Application of Dimethyl Sulfoxide as a Therapeutic Agent and Drug Vehicle for Eye Diseases

Introduction

Dimethyl sulfoxide (DMSO) is a transparent and colorless organosulfur compound derived as a byproduct from lignin, a fiber in wood pulp. It was first synthesized in 1867 by Alexander Saytzeff, a Russian chemist, oxidizing dimethyl sulfide with concentrated nitric acid. ¹ Currently, a synthetic version of DMSO is the approved drug and pharmaceutical solvent by the U.S. and European countries. ²

Meanwhile, the plastic industry noted the unique solvent properties of DMSO and began mass producing it for research and developmental purposes starting in the 1940s. ³ The fascinating solvent properties lie in the trigonal pyramidal molecular geometry with a lone pair on the tetrahedral sulfur, DMSO has a large dipole moment that can react readily with various organic and inorganic compounds. Along with the lack of hydrogen atoms to donate to hydrogen bonding, it is utilized as a powerful polar aprotic solvent that can dissolve various polar and nonpolar compounds.

Due to its amphiphilic property, DMSO is permeable to the phospholipid bilayer membrane at the cellular level. Hence, DMSO was discovered as a membrane penetration enhancement agent that can quickly penetrate the skin and deliver drugs transdermally.^4,5 Mechanistic studies have shown that water pore formations in phospholipid bilayers by DMSO create an entry for molecules to enter cells. ⁶ DMSO can also profoundly affect the aqueous solubility of less-soluble agents and has been employed in various pharmaceutical preparations to promote the delivery of a greater concentration of drugs to the target tissues.

Therapeutically, DMSO has shown many different characteristics, including anti-inflammatory and analgesic properties. In the United States, it is currently used as a transdermal carrier in diclofenac sodium topical solution to treat signs and symptoms of osteoarthritis as well as for other topical conditions. ⁶ Another medical indication that DMSO is currently approved is for interstitial cystitis—a painful inflammatory infection of the bladder. Intravesical instillation of DMSO is purported to reduce inflammatory response related to the inhibition of interleukin-8 (IL-8), ⁷ nuclear factor-kappaB (NF-κB), and the stimulation of prostaglandin E2 (PGE2). ⁸ DMSO alone or combined with other synergistic drugs can be potentially helpful in treating head and spinal cord injury, stroke, memory dysfunction, and ischemic heart disease. ³ Furthermore, this chemical is currently being used as a component of various cellular therapies and immunotherapy for cancers. ⁹ In our prior publications, we have reported DMSO's efficacy and safety for palliative care ¹⁰ and pain control ¹¹ in patients with advanced cancer, suggesting this agent's strong clinical values.^12,13

DMSO (10%) is the standard cryoprotectant added to the culture medium for preserving and storing biological tissue. It acts as a penetrating cryopreservation agent (CPA) due to its high membrane permeability, allowing it to permeate, and water to escape the cells readily, avoiding any issues with ice crystal formation. ¹⁴ Concentrations of this polar aprotic solvent have been demonstrated to be favorable in preserving viable cells over other agents, such as glycerol ¹⁵ and polyethylene glycol.^16–18 It is currently Food and Drug Administration (FDA) approved to be used as a CPA of sperms, eggs, stem cells, bone marrow cells, and organs for transplant.

Inflammation-related symptoms and consequences are significant compartments of eye diseases and remain hard-to-treat pathologies for ophthalmologists, dermatologists, allergists, and rheumatologists. Eye inflammation can be caused by numerous pathogens like bacteria, viruses, parasites, fungi, chemical and environmental irritants, burns, and traumas. Moreover, eye inflammation is a part of multiple autoimmune diseases, proliferative and allergic disorders. Currently, ophthalmic corticosteroids remain the primary core treatment used alone or with other drugs for internal and external ocular inflammation associated with eye diseases despite the widespread local and systemic adverse side effects such as elevated intraocular pressure, infection, and cataract formation. In the long run, other immunosuppressive and biological therapeutic agents are also toxic, expensive, and very difficult to apply to patients to control ocular inflammation, especially in chronic and repeatedly recurrent disease courses.

Given that DMSO is an FDA-approved, well-studied, inexpensive compound with low toxicity as a therapeutic agent and pharmaceutical solvent, this agent should be further explored and implemented more comprehensively in clinical ophthalmology. The attractive clinical properties of DMSO also facilitates the penetration of other therapeutic substances through biological membranes, making it a potential pharmaceutical vehicle and solvent for topical therapeutic composition. This review will substantiate a possible application of DMSO as an effective and safe therapeutic and drug-delivering (vehicle) agent to manage numerous ocular diseases.

Clinical Evidence of DMSO in Treatment of Ocular Diseases in Human and Animals

DMSO has been used for the treatment of ophthalmological diseases. In 1968, Gordon and Kleberger ¹⁹ research group documented the utilization of DMSO in the human eye. They reported 157 eyes in which DMSO (7.5%–66%) was applied locally for various ophthalmic indications with favorable clinical results. There was no reported ocular toxicity observed in these patients for up to 19 months after treatment.

The first evidence of the possible efficacy of DMSO in retinal diseases was accidentally discovered when some retinitis pigmentosa patients reported that their vision had improved while they were taking DMSO for musculoskeletal disorders. ²⁰ The investigation began in 1972 when 1 patient suffering from retinitis pigmentosa had a spectacular recovery of vision after treatment with 50% aqueous DMSO solution applied to the cornea by eyecup immersion, for 30 s, twice daily. The patient maintained good progress with DMSO treatment during 2 years of follow-up.

In the same clinical study, another 50 patients with retinal deteriorations, macular degenerations, and retinitis pigmentosa were similarly treated with DMSO and showed encouraging results. Outcomes of the treatment included stabilized and enhanced visual acuity (22 patients), visual fields (9 patients), and improved night vision (5 patients). The rest of the patients exhibited no measurable or personally noted vision changes, and only 2 patients had their conditions continuing to regress. The serial fundus photography and slit-lamp photomicrography were obtained and displayed no adverse tissue reactions. The side effects were temporary stinging (about 20–30 s) along with some occasional burning sensation or dryness on the eyelid.^19,20

DMSO in the Treatment of Retinal Disease

In the case of chronic superficial keratitis (CSK) in dogs, administration of 50% DMSO combined with dexamethasone has been reported to be much more effective in reducing the inflammatory process than the administration of dexamethasone alone. ²¹ Further study of long-term administration (10 months) of DMSO in the treatment of CSK has also demonstrated the ability to reduce the inflammatory responses without any side effects on the corneal epithelium.^22,23

Taken from previous studies, DMSO combined with a low dose of an antiseptic agent povidone/iodine (PVP-I) was used and showed remarkable efficacy and a good safety profile for several types of blepharitis and blepharoconjunctivitis. Blepharitis is a chronic ocular condition that is difficult to manage. Patients with blepharitis are often prone to other eye problems, such as chalazion, rosacea, dry eye, and contact lens intolerance. ²⁴ The complex nature of blepharitis makes curative treatment challenging since there are no currently FDA-approved treatments. ²⁵ In a series of studies by Pelletier et al.,^26–28 the multiple potential therapeutic activities and preliminary clinical data indicated that DMSO could be used as a therapeutic product or a component of a pharmaceutical composition for treatment for various ophthalmological diseases, such as retinitis, pigmentosa, blepharitis, and conjunctivitis. The importance of using DMSO was demonstrated through the study of the PVP-I/DMSO gel system. ²⁷ DMSO helps the water pore formation leading to greater PVP-I penetration through the cellular membrane. Comparatively, when high concentration of PVP-I was used without DMSO the treatment of blepharitis had worse outcomes and was reported as failed. Thus, the authors concluded that DMSO could potentiate the delivery and the effectiveness of numerous topical drugs for ocular diseases and avoid the need for injection of these drugs in a large dose.

Potential Application of DMSO to Treat Eye Injuries Due to Chemical Burns

Another potential area of interest for the use of DMSO is wound healing. Applying DMSO cream at the early stages can decrease pressure ulcer occurrence among high-risk patients. ²⁹ Duimel-Peeters et al. ³⁰ performed a systematic review of the efficacy of topical DMSO on wound healing from decubitus ulcers and its use as an anti-inflammatory drug. The effects reported were beneficial, both for wound healing and analgesia. The most frequent outcomes were reducing erythema and rapid recovery of ulcers, along with decreased signs of inflammation. ³⁰ In another study, DMSO was dramatically effective in healing severe skin necrosis caused by accidental extravasation of the anticancer drug mitomycin C during intravenous administration. ³¹

The use of DMSO has been demonstrated to accelerate the healing of corneal ulceration in rabbits, reduced neovascularization, and proven to be effective, especially in cases of corneal alkali burn.^32,33 Another severe and painful type of chemical burn is hydrofluoric acid (HF) burn. As HF is becoming increasingly common with its wide use in industrial and domestic areas, the number of burned patients has increased significantly. Compared with other acids, HF results in more extensive injury in ocular tissue because of the small corrosive hydrogen ions and small toxic fluoride ions that can penetrate deep into the tissue, causing subsequent liquefaction necrosis. The failure of proper corneal repair following such severe chemical burns often causes loss of vision.^34–36 A recent study demonstrated the effectiveness of using indomethacin and 40% DMSO to heal HF eye burns in rabbits. ³⁷ Compared with the use of 0.1% indomethacin, the combination of drug and DMSO showed the greater capability to induce reepithelization and reduce inflammation.

Corneal neovascularization (CNV) happens when new blood vessels invade the cornea from the limbus due to an excess of angiogenic factors. The disruption in the balance between angiogenic and antiangiogenic factors can occur because of chemical burns, external and thermal injuries, infections, inflammation, or graft rejection. Severe cases of CNV can lead to loss of vision and blindness.^38–40 Topical administration of DMSO was found to inhibit CNV effectively and promote corneal repair in rabbits following acid burn. ⁴¹ In the DMSO-treated group, there was a lower expression of vascular endothelial growth factor (VEGF) and its receptors in the inflammatory cells, which indicates that the anti-inflammatory effect of DMSO was robust after topical application. The authors suggested that DMSO makes an effective topical therapy to treat corneal burns and prevent the long-term complications of the injuries. ⁴¹

The citing literature reports DMSO's superior efficacy as a topical treatment for thermal burns in humans and animals, with the application of up to 40% aqueous DMSO solution.^42,43 Further clinical trials are needed to validate the safety and efficacy in a larger population. However, the administration of DMSO has been proven to be a practical control of acute symptoms, a promotion of the healing process, and, most importantly, an effective preventive method for long-term damages to the patients' eyes and vision in all types of burns.

DMSO as an Ideal Antihypoxic and Angiogenesis Modulator for the Treatment of Ocular Neovascular Diseases

Pathological angiogenesis occurs in numerous ocular diseases, including diabetic retinopathy, retinal vein occlusions, sickle cell retinopathy, hyperviscosity syndromes, pathologic myopia, age-related macular degeneration, and many others. While macular edema and retinal neovascularization contribute to visual loss in several ocular diseases, the most common ones are proliferative diabetic retinopathy, neovascular age-related macular degeneration, and retinopathy of prematurity. Altogether, these 3 diseases caused legal blindness and accounted for the affliction in various stages of life. Pharmacological antiangiogenic therapy can potentially assist in the prevention of the onset or progression of ocular neovascularization.^44,45

VEGF has been among the most essential and widely investigated angiogenic molecules. VEGF plays numerous roles in the human body, including the cardiovascular system and central nervous system. In the case of inflammation and injuries, it is produced as an adaptive response to increase vessel permeability for tissue remodeling. However, various case studies and clinical trials have reported that VEGF is one of the leading causes of neovascularization in both ischemic and inflammatory retinopathies.^46,47 In addition, the inhibition of VEGF can lead to neurodegeneration. ⁴⁸ Currently, approved antiangiogenetic drugs for long-term or constant blocking of VEGF are expensive, complicated to use, and causing severe side effects. ⁴⁹

Several medical and surgical treatment methods have been described for controlling ocular neovascular diseases, including the administration of topical steroids. Anti-VEGF agents and nonsteroidal agents, such as rapamycin, bevacizumab, ranibizumab, and pegaptanib, have been used clinically. While anti-VEGF agents, alone or in combination with steroids, have been used to treat CNV.^40,50–52 Despite numerous treatment modalities, there is no consensus regarding the best treatment.

The application of DMSO as topical treatment with a concentration of up to 40% in aqueous solution as eye drops could be an effective alternative. The therapy reduced angiogenic cytokines, inflammation, and promoted corneal repair and healing of CNV following chemical burns in the rabbit eyes. ⁴¹ Mechanistically, the findings suggested that angiogenic cytokines respond to other inflammatory mediators, such as interleukin-1 (IL-1), IL-8, leukotriene, matrix metalloproteinase-9, and promote neovascularization by increasing the synthesis of VEGF. DMSO exerts an anti-inflammatory effect by inhibiting the influx of polymorphonuclear cells and monocytes into the sites of inflammation and by stimulating prostaglandin synthesis. DMSO has also shown a potentiating activity when combined with other conventional anti-inflammatory and antiangiogenetic drugs to treat dogs with superficial keratitis.^22,23

In a different study by Şimşek et al., ⁵³ substance P (SP) levels were significantly reduced in DMSO-treated HeLa cell media. SP, released from the peripheral nerve C fibers, prolongs cancer progression and metastasis by inducing angiogenesis and local inflammatory responses. DMSO-soluble thalidomide is widely used in the clinical treatment of cancer as an antiangiogenic agent combined with traditional therapies. The author reported that a substantial antiangiogenetic effect of DMSO by dramatically decreasing the SP levels, caused a 1.61-fold reduction in VEGF mRNA level, and strikingly increases 2.19-folds in interferon-γ (IFN-γ) mRNA level. ⁵³

Human aortic endothelial cells were investigated in vitro to determine the antiangiogenic effects of DMSO and study the mechanisms of its anti-inflammatory activity. Koizumi et al. ⁵⁴ demonstrated that during endothelial cell migration, the preliminary step for angiogenesis, DMSO effectively suppresses the production of matrix metalloproteinase-2 (MMP-2), which then results in the inhibition of the capillary tube formation. They showed strong antiangiogenic effects of DMSO on endothelial cells and that DMSO blocked endothelial cell tube formation on a Matrigel. Additionally, DMSO treatment caused a significant decrease in MMP-2 levels. MMP-2 is an angiogenic factor released from endothelial cells that degrades the fibronectin and types IV, V, VII, and X collagens, which are the constituents of the basal membrane ⁵⁴

Antiangiogenic pharmacologic therapy has become an important component in the management of diseases of the vitreous and retina. It has revolutionized the treatment of many ocular conditions, including diabetic retinopathy, retinal vein occlusions, pathologic myopia, choroidal neovascularization, and age-related macular degeneration. There are numerous considerations to identify an optimal approach for the treatment of ocular neovascular disease. Minimal levels of the target in normal tissue would lessen potential side effects of drugs. In addition, an ideal therapeutic agent would be administered locally to the eye in an easily accessible form, such as topical instillation, subconjunctival depot. The administration would preferably be noninvasive, so that would involve minimal risk to patients. The existing literature has shown that DMSO is an effective anti-inflammatory drug, indicating that this compound can be developed and applied as a viable and inexpensive therapeutic agent for a wide range of neovascular ocular diseases.

DMSO as an Immunomodulator and Potential Application in Ocular Inflammatory and Autoimmune Disease

Ocular inflammation is known as one of the most common indications of eye disorders, ocular and systemic autoimmune diseases. Besides nonsteroidal anti-inflammatory drugs and corticosteroids, several existing drugs are being assessed, including anti-VEGF compounds, such as ranibizumab and bevacizumab; antitumor necrosis factor-alpha antibodies, such as infliximab; as well as older cytotoxic medications, such as methotrexate and cyclosporine; and intravitreal sirolimus have also been proposed as suitable therapeutic targets. ⁵⁵

DMSO has been used as an anti-inflammatory drug for over 60 years for treating numerous inflammatory illnesses. In 1978, DMSO was approved by the United States FDA for the treatment of interstitial cystitis by intravesical instillation due to its anti-inflammatory and analgesic effects. ⁵⁶ Application of DMSO has been reported to effectively treat several types of amyloidosis as a complication of infective, autoimmune, and inflammatory diseases and improve the renal function in patients with renal amyloidosis that resulted from Crohn's disease.^57,58 Treatment of rheumatoid arthritis when using DMSO together with corticosteroids showed better results than those treated with the drugs alone. ⁵⁹

A clinical trial conducted in Germany, administered percutaneous treatment of 25% DMSO daily for 3 weeks, showed improved pain symptoms in osteoarthritis patients.^60,61 An in vitro study demonstrated that 1% DMSO treatment inhibited the receptor activator of NF-κB ligand-induced differentiation of osteoclastogenesis in RAW 264.7 cells, suggesting a novel effect of DMSO in the protection of articular cartilage. ⁶² In a separate study, DMSO (500 mg 4 times a day by oral administration) in conjunction with sulfasalazine and prednisolone has been used to treat ulcerative colitis. ⁶³ The response rate and recurrent events of the patients treated with a combination of drugs with DMSO were significantly better compared with patients treated without DMSO.

The anti-inflammatory activities of DMSO were investigated and verified at the cellular level in different animal and human research. Kelly et al. ⁶⁴ has demonstrated that treatment with 2% DMSO suppressed the expression of the lipopolysaccharide-induced inflammatory cytokines and the activation of NF-κB in the J774 macrophage-like cell lines and primary murine peritoneal macrophage. Another study showed that when preincubating the intestinal Caco-2 cells with DMSO (0.2%, 0.5%, or 1%) 1 h before IL-1β stimulation, the inflammatory response was significantly attenuated. ⁶⁵ In a mouse paw model, Colucci et al. ⁶⁶ reported that the oral administration of DMSO (10 mL per 1 kg of body weight in 10 min) before the zymosan-induced edema produced an anti-inflammatory effect.

In a recent study, Elisia et al. ⁶⁷ indicated that treatment with 2% DMSO repressed the production of inflammatory cytokines, such as TNF-α, IFN-α, and IFN-γ, elicited by Escherichia coli infection or by herpes simplex virus-1 (HSV-1) infection in human whole blood cells. The same authors also reported that immersion of the hind paws of the C57BL/6 mice in 70% DMSO, twice daily, effectively reduced the swelling of arthritis in the K/BxN mice model. In addition, DMSO treatment (6 mL/kg intraperitoneal administration) has been shown to inhibit the sepsis-induced activation of the NF-κB and the activating protein-1 (AP-1), resulting in the suppression of the intercellular adhesion molecule 1 (ICAM-1) expression in the liver of rats with septic peritonitis model. ⁶⁸ Other authors reported that the intraperitoneal administration of 6 mg/kg DMSO resulted in a decreased activation of the NF-κB in the livers, kidneys, and intestines of Sprague–Dawley rats with hemorrhagic shock. ⁶⁹ Ahn et al. ⁷⁰ showed that DMSO treatment suppressed the production of IL-1β in the bone marrow-derived macrophages via inhibition of the activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. These data indicate that DMSO exhibits an anti-inflammatory effect that may result from the suppression of the activation of the NF-κB or the NLRP3 inflammasome. The findings from these studies suggest that DMSO may possess a modulatory effect on the innate immune system.^71,72

DMSO exerts a protective effect by preventing spontaneous autoimmune diabetes and inhibiting the autoimmune reactivation in islet graft rejection. ⁷³ DMSO administration with a dose of 0.22 g/kg/day effectively suppressed the onset of autoimmune diabetes in nonobese diabetic (NOD) mice. This treatment also significantly prolonged the survival of the islet grafts in the NOD recipients. DMSO administration reduced the percentage of the splenic dendritic cells and the T helper (Th) 1 cells in NOD mice. Lin et al. ⁷⁴ also reported in vivo DMSO treatment inhibited the extracellular polymeric substance (EPS) formation in a mouse model. Moreover, adoptive transfer of the Treg cells that differentiated in vitro from the naive CD4 T cells in response to the treatment with DMSO exhibited a comparable effect to the in vivo DMSO administration on the suppression of EPS formation. These studies suggested that DMSO may exhibit an immunomodulatory effect on the adaptive immune system and implied a clinical therapeutic potential of DMSO for autoimmune diseases or chronic inflammatory diseases by cell therapy with the adoptive transfer of in vitro DMSO-induced Treg cells.

To add to the benefit of an anti-inflammatory and immunomodulating agent, DMSO also inhibits the growth of or inactivates bacteria, fungi, and viruses; reduces antibiotics resistance of some bacterial species; and improves the efficacy of anti-infective treatment. Published reports showed that the inclusion of small amounts (2.8%) of DMSO could enhance the effectiveness of several currently used skin antiseptics. ⁷⁵ A new class of antiseptics based on the inclusion of DMSO may offer general improvements in skin antisepsis, including lower rates of wound infection.

The literature shows the efficacy of including DMSO in treating autoimmune and inflammatory diseases. At the same time, basic experimental data indicated that DMSO could be used and further studied for ocular inflammatory diseases.^76,77 DMSO can be effectively applied as eye drops or topical gel in treating ocular surface and anterior segment inflammation of all etiologies, pain and postoperative inflammation, seasonal allergic conjunctivitis, uveitis, blepharitis, keratitis, and possible others. A possible systemic administration of DMSO orally and parenterally should be explored and studied as a perspective therapy of the most severe cases of ocular inflammation, including autoimmune diseases.

DMSO as a pharmaceutical solvent and vehicle for the improvement of drug efficacy in the treatment of ocular diseases

Inflammation of the ocular surface has been treated topically using anti-inflammatory drugs and immunosuppressive agents.^78–81 However, these drugs have a known limitation to have difficulty penetrating through the anatomical and physiological ocular barriers. Moreover, they exhibit low aqueous solubility, which only allows 1%–5% of bioavailability for cornea penetration. DMSO has been proven to profoundly affect the aqueous solubility of less-soluble agents and is employed in various pharmaceutical preparations.^82–85 These interactions remain subject to molecular weight, structure, and chemical properties afforded by the solvent; however, the result delivers a greater concentration of solute to the target.^86,87 DMSO can improve the most preferred topical route of drug administration to manage ocular diseases as it is easy to handle, noninvasive, and rather well tolerated. Furthermore, DMSO provides good drug solubility and sufficient ocular drug concentrations while avoiding the systemic side effects of the systemic route of administration.

As shown in previous studies, DMSO could increase the permeability of therapeutic agents by several times, which means that ophthalmic formulations containing DMSO may increase the systemic bioavailability of administered drugs. Given the fact that ophthalmic solution usually only contains a small number of active drugs per dose for fear of side effects, this potential concern can be resolved by lowering the concentration of therapeutic drugs in the formulation with DMSO as a solvent or pharmaceutical vehicle. Clinical evidence has shown that DMSO in a high concentration of 50% and above in the topical approval drugs for arthritic pain and vesical instillation for interstitial cystitis have not caused significant systemic side effects while sustaining therapeutic analgesic and anti-inflammatory activities of the drugs.^56,88

Finally, DMSO in low concentration also serves as an effective stabilizer and preservative for pharmaceutical composition due to its potent antioxidant and antiseptic properties.

DMSO Systemic and Ocular Toxicity

DMSO as a therapeutic, cryoprotective agent, and a pharmaceutical solvent has been demonstrated to have very low toxicity. However, there have been reported side effects when administering DMSO. In a systematic review, Madsen et al. ⁸⁹ reported that gastrointestinal and skin reactions were the 2 most reported adverse reactions to DMSO. When administering DMSO intravenously, nausea and vomiting in patients were common side effects. However, these symptoms quickly went away postinfusion and were less reported at lower dosages. ⁹⁰ In terms of dermatological effects, the most commonly reported symptoms were skin reactions to topical application. These symptoms were very brief, lasting only minutes, and would typically not reappear with conditional treatment. ⁹¹ The majority of reported effects were transient and passed without intervention or harm to the patient. Interestingly, another commonly reported side effect of DMSO application is a garlic-like odor and taste due to the pulmonary excretion of DMSO as dimethyl sulfide. ⁹⁰ This phenomenon can also be a potential cause of discomfort.

Although DMSO was reported to induce minor side effects during clinical topical and systemic applications, ³ it has been reported to be the most severe observed adverse effect in intravascular hemolysis using 40% or higher concentration solution. The osmotic pressure in the erythrocytes caused by an intravenous infusion of high concentrations of DMSO has been reported to be the cause of this adverse effect rather than toxicity. Systematically, this negative effect can be avoided by treating with a DMSO solution at a concentration of less than 30%.^92,93

In terms of application to the eye, there are 2 published studies that investigated the adverse effects following intravitreal injection of DMSO in animal studies. Silverman and Yoshizumi ⁹⁴ tested different concentrations of DMSO at strengths of 1%, 10%, 50%, and 100% injected into rabbit eyes. The most noticeable changes were conjunctival erythema and focal retinal edema after injection. However, these effects were transient and cleared after 1 week. No cataract formation was noted at any concentration of the injected solution. However, repeated (twice weekly) injections for 2 months (total of 5 injections) gave transient retinal edema for high concentrations (>50%) and abnormal electroretinogram (ERG) responses at all concentrations (1% to 100%), 1 h after the injection. Lastly, this group noted a dose/response effect on retinal ERG signals and retinal tissues where retinal edema is found. They concluded that DMSO had minimal toxicity to the eye and could be used as a vehicle for therapeutic agents. In a similar study, Tsai et al. ⁹⁵ intravitreally injected rats with a much lower concentration of DMSO ranging from 0.01% to 8% DMSO. This group found reduced retinal physiology for doses >0.6% with the most remarkable effects on retinal ganglion cells. This study contradicted a previous in vivo rodent study that showed DMSO up to 2% having little effect on functionality. ⁹⁶

However, these experimental studies with direct intravitreal injections of DMSO solution with doses from 0.6% to more than 50% are highly unlikely to represent the human application of DMSO where a much lower concentration of DMSO in the targeted tissues would result from oral, intravenous, or topical application of less than 0.5 mL of DMSO per 1 kg body weight.

DMSO administered in some animal models, including rabbits, dogs, and pigs, has been shown to produce changes in the refractive index of the lens of their eyes. Pharmacologically, a high-dose oral administration of DMSO appeared to most likely cause such ocular changes at doses of 1 g/kg/day of DMSO over 69 days. ⁹⁷ From toxicology studies carried out by Mylan Pharmaceuticals (Etobicoke, ON) for their product RIMSO-50 (50% DMSO), the rabbit was the most susceptible for refractive index changes while the monkey was most resistant. ⁹⁷ Refractive index changes in the lens have also been observed in other animals, including dogs, rabbits, and pigs; however, they were much more resistant and only appeared after 3 months at a dose of ∼5 g/kg. Despite these reports, no microscopic or chemical differences could be found between the lenses of the treated animals and the controls. These lens changes appeared to be a dose-related effect, and its side effects diminished as the dose was reduced. It is noteworthy that the effect was only produced at 50 to 100 times the usual human therapeutic dose. Finally, extensive toxicology studies have been conducted in numerous animal species in addition to the ones mentioned above. These were given with treatment periods up to 18 months, with doses greater than 30 times anticipated for humans with minimal side effects. Therefore, high DMSO concentrations appear to be a relatively safe drug for human administration, and the lens changes observed in animals have not yet been reported in humans. ⁹⁷

In humans, even with prolonged administration of large amounts of DMSO, no cases of lens changes have been observed due to systemic, topical, or local ophthalmic administration. ⁹⁸

Despite some concerns generated from experimental animal studies regarding DMSO cataract-causing effects, there were no reports of cataract formation from DMSO in human application of DMSO orally, intravenously, and topically. In a DMSO eye drop study with 65 patients treated with 50% DMSO, patients were followed for 2 years, and researchers observed minimal deterioration in visual acuity that was carried out even 4 to 7 years post-treatment. ⁹⁹ Even though there was no reported ocular toxicity, 2 patients developed conjunctival hyperemia due to their allergies to the drops. Moreover, DMSO with a concentration from 6.25% to 42% has been used in several eye drop preparations for treating and preventing cataracts in humans. There was some anecdotal evidence that the combination of DMSO with N-acetyl carnosine, DMSO with lanosterol, or glutathione as ophthalmic drops might be effective as a cataract treatment. ¹⁰⁰

Using a high concentration of DMSO has shown to be the least toxic when administering topically. ¹⁰¹ Even after using concentrated (90%) topical DMSO on 33 dogs and monkeys over an extended period, no serious adverse events or toxicity were reported other than the dehydration of local tissues due to its hygroscopic property. ¹⁰¹ DMSO toxicity is summarized in Table 1.

For the past 20 years, there has been a significantly greater number of new registrations globally for DMSO-based pharmaceutical products, over-the-counter drugs, and medical devices. The use of DMSO as an excipient as well as the active drug in formulations is expanding to include topicals, oral solutions, and parenteral products. ¹⁰² Regulatory acceptance of DMSO products manufactured under good manufacturing practices has broadened to the European Union, establishing a Certification of Suitability (CEP) in 2014. In cellular products, DMSO with a concentration from 5% to 17% is a critical component of preserving cell therapy such as Chimeric antigen receptor T cells for cancer, stem cell transplantation, and anticancer drugs such as GlaxoSmithKline's (Brentford, United Kingdom) 2013 FDA approval to market Mekinist (trametinib DMSO) as a melanoma treatment.^11,77 Table 2 summarizes the pharmaceutical formulations that incorporate DMSO as an active ingredient or as an excipient.

In summary, the uses of DMSO were proven to have little to no toxicity when used in clinically adequate doses. The toxic side effects are most frequently seen in abnormally high experimental doses and concentrations.

Conclusion and Perspectives

The medical uses of DMSO have generally fallen into 3 functional categories encompassing tissue/organ preservation, penetration-enhancing solvent excipients, and active pharmaceutical agents. Although FDA has relaxed the restrictions regarding clinical research of DMSO for the last 20 years, the initial enthusiasm for research and development of DMSO-derived drugs and the clinical use of DMSO has not resurfaced. DMSO remains and continues to be a vital component of the most sophisticated modern therapeutic approach, such as stem cell transplantation, cell therapy, and immunotherapy for cancer and genetic disorders. One of the main reasons for the undesirable use of DMSO is economic reason. Since it is inexpensive and nonpatentable, pharmaceutical companies and medical doctors have no profit motive to pursue this therapeutic agent's translational research and practical applications.

There have been minimal ophthalmological studies using DMSO in humans even though it is not dangerous, inexpensive, therapeutically viable, and easy to use. DMSO has been heralded as a potent therapeutic of a wide range of therapeutic activities and has resulted in numerous published experimental and clinical studies. The literature suggests that DMSO has remarkable properties that could be useful in the therapy for wide-ranged ocular diseases. The robust anti-inflammatory, anti-angiogenic, and immunomodulating properties support the possible application of this agent for the treatment of inflammatory, autoimmune, and neovascular diseases of all compartments of the eyes as well as ocular traumas, burns, thrombotic, and infective disorders.

Along with the potential use for ocular diseases as an effective and safe therapeutic agent, DMSO is also well characterized as a superior pharmaceutical solvent and membrane penetration enhancement agent. In this context, DMSO is currently widely used in various pharmaceutical preparations to enhance the solubility of drugs in aqueous solutions. This increased solubility leads to the ability to deliver a higher concentration of medication to the target tissues. Thus, DMSO should be explored and utilized wider to develop more effective topical therapeutic products for ocular diseases.