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Ophthalmology Clinics of North America Sep 2006Squalamine lactate inhibits angiogenesis by a long-lived, intracellular mechanism of action. The drug is taken up into activated endothelial cells through caveolae,... (Review)
Review
Squalamine lactate inhibits angiogenesis by a long-lived, intracellular mechanism of action. The drug is taken up into activated endothelial cells through caveolae, small invaginations in the cellular membrane. Subsequently, the drug binds to and "chaperones" calmodulin to an intracellular membrane compartment and blocks angiogenesis at several levels. A series of basic investigations, preclinical studies, and human clinical trials have begun to establish the proof of concept, efficacy, and safety parameters for use of squalamine lactate as a therapeutic agent for exudative age-related macular degeneration and several types of malignancies.
Topics: Animals; Cholestanols; Exudates and Transudates; Humans; Lactates; Macular Degeneration; Treatment Outcome
PubMed: 16935213
DOI: 10.1016/j.ohc.2006.05.003 -
Retina (Philadelphia, Pa.) Dec 2003To determine if systemically administered squalamine lactate, a novel aminosterol with antineoplastic and antiangiogenic activity, inhibits the development of...
PURPOSE
To determine if systemically administered squalamine lactate, a novel aminosterol with antineoplastic and antiangiogenic activity, inhibits the development of experimental choroidal neovascularization membranes (CNVMs) induced by laser trauma in a rat model.
METHODS
Twenty anesthetized male Brown-Norway rats received a series of 8 krypton red laser lesions per eye (647 nm, 0.05 second, 50 microm, 150 mW). One half the animals received an intraperitoneal injection of squalamine and the other one half received an injection of 5% dextrose in water, all performed in a masked fashion. Fundus photography and fluorescein angiography were performed at postlaser treatment days 14 and 28, and ocular tissues were processed for light microscopic examination following euthanasia of the rats on postlaser treatment day 28.
RESULTS
Although fundus photography and fluorescein angiography yielded no statistically significant quantitative differences between the two groups, histologic analysis of the lesion sites revealed a partial but statistically significant reduction of experimental CNVM development in the squalamine-treated population. In particular, the squalamine-treated eyes (n = 20) demonstrated lesions (n = 149) with a mean CNVM thickness +/- SD of 47 +/- 11 microm, as compared with the control eyes (n = 20) that had lesions (n = 142) with a mean CNVM thickness +/- SD of 63 +/- 14 microm (P < 0.001).
CONCLUSION
Systemically administered squalamine lactate partially reduced choroidal neovascular membrane development induced by laser trauma in this animal model. In conjunction with other existing and developing therapies, this agent may have a potential role in the treatment of human CNVM formation. Further study of squalamine lactate for treatment of neovascular eye disease is warranted.
Topics: Angiogenesis Inhibitors; Animals; Anticarcinogenic Agents; Cholestanols; Choroid; Choroidal Neovascularization; Disease Models, Animal; Fluorescein Angiography; Injections, Intraperitoneal; Laser Coagulation; Male; Rats; Rats, Inbred BN
PubMed: 14707832
DOI: 10.1097/00006982-200312000-00011 -
Expert Opinion on Pharmacotherapy Oct 2019: Investigational anti-VEGF treatments for neovascular age-related macular degeneration (nAMD) aim to improve visual outcomes and reduce treatment burden; these include... (Review)
Review
: Investigational anti-VEGF treatments for neovascular age-related macular degeneration (nAMD) aim to improve visual outcomes and reduce treatment burden; these include long-acting agents, combination strategies, topical agents, sustained-release, and genetic therapies. : The authors provide a comprehensive review of investigational therapies for nAMD, focusing on therapies currently in clinical trial. : Long-acting anti-VEGF agents have demonstrated promising results in phase 3 studies, and include Brolucizumab, a single-chain antibody fragment, and Abicipar, a designed ankyrin repeat protein (DARPin). Other unique anti-VEGF agents in current trials include Conbercept - a fusion protein of the VEGF receptor domains, KSI-301 - an anti-VEGF antibody biopolymer conjugate, and OPT-302 - an inhibitor of VEGF-C/D. Strategies to activate the Tie-2 receptor, some in combination with VEGF inhibition, are of interest, with recent trials of Faricimab, ARP-1536, and nesvacumab. Topical anti-VEGF ± anti-PDGF agents, such as pazopanib, squalamine lactate, regorafenib, and LHA510 have shown limited efficacy and/or have not been advanced, although PAN-90806 continues to advance with promising initial results. Sustained-release anti-VEGF treatments, to address treatment burden, include the ranibizumab Port Delivery System, GB-102, NT-503, hydrogel depot, Durasert, and ENV1305. Similarly, genetic therapies, including RGX-314 and ADVM-022, aim to provide sustained anti-VEGF expression from the retina.
Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Humans; Macular Degeneration
PubMed: 31298960
DOI: 10.1080/14656566.2019.1636031 -
Journal of Pharmaceutical and... Apr 2003Heat, acid and base stress methods were applied to study the stability of squalamine lactate. Liquid chromatography coupled with mass spectrometry was used to analyze...
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 degrees 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.
Topics: Cholestanols; Chromatography, Liquid; Drug Stability; Indicators and Reagents; Injections; Mass Spectrometry; Reproducibility of Results; Sensitivity and Specificity
PubMed: 12852451
DOI: 10.1016/s0731-7085(03)00047-5 -
Clinical Cancer Research : An Official... Sep 2003Squalamine is an antitumor agent that has been shown to have antiangiogenic activity in animal models. This Phase I/IIA study was designed to assess the safety, clinical... (Clinical Trial)
Clinical Trial
A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer.
PURPOSE
Squalamine is an antitumor agent that has been shown to have antiangiogenic activity in animal models. This Phase I/IIA study was designed to assess the safety, clinical response, and pharmacokinetics of squalamine when administered as a 5-day continuous infusion in conjunction with standard chemotherapy every 3 weeks in patients with stage IIIB (pleural effusion) or stage IV non-small cell lung cancer.
EXPERIMENTAL DESIGN
Patients with chemotherapy-naive non-small cell lung cancer were treated with escalating doses of squalamine in combination with standard doses of paclitaxel and carboplatin. Paclitaxel and carboplatin were administered on day 1, followed by squalamine as a continuous infusion on days 1-5, every 21 days.
RESULTS
A total of 45 patients were enrolled (18 patients in the Phase I dose escalation arm and 27 in the Phase IIA arm). The starting dose of squalamine was 100 mg/m(2)/day and escalated to 400 mg/m(2)/day; two of three patients at 400 mg/m(2)/day had dose-limiting toxicity that included grade 3/4 arthralgia, myalgia, and neutropenia. On the basis of safety and toxicity, 300 mg/m(2)/day was selected as the Phase II dose of squalamine in this combination regimen. An additional 27 patients (a total of 33) were enrolled according to the protocol treatment schema at 300 mg/m(2)/day. There was no pharmacokinetic evidence of drug interactions for the combination of squalamine, carboplatin, and paclitaxel. Forty-three patients were evaluable for response. Partial tumor responses were observed in 12 (28%) of these patients; an additional 8 evaluable patients (19%) were reported to have stable disease. For all of the patients treated, the median survival was 10.0 months; and 1-year survival was 40%.
CONCLUSIONS
The combination of squalamine given continuously daily for 5 days, with paclitaxel and carboplatin given on day 1, is well tolerated. Patient survival data and the safety profile of this drug combination suggests that the use of squalamine given at its maximum tolerated dose with cytotoxic chemotherapy should be explored further as a potentially effective therapeutic strategy for patients with stage IIIB or IV non-small cell lung cancer.
Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cholestanols; Disease-Free Survival; Female; Humans; Infusions, Intravenous; Lactates; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Patient Selection; Pleural Effusion; Survival Analysis; Time Factors
PubMed: 14519633
DOI: No ID Found -
Current Opinion in Ophthalmology May 2015The purpose of this review is to provide an update of phase 1 and 2 clinical trials in neovascular age-related macular degeneration that are either currently underway or... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to provide an update of phase 1 and 2 clinical trials in neovascular age-related macular degeneration that are either currently underway or recently completed by the end of 2014.
RECENT FINDINGS
Three gene therapy options are currently in early clinical trials, administered via intravitreal (AAV2-sFLT01) or subretinal (AVA-101 and RetinoStat) injection to express angiogenesis inhibitors. Several eye drops are being developed for topical administration for various angiogenic inhibitors, including regorafenib, squalamine lactate, and PAN-90806. Early development of systemic administration options may be intravenous (iSONEP) or oral (X-82). Initial study of local radiation therapy may be via proton beam irradiation or stereotactic radiotherapy. Several intravitreal injections are being studied including human immuno-conjugate molecule (hl-con1), abicipar pegol, PF582, DE-120, ESBA 1008, and REGN2176-3.
SUMMARY
Numerous treatment options of neovascular age-related macular degeneration are in phase 1/2 clinical trials including gene therapy, eye drops, systemic dosing, localized irradiation, and various intravitreal injections. Future phase 3 trial results will be observed closely to determine which of these therapies will be the next novel treatment of neovascular age-related macular degeneration.
Topics: Angiogenesis Inhibitors; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Genetic Therapy; Humans; Immunoconjugates; Proton Therapy; Wet Macular Degeneration
PubMed: 25822255
DOI: 10.1097/ICU.0000000000000147 -
Clinical Cancer Research : An Official... Dec 2001A Phase I study of squalamine, a novel antiangiogenic agent originally isolated from the dogfish shark Squalus acanthias, was conducted in patients with advanced cancers... (Clinical Trial)
Clinical Trial
PURPOSE
A Phase I study of squalamine, a novel antiangiogenic agent originally isolated from the dogfish shark Squalus acanthias, was conducted in patients with advanced cancers to: (a) determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of squalamine lactate when given as a 120-h continuous i.v. infusion every two weeks; and (b) to obtain information on prolonged (>120-h) continuous i.v. infusions in patients who have tolerated 120-h infusions.
EXPERIMENTAL DESIGN
A rapid dose escalation scheme was used that permitted intrapatient dose escalation. Three or more patients were treated at each dose, of which at least one patient started treatment de novo at that dose. Once DLT was encountered, the dose was decreased by one dose level, and the duration of infusion was prolonged from 10 up to 30 days in 5-day increments.
RESULTS
Nineteen patients were treated at eight squalamine dose levels; the number of patients/dose level who received 120-h infusions were [expressed as dose in mg/m(2)/day (number of patients initiated de novo at that dose/total number of patients treated at that dose)]: 6 (3/3), 12 (3/6), 24 (1/5), 48 (2/6), 96 (4/10), 192 (2/6), 384 (3/8), and 538 (1/5). DLT was encountered at 384 mg/m(2)/day (1/3 de novo patients, 5/8 total patients) and 538 mg/m(2)/day (1/1 de novo patients, 4/5 total patients) and consisted of hepatotoxicity, characterized by grade 3 transaminase elevations that resolved 3-11 days after ceasing squalamine infusion. Three patients did not experience hepatotoxicity when first treated at 384 mg/m(2)/day but developed DLT at the same dose when de-escalated from 538 mg/m(2)/day. Other toxicities included grade 1-3 fatigue, grade 1-2 nausea, anorexia, and neuromuscular symptoms. The maximum duration of continuous i.v. infusion was 20 days at a dose rate of 192 mg/m(2)/day in one patient without adverse effects. Pharmacokinetic calculations revealed a linear relationship between area under the curve or Cmax and squalamine dose rate up to 384 mg/m(2)/day, with a prolonged terminal squalamine persistence in patient plasma (median t(1/2) = 18 h; range, 8-48 h). Transient tumor responses were observed in a patient with synovial cell sarcoma and a patient with breast carcinoma with cutaneous metastases.
CONCLUSIONS
The best tolerated dose rate of squalamine when administered as a 120-h continuous i.v. infusion was 192 mg/m(2)/day; however, patients without prior exposure to squalamine appeared to tolerate a dose rate of 384 mg/m(2)/day without DLT. On the basis of preclinical evidence of synergy with cytotoxic agents and demonstration of human safety from this trial, additional clinical trials have been initiated with squalamine in combination with chemotherapy for patients with late stage lung cancer and ovarian cancer.
Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Anticarcinogenic Agents; Cholestanols; Dose-Response Relationship, Drug; Fatigue; Female; Humans; Liver; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms
PubMed: 11751482
DOI: No ID Found -
Expert Opinion on Emerging Drugs Sep 2017Evolving anti-vascular endothelial growth factor (VEGF) treatments for neovascular age-related macular degeneration (nAMD) include long acting agents, combination... (Review)
Review
Evolving anti-vascular endothelial growth factor (VEGF) treatments for neovascular age-related macular degeneration (nAMD) include long acting agents, combination strategies involving new pathways, topical agents, sustained-release, and genetic therapy strategies. Areas covered: Brolucizumab and abicipar pegol have smaller molecular size, facilitating higher concentrations and potentially longer duration than current anti-VEGF agents. Agents being combined with anti-VEGFs include OPT-302 (to inhibit VEGF-C and VEGF-D); pegpleranib and rinucumab (to inhibit platelet derived growth factor, PDGF - but both failed to show consistently improved visual outcomes compared to anti-VEGF monotherapy); and RG7716, ARP-1536 and nesvacumab (to activate the Tie-2 tyrosine kinase receptor, which reduces permeability). X-82 is an oral anti-VEGF and anti-PDGF being tested in phase 2 studies. Topical anti-VEGF ± anti-PDGF drugs under study include pazopanib, PAN-90806, squalamine lactate, regorafinib, and LHA510. Sustained-release anti-VEGF delivery treatments, such as the ranibizumab Port Delivery System, GB-102, NT-503, hydrogel depot, Durasert, and ENV1305 aim to reduce the burden of frequent injections. Gene therapies with new viral vectors hold the potential to induce sustained expression of anti-angiogenic proteins via the retina's cellular apparatus, and include AVA-101/201, ADVM-202/302, AAV2-sFLT01, RGX314, and Retinostat. Expert opinion: There are many emerging anti-VEGF treatments that aim to improve visual outcomes and reduce the treatment burden of nAMD.
Topics: Angiogenesis Inhibitors; Choroidal Neovascularization; Delayed-Action Preparations; Drug Design; Drug Therapy, Combination; Genetic Therapy; Humans; Macular Degeneration; Vascular Endothelial Growth Factor A
PubMed: 28756707
DOI: 10.1080/14728214.2017.1362390 -
BioDrugs : Clinical Immunotherapeutics,... 2007Diabetic macular edema (DME) and choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) are the leading causes of vision loss in the... (Review)
Review
Diabetic macular edema (DME) and choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) are the leading causes of vision loss in the industrialized world. The mainstay of treatment for both conditions has been thermal laser photocoagulation, while there have been recent advances in the treatment of CNV using photodynamic therapy with verteporfin. While both of these treatments have prevented further vision loss in a subset of patients, vision improvement is rare. Anti-vascular endothelial growth factor (VEGF)-A therapy has revolutionized the treatment of both conditions. Pegaptanib, an anti-VEGF aptamer, prevents vision loss in CNV, although the performance is similar to that of photodynamic therapy. Ranibizumab, an antibody fragment, and bevacizumab, a full-length humanized monoclonal antibody against VEGF, have both shown promising results, with improvements in visual acuity in the treatment of both diseases. VEGF trap, a modified soluble VEGF receptor analog, binds VEGF more tightly than all other anti-VEGF therapies, and has also shown promising results in early trials. Other treatment strategies to decrease the effect of VEGF have used small interfering RNA to inhibit VEGF production and VEGF receptor production. Corticosteroids have shown efficacy in controlled trials, including anacortave acetate in the treatment and prevention of CNV, and intravitreal triamcinolone acetonide and the fluocinolone acetonide implant in the treatment of DME. Receptor tyrosine kinase inhibitors, such as vatalanib, inhibit downstream effects of VEGF, and have been effective in the treatment of CNV in early studies. Squalamine lactate inhibits plasma membrane ion channels with downstream effects on VEGF, and has shown promising results with systemic administration. Initial results are also encouraging for other growth factors, including pigment epithelium-derived factor administered via an adenoviral vector. Ruboxistaurin, which decreases protein kinase C activity, has shown positive results in the prevention of diabetic retinopathy progression, and the resolution of DME. Combination therapy has been investigated, and may prove to be quite effective in the management of both DME and AMD-associated CNV, although ongoing and future studies will be crucial to treatment optimization for each condition.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Cholestanols; Choroidal Neovascularization; Diabetic Retinopathy; Drug Therapy, Combination; Humans; Indoles; Lactates; Laser Coagulation; Macular Degeneration; Macular Edema; Maleimides; Octreotide; Photochemotherapy; Photosensitizing Agents; Porphyrins; Pregnadienediols; Protein-Tyrosine Kinases; Vascular Endothelial Growth Factors; Verteporfin; Vitrectomy
PubMed: 17628122
DOI: 10.2165/00063030-200721040-00005 -
Expert Opinion on Investigational Drugs Jul 2006Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular age-related... (Review)
Review
Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular age-related macular degeneration (AMD), the leading cause for legal blindness in many industrialised countries, abnormal blood vessels grow in the macula and cause blindness. There are a number of factors important in the angiogenic cascade but VEGF-A has been implicated in recent years as the major factor responsible for neovascular and exudative diseases of the eye. Numerous antiangiogenic drugs are in development but anti-VEGF drugs have shown great promise in treating neovascular AMD and other ocular diseases, and many of these drugs have been adopted from oncology where antiangiogenic therapy is gaining wide acceptance. For the first time in neovascular AMD, anti-VEGF drugs have brought the hope of vision improvement to a significant proportion of patients. This review provides an overview on angiogenic mechanisms, potential antiangiogenic treatment strategies and different antiangiogenic drugs with special focus on neovascular AMD.
Topics: Aging; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Aptamers, Nucleotide; Bevacizumab; Capillary Permeability; Cholestanols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Double-Blind Method; Drug Design; Drugs, Investigational; Eye Proteins; Humans; Injections; Lactates; Macular Degeneration; Models, Animal; Multicenter Studies as Topic; Neovascularization, Pathologic; Nerve Growth Factors; Pigment Epithelium of Eye; Protein Isoforms; RNA Interference; RNA, Small Interfering; Randomized Controlled Trials as Topic; Serpins; Stilbenes; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vitreous Body
PubMed: 16787141
DOI: 10.1517/13543784.15.7.779