Researchers at Texas A&M University have produced a therapeutic derived from turmeric, a spice long-praised for its natural anti-inflammatory properties, that shows promise in decreasing ocular inflammation in dogs suffering from uveitis, an inflammation of the eye that leads to pain and reduced vision.
Uveitis – a common condition in dogs, humans, and other species – can have many causes, often occurring secondary to infectious diseases cancer, and autoimmune diseases; it also is found in patients with longstanding cataracts and after operations correcting cataracts.
“Uncontrolled inflammation inside the eye, also known as uveitis, is a leading cause of complications after cataract surgery in dogs.
The management of postoperative ocular inflammation is a major challenge observed in both human and veterinary ophthalmology,” said Dr. Erin Scott, an assistant professor at the Texas A&M University College of Veterinary Medicine & Biomedical Sciences.
In a recent paper published in Science Advances, Scott and her colleagues at the Texas A&M University College of Pharmacy tested the anti-inflammatory properties of curcumin, a compound found in turmeric, and discovered that when processed to a special nanoparticle formulation to boost absorption, the natural compound is safe and effective at managing uveitis without any known side effects.
Oral medications currently used to treat uveitis must be adequately absorbed into the blood stream for their medicinal effects to be effective.
This requires the medication to successfully pass through the intestinal barrier – the physical barrier between the gut and the rest of the body via the circulatory system – which limits the absorption of many drugs.
Drug delivery to the eye presents additional challenges because of the blood-ocular barrier – the physical barrier between blood vessels and tissues of the eye – which tightly controls what substances can pass into the eye.
Therefore, researchers must find ways to bypass such barriers to improve drug availability within the body.
Scott and her colleagues’ research implemented a novel formulation of curcumin that improved transport of the substance across both intestinal and ocular barriers.
By adding nanoparticle molecules that interact with receptors on a ubiquitous transmembrane carrier protein, known as the transferrin receptor, curcumin is able to hitch a ride across crucial barriers, improving absorption of the substance and reducing ocular inflammation.
Curcumin is especially attractive as a candidate for management of uveitis because it has no known side effects.
“Current treatments include a combination of systemic and topical anti-inflammatory medications, either in the form of steroids or non-steroidal anti-inflammatory drugs (NSAIDs),” Scott said.
“While both these medications are effective in the treatment of uveitis, they can cause unwanted side effects, such as vomiting, diarrhea, stomach ulcers, negatively impact kidney and liver function, and increase glucose levels in diabetic patients.”
Scott and her colleagues hope to start a clinical trial in the Texas A&M Veterinary Medical Teaching Hospital using this new medication in the near future and are optimistic that the utility of their findings may benefit populations beyond dogs.
“This medication may translate to the treatment of cataracts and uveitis in humans,” she said. “By studying animal patients with naturally occurring eye diseases, our findings may accelerate the development of medications to benefit both animals and humans.”
Curcumin is a bright yellow chemical compound isolated from Curcuma longa L. (turmeric) plants (Zingiberaceae) [1]. Turmeric has been historically used in herbalism as a traditional medical remedy for cutaneous and gastrointestinal inflammation, weight control, and poor digestion [2,3,4].
Recently, conventional medicine is directing a lot of effort towards identifying novel, low-cost, safe molecules that may be used in the treatment of inflammatory, neoplastic, and infectious diseases. Numerous in vitro and in vivo studies have examined curcumin’s anti-inflammatory, anticancer, and antimicrobial properties, both individually and combined with traditional treatments.
This paper aims to provide an overview on the current knowledge regarding curcumin’s effects on skin conditions alongside with its bioavailability and safety profile through the analysis of the most relevant studies published to date, providing suggestions for further research (Figure 1).
Molecular docking studies describing the interaction of curcumin with molecular targets involved in the development of skin disorders are nowadays not available in literature.
We therefore complemented our data with original results, obtained through molecular docking analysis, regarding curcumin’s binding mode and interaction towards six major enzymatic targets, indicated in this review as responsible for several dermatological conditions.
Bioavailability of Curcumin
According to Nutraceutica Bioavailability Classification Scheme (NuBACS), curcumin shows poor bioaccessibility, due to its low solubility in water and low stability [5].
Curcumin also undergoes extensive first-pass metabolism through its glucuronidation and sulfation, with the production of metabolites that have shown to have significant lower biological activities compared to parent curcumin and that are rapidly eliminated [6].
A curcumin-converting enzyme named “NADPH-dependent curcumin/dihydrocurcumin reductase” (CurA) has been purified from Escherichia Coli, shedding new light on the role of human intestinal microorganisms in the mechanism of curcumin metabolism in vivo [7].
Preclinical and clinical studies assessed that curcumin is poorly absorbed following oral administration. In rats, only 60% of the dose of curcumin administered orally was adsorbed, with negligible quantities (<20 μg/tissue) detected in liver and kidney from 15 min up to 24 h after administration albeit 38% of the initial dose being detected in the large intestine and patients taking curcumin orally show plasmatic concentration of the compound at nanomolar levels, with limited biological effects [8,9,10,11,12].
To overcome this limitation, combination with adjuvant substances such as piperine, encapsulation with polylactic-co-glycolic acid (PLGA) and cyclodextrin (CD), or formulation in liposome, micelles, nanoparticles, nanomicellizing solid dispersion based on rebaudioside A and dispersion with colloidal submicron-particles have been recently proposed, showing to enhance curcumin bioavailability and therapeutic potential [6,13,14,15,16,17,18].
We present some significant results induced by curcumin administered in several formulations below in this review (Table 1). Ongoing clinical trials investigating the topical or systemic use of curcumin in skin conditions are listed in Table 2.
Table 1
Formulations of curcumin for oral, topical, or intravenous use investigated in preclinical and clinical studies for enhanced bioavailability listed in this review.
| Route of Administration | Formulation | Reference |
|---|---|---|
| Oral | Curcumin-piperine nanoparticles | [6] |
| Curcumin-loaded PLGA nanoparticles | [13] | |
| CE-complexed curcumin | [14] | |
| Curcumin-loaded self-nanomicellizing solid dispersion based on RA (RA-Cur) | [15] | |
| Colloidal Submicron-Particle Curcumin (Theracurmin®) | [16] | |
| Curcumin-loaded liposomes | [6,17] | |
| Curcumin micelles | [17,18] | |
| Lecithin-based formulation (Meriva®) | [19] | |
| Curcumin nanocapsules | [20] | |
| Topical | Curcumin-loaded chitosan-alginate sponges | [21] |
| Curcumin-loaded oleic acid-based polymeric bandages | [22] | |
| Curcumin-loaded alginate foams | [23] | |
| Curcumin-incorporated collagen films | [24] | |
| Hydrogel system containing curcumin micelles | [25] | |
| Curcumin nano-emulsion | [26] | |
| Curcumin-β-Cyclodextrin nanoparticles | [27] | |
| Chrysin-curcumin-loaded nanofibers | [28] | |
| Curcumin-loaded transdermal patches | [29] | |
| Curcumin nanoparticles | [30,31,32] | |
| Curcumin-loaded-liposomes | [30,33,34] | |
| Curcumin-loaded chitosan nanoparticles impregnated into collagen-alginate scaffolds | [35] | |
| Intravenous | Curcumin-loaded solid lipid nanoparticles | [36] |
| Curcumin-loaded liposomes | [37,38,39] |
Table 2
Ongoing clinical trials with curcumin in skin disorders.
| Major Outcome Measures | Pain Intensity Measured by Visual Analog Scale (VAS) | Change in Erythema 1 Day After UV Exposure Change in Erythema 2 Days After UV Exposure Change in Erythema 1 Day After UV Exposure |
|---|---|---|
| Study design | Randomized, double-blind, Phase 1 clinical trial | Randomized, double-blind |
| Intervention model | Parallel assignment | Parallel assignment |
| Topical or ingested curcumin containing product | Topical | Ingested |
| Intervention/treatment | Drug: Triamcinolone Drug: Turmeric paste | Dietary supplement: Crucera-SGSDietary Supplement: Meriva 500-SF |
| ClinicalTrials.gov Identifier | NCT03877679 | NCT03289832 |
| Study | The Effect of Topical Curcumin Versus Topical Corticosteroid on Management of Oral Lichen Planus Patients | Effect of Orally Delivered Phytochemicals on Aging and Inflammation in the Skin |
| Condition or disease | Oral lichen planus | UV-induced skin erythema |
Intravenous use of curcumin has been proposed in order to improve curcumin bioavailability and increase its efficacy.
Serum curcumin levels after intravenous administration were significantly higher than the one observed after oral administration in rats [36,40]. In animal models, curcumin infusion showed significant anticancer effects without inducing toxicity [6,41].
A randomized, placebo-controlled double-blind phase I dose escalation study investigated the pharmacokinetics, safety, and tolerability of short-term intravenous administration of liposomal curcumin in healthy subjects with good results in terms of bioavailability and safety [37].
Pharmacokinetics of curcumin infusion seems to depend on co-medication and health status, as highlighted by a recent clinical study [38]. However, these interesting albeit limited data must be confirmed by larger clinical trials with longer follow-up in order to recommend this route of administration.
Curcumin showed a good accessibility and bioactivity when administered topically, especially when incorporated in novel formulations such as chitosan-alginate sponges, polymeric bandages, alginate foams, collagen films, nano-emulsion, hydrogel, and β-cyclodextrin-curcumin nanoparticle complex, making curcumin eligible as a therapeutic agent for the topical treatment of skin conditions [21,22,23,24,25,26,27,42].
Investigating the possible interactions between curcumin and other chemicals commonly used in topical skin treatments may provide useful insights for the development of new effective combination preparations, tailored for different conditions.
Curcumin’s Safety Profile
Curcumin is recognized as a safe compound by Food and Drug Administration (FDA). Numerous preclinical and clinical studies assessed the safety of this compound [43,44,45]. The maximum recommended dose varies, ranging from a maximum daily intake of 3 mg/kg to 4–10 g [46].
In a clinical study, curcumin was not detected in the serum of healthy subjects administered up to 8000 mg/day, and only low levels were detected in two subjects administered 10,000 or 12,000 mg. No harmful effect was observed in any of the subjects, regarding a daily intake of 12,000 mg as safe in healthy individuals [47].
A good safety profile of curcumin was observed also in patients with cardiovascular risk factors and patients affected by high risk conditions or pre-malignant lesions of internal organs taking a dose of curcumin ranging from 500 to 8000 mg/day for 3 months [43,48].
This safety has been observed also in patients with advanced colorectal cancer taking a dose of curcumin ranging from 36 to 180 mg/day for up to 4 months, in breast cancer patients undergoing radiotherapy while taking up to 6000 mg/day of curcumin, and advanced pancreatic cancer patients taking 8000 mg/day of curcumin for 2 months [49,50,51].
Other studies in both healthy subjects and patients affected by several conditions such as advanced colorectal cancer, cholangitis and ulcerative colitis reported mild and manageable gastrointestinal symptoms with a daily intake of up to 8000 mg of curcumin [52,53,54,55].
Alongside these data, a minority of patients affected by primary sclerosing cholangitis taking up to 1400 mg/day of curcumin reported only mild symptoms such as headache or nausea [56]. Controversially, intractable abdominal pain after assumption of curcumin at a dose of 8000 mg/day has also been reported in patients affected by advanced pancreatic cancer taking gemcitabine [57].
It may be speculated whether curcumin-induced COX inhibition and the subsequent inhibition of prostaglandin (PG) synthesis (see below) plays a role in the development of gastrointestinal side effects in patients suffering other gastrointestinal conditions. However, no sound explanation is available to date.
Short-term intravenous dosing of liposomal curcumin has been indicated as safe up to a dose of 120 mg/m in a clinical trial on healthy subjects, whereas in a dose escalation study on metastatic cancer patients a dose of 300 mg/m2 over 6 h appeared to be the maximum tolerated dosage [37,39].
However, changes in red blood cell morphology may represent a dose limiting sign of toxicity, and one case of hemolysis and one death associated with intravenous curcumin preparation were reported, suggesting the need for further data regarding the safety and recommended dosages of curcumin administered intravenously [36,39,58].
It is worth mentioning that the majority of studies assessing curcumin safety profile has been conducted for short periods of time. No sound evidence is available to date regarding the consequences of long-term use of this compound. Although doses recommended for over-the-counter curcumin are generally lower than the ones in clinical studies mentioned above, supplements containing this compound are widely available to the general public and are increasingly popular.
In this regard, recent reports of liver diseases related to curcumin assumption drove the medical community’s attention to the possible liver toxicity of this molecule [59].
The exact role of curcumin in the development of these conditions still has to be elucidated, and a possible contamination of supplements with lead has been postulated. Until further data is available, surveillance is needed, especially in long-term use, in the over-the-counter context and in patients affected by liver conditions.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770633/
More information: R. Ganugula et al, Systemic anti-inflammatory therapy aided by double-headed nanoparticles in a canine model of acute intraocular inflammation, Science Advances (2020). DOI: 10.1126/sciadv.abb7878
