gut-brain sensory signaling. Using in vitro preparations from young (3 months) and old (18–24 months) male CD1 mice we report functional age-related differences in colonic motility and jejunal mesenteric afferent firing. Furthermore, we tested the effect of the aminosterol squalamine on colonic motility and jejunal vagal firing rate. Old mice had significantly reduced velocity of colonic migrating motor complexes (MMC) by 27% compared to young mice (p = 0.0161). Intraluminal squalamine increased colonic MMC velocity by 31% in old mice (p = 0.0150), which also had significantly reduced mesenteric afferent single-unit firing rates from the jejunum by 51% (p < 0.0001). The jejunal vagal afferent firing rate was reduced in aged mice by 62% (p = 0.0004). While the time to peak response to squalamine was longer in old mice compared to young mice (18.82 ± 1.37 min vs. 12.95 ± 0.99 min; p = 0.0182), it significantly increased vagal afferent firing rate by 36 and 56% in young and old mice, respectively (p = 0.0006, p = 0.0013). Our results show for the first time that the jejunal vagal afferent firing rate is reduced in aged-mice. They also suggest that there is translational potential for the therapeutic use of squalamine in the treatment of age-related constipation and dysmotility. [ABSTRACT FROM AUTHOR]

Angiogenesis is critical for breast cancer progression. Overexpression of HER-2/neu receptors occur in 25-30% of breast cancers, and treatment with trastuzumab inhibits HER-2-overexpressing tumor growth. Notably, HER-2-mediated signaling enhances vascular endothelial growth factor (VEGF) secretion to increase tumor-associated angiogenesis. Squalamine (aminosterol compound) suppresses VEGF-induced activation of kinases in vascular endothelial cells and inhibits tumor-associated angiogenesis. We assessed antitumor effects of squalamine either alone or with trastuzumab in nude mice bearing breast tumor xenografts without (MCF-7) or with HER2-overexpression (MCF-7/HER-2). Squalamine alone inhibited progression of MCF-7 tumors lacking HER2 overexpression, and squalamine combined with trastuzumab elicited marked inhibition of MCF-7/HER2 growth exceeding that of trastuzumab alone. MCF-7/HER-2 cells secrete higher levels of VEGF than MCF-7 cells, but squalamine elicited no growth inhibition of either MCF-7/HER-2 or MCF-7 cells in vitro. However, squalamine did stop growth of human umbilical vein endothelial cells (HUVECs) and reduced VEGF-induced endothelial tube-like formations in vitro. These effects correlated with blockade of focal adhesion kinase phosphorylation and stress fiber assembly in HUVECs. Thus, squalamine effectively inhibits growth of breast cancers with or without HER-2-overexpression, an effect due in part to blockade of tumor-associated angiogenesis. [ABSTRACT FROM AUTHOR]

Highlights • Squalamine did not induce dormant cells, i.e. persisters and VBNCs, in Acinetobacter baumannii ATCC 17978. • High doses of ciprofloxacin (500 mg/L) generated persisters in A. baumannii in rich and poor medium. • Colistin and squalamine had anti-persister and anti-VBNC activities on A. baumannii dormant cells induced by ciprofloxacin. ABSTRACT Squalamine is a natural polycationic aminosterol extracted from the shark Squalus acanthias. Squalamine displays remarkable efficacy against antimicrobial-resistant Gram-negative and Gram-positive bacteria. Its membranolytic activity and low cytotoxicity make squalamine one of the most promising agents to fight nosocomial pathogens such as Acinetobacter baumannii. In the context of chronic diseases and therapeutic failures associated with this pathogen, the presence of dormant cells, i.e. persisters and viable but non-culturable cells (VBNCs), highly tolerant to antimicrobial compounds is problematic. The aim of this study was to investigate the antibacterial activity of squalamine against this bacterial population of A. baumannii. Bacterial dormancy was induced by cold shock and nutrient starvation in the presence of high doses of either colistin, ciprofloxacin or squalamine. Persisters and VBNCs induced by these treatments were then challenged with 100 mg/L squalamine. The efficacy of each treatment was determined by evaluating culturability on agar medium, membrane integrity (LIVE/DEAD® Bac LightTM staining) and respiratory activity (Bac LightTM RedoxSensorTM CTC staining) of bacteria. A. baumannii ATCC 17978 generated persisters as well as VBNCs in the presence of high doses of ciprofloxacin but not colistin or squalamine. Squalamine at 100 mg/L (below its haemolytic concentration) was able to kill dormant cells. Squalamine did not induce persister cell or VBNC formation in A. baumannii ATCC 17978. Interestingly, squalamine was significantly active against this type of dormant population generated by ciprofloxacin, making it a very promising anti-persister agent. Graphical abstract Image, graphical abstract [ABSTRACT FROM AUTHOR]

The methods of synthesis as well as physical, spectroscopic (1H-NMR, 13C-NMR, and FT-IR, ESI-MS), and biological properties of quaternary and dimeric quaternary alkylammonium conjugates of steroids are presented. The results were contrasted with theoretical calculations (PM5 methods) and potential pharmacological properties (PASS). Alkylammonium sterols exhibit a broad spectrum of antimicrobial activity comparable to squalamine.

A series of two new and twenty earlier synthesized branched extra-amino-triterpenoids obtained by the direct coupling of betulinic/betulonic acids with polymethylenpolyamines, or by the cyanoethylation of lupane type alcohols, oximes, amines, and amides with the following reduction were evaluated for cytotoxicity toward the NCI-60 cancer cell line panel, α-glucosidase inhibitory, and antimicrobial activities. Lupane carboxamides, conjugates with diaminopropane, triethylenetetramine, and branched C3-cyanoethylated polyamine methyl betulonate showed high cytotoxic activity against most of the tested cancer cell lines with GI50 that ranged from 1.09 to 54.40 µM. Betulonic acid C28-conjugate with triethylenetetramine and C3,C28-bis-aminopropoxy-betulin were found to be potent micromolar inhibitors of yeast α-glucosidase and to simultaneously inhibit the endosomal reticulum α-glucosidase, rendering them as potentially capable to suppress tumor invasiveness and neovascularization, in addition to the direct cytotoxicity. Plausible mechanisms of cytotoxic action and underlying disrupted molecular pathways were elucidated with CellMinner pattern analysis and Gene Ontology enrichment analysis, according to which the lead compounds exert multi-target antiproliferative activity associated with oxidative stress induction and chromatin structure alteration. The betulonic acid diethylentriamine conjugate showed partial activity against methicillin-resistant S. aureus and the fungi C. neoformans. These results show that triterpenic polyamines, being analogs of steroidal squalamine and trodusquemine, are important substances for the search of new drugs with anticancer, antidiabetic, and antimicrobial activities.

Peptidoglycan (PG) is an essential polymer of the bacterial cell wall and a major antibacterial target. Its synthesis requires glycosyltransferase (GTase) and transpeptidase enzymes that, respectively, catalyze glycan chain elongation and their cross-linking to form the protective sacculus of the bacterial cell. The GTase domain of bifunctional penicillin-binding proteins (PBPs) of class A, such as Escherichia coli PBP1b, belong to the GTase 51 family. These enzymes play an essential role in PG synthesis, and their specific inhibition by moenomycin was shown to lead to bacterial cell death. In this work, we report that the aminosterol squalamine and mimic compounds present an unexpected mode of action consisting in the inhibition of the GTase activity of the model enzyme PBP1b. In addition, selected compounds were able to specifically displace the lipid II from the active site in a fluorescence anisotropy assay, suggesting that they act as competitive inhibitors.

Members of the subclass of fishes collectively known as elasmobranchs (Class Chondrichthyes, Subclass Elasmobranchii) include sharks, skates, rays, guitarfish, and sawfish. Having diverged from the main line of vertebrate evolution some 400 million years ago, these fishes have continued to be successful in our ever-changing oceans. Much of their success must be attributed to their uncanny ability to remain healthy. Based on decades of basic research, some of their secrets may be very close to benefitting man. In this short review, some of the molecular and cellular biological areas that show promise for potential human applications are presented. With a brief background and current status of relevant research, these topics include development of new antibiotics and novel treatments for cancer, macular degeneration, viral pathogens, and Parkinson’s disease; potentially useful genomic information from shark transcriptomes; shark antibody-derived drug delivery systems; and immune cell-derived compounds as potential cancer therapeutic agents.

The self-assembly of α-synuclein is closely associated with Parkinson's disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic reduction of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson's disease and related conditions. [ABSTRACT FROM AUTHOR]

The methods of synthesis as well as physical, spectroscopic (1H-NMR, 13C-NMR, and FT-IR, ESI-MS), and biological properties of quaternary and dimeric quaternary alkylammonium conjugates of steroids are presented. The results were contrasted with theoretical calculations (PM5 methods) and potential pharmacological properties (PASS). Alkylammonium sterols exhibit a broad spectrum of antimicrobial activity comparable to squalamine. [ABSTRACT FROM AUTHOR]

Background: Culture of Mycobacterium tuberculosis is the gold standard method for the laboratory diagnosis of pulmonary tuberculosis, after effective decontamination. Results: We evaluated squalamine and chlorhexidine to decontaminate sputum specimens for the culture of mycobacteria. Eight sputum specimens were artificially infected with 105 colony-forming units (cfu)/mL Mycobacterium tuberculosis and Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans as contaminants. In the second step, we tested chlorhexidine-based decontamination on 191 clinical specimens, (Chlorhexidine, 0.1, 0.5 and 0.7 %). In a last step, growth of contaminants and mycobacteria was measured in 75 consecutive sputum specimens using the routine NALC-NaOH decontamination protocol or with 0.7 % chlorhexidine decontamination and an inoculation on Coletsos medium. In the artificially model, contaminants grew in 100 % of the artificially infected sputum specimens decontaminated using 100 mg/mL squalamine, in 62.5 % of specimens decontaminated using N-Acetyl-L-Cysteine-Sodium Hydroxide (NALC-NaOH), and in 0 % of specimens decontaminated using 0.1 %, 0.35 %, or 1 % chlorhexidine (P < 0.05). These specimens yielded <102 cfu M. tuberculosis using NALC-NaOH and > 1.4.102 cfu M. tuberculosis when any concentration of chlorhexidine was used (P < 0.05). In the second step we found that 0.7 %-chlorhexidine yielded 0 % contamination rate, 3.2 % for 0.5 %-chlorhexidine and 28.3 % for 0.1 %-chlorhexidine. As for the 75 specimens treated in parallel by both methods we found that when using the standard NALC-NaOH decontamination method, 8/75 (10.7 %) specimens yielded M. tuberculosis colonies with a time to detection of 17.5 ± 3 days and an 8 % contamination rate. Additionally, 14 specimens yielded mycobacteria colonies (12 M. tuberculosis, and 2 Mycobacterium bolletii) (18.7 %) (P = 0.25), which has yielded a 100 % sensitivity for the chlorhexidine protocol. Time to detection was of 15.86 ± 4.7 days (P = 0.39) and a 0 % contamination rate (P < 0.05) using the 0.7 %-chlorhexidine protocol. Conclusion: In our work we showed for the first time that chlorhexidine based decontamination is superior to the standard NALC-NaOH method in the isolation of M. tuberculosis from sputum specimens. We currently use 0.7 %-chlorhexidine for the routine decontamination of sputum specimens for the isolation of M. tuberculosis and non-tuberculosis mycobacteria on egg-lecithin containing media. [ABSTRACT FROM AUTHOR]

The antibiotic squalamine forms a lyotropic liquid crystal at very low concentrations in water (0.3-3.5% w/v), which remains stable over a wide range of temperature (1-40 °C) and pH (4-8). Squalamine is positively charged, and comparison of the alignment of ubiquitin relative to 36 previously reported alignment conditions shows that it differs substantially from most of these, but is closest to liquid crystalline cetyl pyridinium bromide. High precision residual dipolar couplings (RDCs) measured for the backbone ¹H-15N, 15N-13C′, ¹Hα-13Cα, and 13C′-13Cα one-bond interactions in the squalamine medium fit well to the static structural model previously derived from NMR data. Inclusion into the structure refinement procedure of these RDCs, together with ¹H-15N and ¹Hα-13Cα RDCs newly measured in Pf1, results in improved agreement between alignment-induced changes in 13C′ chemical shift, 3JHNHα values, and 13Cα-13Cβ RDCs and corresponding values predicted by the structure, thereby validating the high quality of the single-conformer structural model. This result indicates that fitting of a single model to experimental data provides a better description of the average conformation than does averaging over previously reported NMR-derived ensemble representations. The latter can capture dynamic aspects of a protein, thus making the two representations valuable complements to one another. [ABSTRACT FROM AUTHOR]

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids. [ABSTRACT FROM AUTHOR]

Abstract: Squalamine and three aminosterol analogs have been shown to inhibit bacterial cell growth and induce lysis of large unilamellar phospholipid vesicles. The analogs differ in the identity of the polyamine attached at C3 of the sterol, and the stereochemistry of a hydroxyl substituent at C7. Analogs with a tetraammonium spermine polyamine are somewhat more active than analogs with a shorter trisammonium spermidine polyamine, and analogs with an axial (α) hydroxyl substituent at C7 are more active than analogs with the corresponding equatorial (β) hydroxyl group. There is some variability noted; the 7β-OH spermine analog is the most active compound against Escherichia coli, but the least effective against Pseudomonas aeruginosa . Lytic activity correlates well with antimicrobial activity of the compounds, but the lytic activity varies with the phospholipid composition of the vesicles. [Copyright &y& Elsevier]

We recently reported that aminosterols are fungicidal due to their disrupting the outer membranes of yeasts and that they have a significant in vitro activity against various mould species. Yet, their activity against dermatophytes had never been tested. This study's objective was to evaluate the in vitro activity of squalamine and a synthetic aminosterol derivative (ASD) against various dermatophytes. Susceptibility testing of squalamine, ASD, terbinafine, and griseofulvin was performed, in triplicate, in accord with the Clinical Laboratory and Standards Institute's M38-A2 procedure, using an 80% growth inhibition endpoint. The studies included the following dermatophytes: Trichophyton rubrum, T. mentagrophytes, T. soudanense, Microsporum canis, M. audouinii, M. persicolor; M. cookie and M. gypseum. Squalamine and ASD showed significant in vitro activity against these dermatophytes. The minimum inhibitory concentrations (MICs) ranged from 4-16 mg/l and from 2-8 mg/l for squalamine and ASD, respectively. These findings support further clinical studies of aminosterols activity against superficial dermatophyte infections. [ABSTRACT FROM AUTHOR]

Abstract: Background: The bacterial contamination of nebulizers represents a major problem for cystic fibrosis (CF) patients that can lead to reduced nebulizer performance and increase the risk of patient reinfection by the contaminating bacteria. Objective: We investigated the potential use of squalamine, a broad-spectrum antimicrobial compound, as a nebulizer disinfectant. Methods: Pari LC nebulizers were artificially contaminated with a suspension of bacteria (Staphylococcus aureus and Pseudomonas aeruginosa; 108 CFU/mL) and fungi (Candidida albicans and Aspergilus niger; 107 CFU/mL) and then disinfected by immersion in squalamine solution for 20min. Glutaraldehyde and Korsolex peracetic acid were used as disinfectant controls. Result: We found that 0.5g/L squalamine reduced the levels of viable S. aureus and P. aeruginosa by 5 log10 and the level of viable C. albicans by 4 log10 after 20min. A concentration of 2g/L was needed to reduce the level of A. niger cells by 4 log10 in 6hours. Finally, a formulation of squalamine in the form of a soluble disinfecting tablet containing 2.5% (w/w) squalamine was developed and successfully applied for nebulizer disinfection. Conclusion: Our results suggest that aminosterol derivatives may be used by CF patients for rapid and easy home nebulizer disinfection and that soluble tablets may be developed for this purpose. [Copyright &y& Elsevier]

Objectives Squalamine is a steroid extracted from sharks with proven in vitro antibacterial activity. We assessed its efficacy in reducing the lung bacterial load and histological lesions when given via inhalation in a rat model of chronic Pseudomonas aeruginosa pneumonia. Methods Sprague-Dawley rats were inoculated by tracheal intubation with 150 μL of a solution containing 108 cfu/mL of agar bead-embedded P. aeruginosa strain PAO1. MICs of squalamine and colistin for this strain were 2–8 and 0.5–1 mg/L, respectively. Starting the day after infection, the animals were treated twice daily with aerosolized squalamine (3 mg), colistin (160 mg) or 0.9% saline for 6 days. The bacterial load and lung histological lesions were evaluated on the seventh day. Results Aerosols of squalamine and colistin resulted in a significant reduction in median (IQR) pulmonary bacterial count compared with saline [103 (6 × 102–2 × 103), 103 (9 × 102–6 × 103) and 105 (9 × 104–2 × 105) cfu/lung, respectively; P < 0.001 for both treated groups versus saline]. The lung weight and the lung histological severity score were significantly lower in both treated groups. Conclusions In a model of chronic P. aeruginosa pneumonia, treatment twice daily with a squalamine aerosol for 6 days leads to a significant reduction in the pulmonary bacterial count and pneumonia lesions with an efficacy comparable to that of colistin. [ABSTRACT FROM PUBLISHER]

Clin Microbiol Infect 2012; 18: 841-848 Abstract We herein review the state of knowledge regarding the in vitro and in vivo susceptibility of archaea to antimicrobial agents, including some new molecules. Indeed, some archaea colonizing the human microbiota have been implicated in diseases such as periodontopathy. Archaea are characterized by their broad-spectrum resistance to antimicrobial agents. In particular, their cell wall lacks peptidoglycan, making them resistant to antimicrobial agents interfering with peptidoglycan biosynthesis. Archaea are, however, susceptible to the protein synthesis inhibitor fusidic acid and imidazole derivatives. Also, squalamine, an antimicrobial agent acting on the cell wall, proved effective against human methanogenic archaea. In vitro susceptibility data could be used to design protocols for the decontamination of complex microbiota and the selective isolation of archaea in anaerobic culture. [ABSTRACT FROM AUTHOR]

Objectives We evaluated the suitability of an aminosterol derivative (ASD), possessing interesting in vitro antimicrobial activities against various resistant pathogens involved in lung infections of cystic fibrosis patients, for aerosol drug delivery. Methods The suitability of 2 and 10 mg/mL ASD solutions for aerosol delivery was evaluated and compared with that of a commercial inhalable solution of tobramycin using Pari LC Plus and eFlow rapid nebulizers. Physicochemical properties of ASD solutions, including pH and osmolarity, were assessed. The particle size distribution of the aerosols was analysed using a laser diffraction method. Effects of mucin on the in vitro antibacterial activities of ASD solutions and tobramycin were assessed using the broth dilution method for MIC determination. Results MICs of ASD and tobramycin for Pseudomonas aeruginosa ATCC 27853 were 4 and 1 mg/L, respectively, and those for Staphylococcus aureus ATCC 25923 were 1 and 0.5 mg/L, respectively. MICs of tobramycin increased at least 4- and 16-fold for both bacteria after addition of mucin at 1 and 10 mg/mL, respectively, while MICs of ASD remained unchanged. ASD solutions should be prepared in 0.9% NaCl solution in order to produce an isotonic state, and need the addition of NaOH to give a suitable pH value for inhalation. ASD solutions were successfully nebulized using both nebulizers, as reflected by the similarity of the aerodynamic parameters to those of a commercial tobramycin solution. Conclusions This introductory study demonstrates the suitability of ASDs for aerosol delivery and calls for further work to evaluate such formulations using a lung-infected animal model. [ABSTRACT FROM PUBLISHER]

Objectives Methanogenic archaea are constant members of the human oral and digestive microbiota retrieved, in particular, from periodontitis lesions. The objective of the study was to determine their susceptibility to antimicrobials. Methods Using the macrodilution method in Hungate tubes with optical microscope observation combined with monitoring methane production, we determined the antibiotic resistance characteristics of eight methanogenic archaea. Results Methanobrevibacter smithii strains were resistant to ampicillin, streptomycin, gentamicin, rifampicin, ofloxacin, tetracycline and amphotericin B, with MICs ≥100 mg/L; these strains were also highly resistant to vancomycin (MIC ≥50 mg/L). They were moderately resistant to chloramphenicol (MIC ≤25 mg/L), and were susceptible to bacitracin (MIC ≤4 mg/L), metronidazole, ornidazole and squalamine (MIC ≤1 mg/L). The susceptibility of Methanosphaera stadtmanae was the same as M. smithii, except for chloramphenicol (MIC ≤4 mg/L), and Methanobrevibacter oralis yielded the same data as M. smithii, except for bacitracin (MIC ≤25 mg/L). The antibiotic susceptibility pattern of ‘Methanomassiliicoccus luminyensis’, which was recently isolated from human faeces, was identical to that of M. smithii. Conclusions Human methanogenic archaea are highly resistant to antibiotics, being susceptible only to molecules that are also effective against both bacteria and eukarya. Methanogenic archaea are good candidates to test for antimicrobial activity against members of this unique domain of life. Further studies to develop new molecules specifically targeting archaea as potential causes of infection are warranted. [ABSTRACT FROM PUBLISHER]

Squalamine and other aminosterols have demonstrated interesting antimicrobial activities against clinical bacterial isolates and a limited number of reference yeast strains. We aimed to test whether squalamine and a synthetic aminosterol derivative (ASD) display any in vitro activity comparable to currently available systemic antifungals, an acceptable safety index, as well as to provide insights into their mechanism of action. The minimum inhibitory concentrations (MICs) of squalamine, ASD and available antifungals were determined against 21 yeast isolates that were recovered from cases of fungemia. Remarkably, homogeneous MICs ranging from 8-16 mg/L and from 1-2 mg/L were noted for squalamine and ASD, respectively, as opposes the heterogenous in vitro activity of available systemic antifungals. Aminosterols induced haemolysis, a surrogate for toxic effects to mammalian cells, at concentrations high above their MICs. In time-kill studies, killing was as fast with ASD as with amphotericin B. Both aminosterols induced a time-dependent disruption of yeast membrane, as evidenced by gradual increase of ATP efflux. In conclusion, our preliminary data indicate that aminosterols have the potential to be further developed as antifungals. Additional work is warranted to assess their toxicity and activity in experimental models. [ABSTRACT FROM AUTHOR]

Abstract: The interaction of squalamine (SQ) with eukaryotic and prokaryotic membranes was studied and compared with the interaction of two other cationic amphipathic antimicrobials (CAAs), i.e. the antibiotic polymyxin B (PMB) and the detergent hexadecyltrimethylammonium bromide (CTAB). Whole cell experiments showed that the three CAA have in common the ability to interact with lipopolysaccharide-containing membranes through a divalent cation sensitive process. Differences were found regarding their kinetics of membrane permeabilisation and their selectivity for bacteria, with a preferential permeabilisation of bacteria by PMB>SQ and no selectivity for CTAB. Experiments with lipid monolayers and bilayers showed that this selectivity did not correlate with a preferential interaction of the CAAs with lipids but rather relies on differences in their ability to penetrate lipid bilayers and to cause electrically active lesions. Incidentally, our results also suggest that the distribution coefficient of CAAs could be used to predict their selectivity for bacteria. [Copyright &y& Elsevier]

Objectives: Respiratory infections with multidrug-resistant (MDR) bacteria are life-threatening in patients with cystic fibrosis (CF). Squalamine and aminosterol derivatives (ASDs) have previously demonstrated interesting antibacterial activity against bacterial reference strains. This study investigated for the first time their activity against MDR clinical isolates recovered from the sputa of CF patients. [ABSTRACT FROM PUBLISHER]

A series of 3-amino- and polyaminosterol analogues of squalamine and trodusquemine were synthesized and evaluated for their in vitro antimicrobial properties against human pathogens. The activity was highly dependent on the structure of the different compounds involved and the best results were obtained with aminosterol derivatives 4b, 4e, 8b, 8e and 8n exhibiting minimum inhibitory concentrations (MICs) against yeasts, Gram positive and Gram negative bacteria at average concentrations of 3.12-12.5 μM. [ABSTRACT FROM AUTHOR]

Abstract: A series of 3-amino and polyaminosterol analogues of squalamine and trodusquemine were synthesized involving a new stereoselective titanium reductive amination reaction in high chemical yields of up to 95% in numerous cases. These derivatives were evaluated for their in vitro antimicrobial properties against human pathogens. Activity was highly dependent on the different compounds'' structures involved and best results have been obtained with aminosterol derivatives 4b, 4e and 6i exhibiting activities against yeasts, Gram positive and Gram negative bacteria at average concentrations of 6.25–12.5μg/mL. [Copyright &y& Elsevier]

Squalamine lactate (Evizon™, Genaera, PA, USA) is a systemically administered antiangiogenic compound that is among the group of drugs being investigated for the treatment of neovascular age-related macular degeneration (AMD). Squalamine lactate is the first drug candidate from the aminosterol class and has a unique and multifaceted mechanism of action. Both preclinical evaluations and clinical studies have demonstrated promise for the treatment of AMD and various cancers. In contrast to antibody-based antiangiogenic compounds, squalamine lactate has a more generalized effect on the cellular signaling cascades that are common to vascular endothelial growth factor and other growth factors, including basic fibroblast growth factor (FGF2), platelet-derived growth factor and thrombin. Due to its systemic (intravenous) mode of delivery, squalamine lactate avoids the severe potential complications (i.e., endophthalmitis, ocular inflammation, vitreous hemorrhage and traumatic cataract) associated with intraocular injections. In addition, hypertension, often severe, related to systemic use of antiangiogenic agents such as bevacizumab has been reported. To date, during therapy in clinical studies, squalamine has not demonstrated acute hypertension, any secondary effects on the cardiovascular system or any pattern of drug-related cardiovascular adverse events. In contrast to intravitreal agents, both eyes are treated simultaneously with a single infusion allowing for therapy in subjects with bilateral exudative AMD. The objective of this article is to summarize the basic science, pharmacokinetic, pharmacodynamic activity, safety and efficacy of squalamine lactate for the treatment of choroidal neovascularization associated with AMD. [ABSTRACT FROM AUTHOR]

Several novel squalamine-related polyaminosterols are reported. The synthesis of 7α-N-[3N-(4-aminobutyl)aminopropyl]aminocholestanol I, 6α-N-[3N-(4-aminobutyl)aminopropyl]aminocholestanol II, 7α and 7β-N-[3N-(4-aminobutyl)aminopropyl]aminocholesterol (III and IV), was accomplished from cholesterol, they provide the first examples in which spermidine is introduced in the B steroidal ring. These molecules showed comparable antibacteria and fungi activities to squalamine, and were cytotoxic on a human non-small cell bronchopulmonary carcinoma line (NSCLC-N6). Therefore, these molecules with antibiotic and cytotoxic activities are promising for immune-compromised patients in cancer chemotherapy. [Copyright &y& Elsevier]

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the industrialised world. Although relatively simple to diagnose through direct visualisation augmented with rapid sequence fluorescein angiography, treatment has presented a far greater challenge because the true aetiology of AMD is largely unknown. Within the past decade, researchers have introduced many new, potentially promising treatment and prevention options in an attempt to minimise the damage imparted from AMD. They capitalise on many of the theoretical and known factors contributing to AMD progression. A high-dose of an orally administered combination of the antioxidants ascorbic acid (vitamin C), tocopherol (vitamin E) and β-carotene, in addition to copper and zinc, is the only widely accepted preventive therapy. Thermal laser photocoagulation and verteporfin photodynamic therapy are the only standard treatment options available based on large scale, randomised, prospective, placebo-controlled trials; however, efficacy is limited and only a minority of patients who present with AMD are eligible for these treatments. Many other preventive and treatment options are in all phases of clinical studies and expected to change the entire approach to AMD management in the near future. For example, alternative antioxidants, drusen ablation, apheresis and HMG-CoA reductase inhibitors have shown promise in some studies by preventing or slowing the progression of certain forms of AMD. In addition, alternative photodynamic therapies, low-intensity laser, antiangiogenic medications, radiation treatment and surgery have demonstrated the ability, albeit to differing degrees, to inhibit or possibly even reverse the severe vision loss often associated with AMD characterised by choroidal neovascularisation. [ABSTRACT FROM AUTHOR]

Stereoselective synthesis of squalamine dessulfates analogues, 7α and 7β-N-[3N-(4-aminobutyl) aminopropyl]aminocholesterol are reported, using 7α and 7β-aminocholesterol as a key intermediate. It''s the first example in which the position of spermidine is modified at the steroid ring. These molecules showed a comparable antibacteria and fungi activities to squalamine. Then, they have a cytotoxic activity on a human non-small cell bronchopulmonary carcinoma line (NSCLC-N6). [Copyright &y& Elsevier]

The special physico-chemical property of squalamine enables the formation of intra- or inter-molecular non-volatile strong salt, which is difficult to ionize in a mass spectrometer’s interface. A sensitive, accurate, precise, and specific method for the quantitative determination of this self ion-suppressing compound in human plasma has been developed and validated using high performance liquid chromatography (HPLC) coupled with positive electrospray tandem mass spectrometry (MS/MS). Solid phase extraction (SPE) technique was utilized to extract human plasma samples using the Waters Oasis HLB cartridges. Deuterated squalamine was used as the internal standard (IS). Positive multiple reaction monitoring (MRM) mode was used to achieve both sensitivity and selectivity. A quadratic linearity range over 5–1000 ng/ml, R>0.999 was achieved. Performance of the method has been validated and met all the specifications set forth in the US Food and Drug Administration’s May 2001 “Bioanalytical Method Validation Guidance for Industry”. Different sample reconstitution solutions were found to have dramatic impact on sensitivity of mass spectrometer used to squalamine. This is the first quantitation method using a positive and true multiple reaction monitoring mode detection for squalamine. [Copyright &y& Elsevier]

Heat, acid and base stress methods were applied to study the stability of squalamine lactate. Liquid chromatography coupled with mass spectrometry was used to analyze the degraded samples and tentative structural identifications were assigned based on their molecular weight measurements, reactivity and MS/MS fragmentation. Solid squalamine lactate generated a new amide, namely lactyl squalamide, when heated to 80 °C. Chemical structure for this new compound has been established by NMR and MS data interpretation and confirmed by direct comparison between the degradant and the synthesized compound. Squalamine lactate in pH 4 acetate buffer solution produced more degradants under stressed conditions. These degradants are formed due to the loss of the sulfate functionality. Squalamine lactate is stable in refrigerated conditions as well as in basic solution. [Copyright &y& Elsevier]

Squalamine (1) was synthesized stereoselectively in 14 steps and 19% overall yield from 3-keto-5α-chenodeoxycholanate (2) by using a modified Sharpless asymmetric dihydroxylation as the key step. [Copyright &y& Elsevier]

Aminosterols isolated from the dogfish shark Squalus acanthias are promising therapeutic agents in the treatment of infection and cancer. One of these, MSI-1436, has been shown to possess antimicrobial activity slightly better than squalamine. In this study, a series of analogs of MSI-1436 have been synthesized from stigmasterol. The 7α-hydroxy substituent of MSI-1436 was either omitted or the stereochemistry modified to the 7β position. Also, analogs of MSI-1436 with 24-sulfate, 24-amino, and 24-hydroxy substituents were synthesized in order to assess the importance of the side chain functional group on antimicrobial activity. All of the analogs possess significant antimicrobial activity, suggesting that substitution at C7 and C24 of the aminosterols plays a minor role in their antimicrobial potency. [Copyright &y& Elsevier]

A series of two new and twenty earlier synthesized branched extra-amino-triterpenoids obtained by the direct coupling of betulinic/betulonic acids with polymethylenpolyamines, or by the cyanoethylation of lupane type alcohols, oximes, amines, and amides with the following reduction were evaluated for cytotoxicity toward the NCI-60 cancer cell line panel, α-glucosidase inhibitory, and antimicrobial activities. Lupane carboxamides, conjugates with diaminopropane, triethylenetetramine, and branched C3-cyanoethylated polyamine methyl betulonate showed high cytotoxic activity against most of the tested cancer cell lines with GI50 that ranged from 1.09 to 54.40 µM. Betulonic acid C28-conjugate with triethylenetetramine and C3,C28-bis-aminopropoxy-betulin were found to be potent micromolar inhibitors of yeast α-glucosidase and to simultaneously inhibit the endosomal reticulum α-glucosidase, rendering them as potentially capable to suppress tumor invasiveness and neovascularization, in addition to the direct cytotoxicity. Plausible mechanisms of cytotoxic action and underlying disrupted molecular pathways were elucidated with CellMinner pattern analysis and Gene Ontology enrichment analysis, according to which the lead compounds exert multi-target antiproliferative activity associated with oxidative stress induction and chromatin structure alteration. The betulonic acid diethylentriamine conjugate showed partial activity against methicillin-resistant S. aureus and the fungi C. neoformans. These results show that triterpenic polyamines, being analogs of steroidal squalamine and trodusquemine, are important substances for the search of new drugs with anticancer, antidiabetic, and antimicrobial activities. [ABSTRACT FROM AUTHOR]

Peptidoglycan (PG) is an essential polymer of the bacterial cell wall and a major antibacterial target. Its synthesis requires glycosyltransferase (GTase) and transpeptidase enzymes that, respectively, catalyze glycan chain elongation and their cross-linking to form the protective sacculus of the bacterial cell. The GTase domain of bifunctional penicillin-binding proteins (PBPs) of class A, such as Escherichia coli PBP1b, belong to the GTase 51 family. These enzymes play an essential role in PG synthesis, and their specific inhibition by moenomycin was shown to lead to bacterial cell death. In this work, we report that the aminosterol squalamine and mimic compounds present an unexpected mode of action consisting in the inhibition of the GTase activity of the model enzyme PBP1b. In addition, selected compounds were able to specifically displace the lipid II from the active site in a fluorescence anisotropy assay, suggesting that they act as competitive inhibitors. [ABSTRACT FROM AUTHOR]

A key intermediate of squalamine, 7α, 24R-dihydroxy-5α-cholestan-3-one has been developed starting from methyl Δ 5 -3β-hydroxycholanate. • Squalamine possess importment antiangiogenic activity. • Synthesis of squalamine becomes a research hotspot in the organic synthesis. • Building the structure of squalamine at 17-position of steroid to form a chiral isopropyl secondary alcohol side chain. A facile novel strategy has been developed to obtain a key intermediate of squalamine, 7α, 24R -dihydroxy-5α-cholestan-3-one, starting from methyl Δ5-3β-hydroxycholanate. The pure product was successfully synthesized and separated from the C-24 position epimers in good purity, d.e.% and yield. [ABSTRACT FROM AUTHOR]

Synthesis of A-ring-modified lupane, oleanane and ursane type triterpenoid conjugates with spermidine through an aldimine linkage or diethylentriamine via an amide bond is described. These derivatives were evaluated for their in vitro antimicrobial properties against human pathogens. Except for derivatives 1 and 7, all compounds have moderate to weak minimum inhibitory concentrations (MICs) against Gram-positive Staphylococcusaureus bacteria, with MICs varying from 3.125 to 200 µM. Compound 11 is efficient against Escherichia coli and Pseudomonas aeruginosa, with MICs of 25 and 50 µM, respectively, while all other derivatives do not possess important antimicrobial activities against these Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

The article reports on the phase three trial of a combination of Lucentis injections and the self-administered squalamine aminosterol eyedrop from Ohr Pharmaceutical to evaluate its efficacy for the treatment of wet advanced macular degeneration (AMD). The results of the phase 2 trial which examined the visual acuity of patients treated with a combination of squalamine eyedrops and ranibizumab compared to ranibizumab monotherapy are presented.

The article discusses the clinical trials of aministerol squalamine in eye-drop form for the treatment of retinal disease conducted by Ohr Pharmaceutical Inc. using proceeds from the sale of its common stock.

The article describes the case of a patient in the investigator-sponsored trial conducted by Ohr Pharmaceutical for its squalamine eyedrops. Based on the study, self-administration of the drug induced regression of neovasculature of the patient who has proliferative diabetic retinopathy (PDR). The study also found no changes in visual acuity.

The article reports on doctor John J. Wroblewski, who initiated a study regarding the use of the eye-drop formulation of the aminosterol squalamine for the treatment of macular edema secondary to retinal vein occlusion (RVO).