|
 
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| REVIEW ARTICLE |
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| Year : 2016 | Volume
: 1
| Issue : 2 | Page : 69-72 |
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Challenges for application of realgar: A critical review
Vineet Sharma1, Narendra Kumar Singh1, Dev Nath Singh Gautam2
1 Department of Ayurvedic Pharmacy Research Laboratory, Rajiv Gandhi South Campus, Banaras Hindu University, Mirzapur, Uttar Pradesh, India
2 Department of Rasa Shastra, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| Date of Submission | 30-Aug-2016 |
| Date of Acceptance | 03-Oct-2016 |
| Date of Web Publication | 19-Dec-2016 |
Correspondence Address:
Dr. Dev Nath Singh Gautam
Department of Rasa Shastra, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2468-838X.196079
Realgar has been not only well-known poisons but also used as healing agent. Realgar has long been used in traditional medicines for different diseases; so far arsenic can be extremely toxic and carcinogenic. In Ayurvedic and Chinese traditional medicines arsenic usually comes from conscious addition for healing purposes, mostly in the form of mineral arsenicals with orpiment (As2S3), realgar (As4S4), and arsenic trioxide (As2O3). Pharmacological studies revealed that realgar is effective against in different cancer cell line. However, it has been critically limited clinical applications because of its many disadvantages, for example, low solubility in water, high toxicity, poor gastrointestinal absorption, and bioavailability. This review evaluates the toxicology, bioaccessibility, and pharmacology of the realgar used in Ayurvedic and Chinese traditional medicines. In recent times, numerous types of realgar nanoparticles (NPs) have been developed due to insolubility of realgar in water and different media. Most of the NPs of realgar possess the exclusive optical qualities of quantum dots. The pharmacological activities and bioavailability of realgar NPs are much more partial by their sizes, building realgar an exciting biomedical and pharmaceutical research applicant. Keywords: Bioaccessibility, cancer, nanoparticles, realgar
How to cite this article:
Sharma V, Singh NK, Gautam DN. Challenges for application of realgar: A critical review. BLDE Univ J Health Sci 2016;1:69-72 |
In recent years, Ayurvedic and Chinese traditional medicines are becoming progressively popular as substitute and supplementary medicine.[1],[2] Arsenic compounds had an extensive Janus-type interface with humanity. On one side, they have been widely utilized; however, on the other hand, their toxic properties have cause misery and numerous deaths. Therapeutic effects of arsenic substances have also been shown.[3] Traditionally, the medicinal use of arsenic has undergone four improvement stages: (1) Early on start at about 100 BC, (2) affluence during the 19th century, (3) turn down in the early 20th century, and (4) stimulation in current decades. At the present time, it has been well documented that both advantage and risk of arsenic are severely dependent on the individual chemical forms of arsenic in place of arsenic content alone.[4] Different health hazards, including skin lesions,[5],[6] hypertension,[7] cardiovascular diseases,[8],[9] cancers,[10] diabetes[11] as well as cognitive impairment[12] can induce by exposure of chronic arsenic. Humans are usually exposed to inorganic arsenic throughout air,[13] food[14] or water.[15] Contact to inorganic arsenic from arsenical drugs is also common in recent time[16],[17] and should not be disregarded. Since earliest period in India and China, arsenic has been used as a curative agent. Using a poison to battle against another poison, or a mixture of different poisons together to balance with each other is a common concept in Indian as well as Chinese medicine.[17] The challenge is that realgar has a long and notable history of pharmacological value. This perception will first assess the available database on realgar in traditional medicines and then effort to evaluate their hazard in light of their possible advantage.
| Use of Realgar in Traditional Medicines | |  |
Realgar has been studied as a drug for the treatment of cancer. More than 1500 years in India and China, it has been used as traditional medicine and also more than 90% tetra-arsenic tetra-sulfide containing in ore crystal realgar. However, it is solubility bioavailability and consequently is major disadvantage to using this mineral origin drug. It has been less poisonous than arsenic trioxide and poorly soluble in water. A clinical study has been done on acute promyelocytic leukemia (APL) patients; they demonstrate that realgar was extremely effective and safe for diagnosed and relapsed patients with APL after oral administration.[18] In Chinese, pharmacopeia processed realgar was found to be 98.56% (As = 78.0% w/w and S = 21.1% w/w) but when it was purified according to the Indian ancient text was found to be 86.46% (As = 62.22% w/w and S = 27.24% w/w).[19],[20],[21] in earliest Chinese and Indian medicine, it was usually applied as a poison to molest another poison or as a drug to treat different ailments.[22] In current time, realgar has been well well-known to be clinically effective for healing of different forms of cancer in vitro and in vivo.[23],[24] However, it has been many disadvantages, for example, low solubility in water, high toxicity, poor gastrointestinal absorption, and bioavailability so it has been critically limited clinical applications.[25],[26]
| Toxicity of Realgar | | |
Arsenical compounds are well-known as Poisons of the King since olden period; it produced many hazardous effect in the body like respiratory liver toxicity skin lesions as well as most importantly the carcinogenic prospective.[27],[28] Previous it has been mentioned that realgar must be micronized following the recommended procedures. Dosage of realgar is recommended to be 0.05-0.1 g/person in Chinese Pharmacopeia (Chinese Pharmacopeia, 1995 edition), as regards ten time lower than that of 0.3-1.0 g which was suggested 30 years ago (Chinese Pharmacopeia, 1963 edition) but in the Indian classical text 3.9-7.8 mg/person.[29] The oral LD50 of a single dose of realgar was found to be 3.2 g/kg body in mice. Whereas oral LD50 of single dose of arsenic trioxide was found to be 0.033-0.039 g/kg which are about 100 time higher than realgar.[30] Using mice of realgar in vivo acute and chronic toxicity studies was done on two formulations which are mentioned in traditional Chinese medicine (An Gong Niu Huang Wan and Liu Shen Wan) in which realgar was found to be 10% and 13%, respectively.[31],[32] In this study, sodium arsenite and arsenate is used as positive control; result suggested that both formulations were significantly less toxic than positive control.
| Low Bioaccessibility and Its Improvement | | |
Realgar nanoparticles (NPs) dissolution test was performed by the novel wet milling method. Finding result suggested that NPs absorb in simulated gastric and intestinal fluids 10% more than raw realgar.[33] In cancer treatment, route and time of administration of continuing use of a drug are important factors that could affect patients compliance. After diagnose of APL patients, the adverse effects of realgar was found to be including mild skin disturbance, asymptomatic QTc prolongation, gastrointestinal discomfort, and transient elevation in liver enzyme levels.[18] In severity of many diseases, realgar toxicity profiles were found tolerable. The preliminary total on a daily basis dosage of realgar was equally divided into 4 doses before achieving the hematology complete diminution was 50 mg/kg b.w. in the clinical study through the 6-year treatment no severe persistent toxicity was observed in that period. Quick oral absorption of realgar was recommended, a daily dosage of 50 mg/kg b.w. with constant administration of realgar and also increased accumulation of arsenic in hair as well as little amount of arsenic absorbed from the intestinal tract each day by each patient. However, in this study, metabolites of realgar were not recognized in humans. The adverse effects of realgar were usually tolerable and reversible even though the dose- and time-dependent toxicity events of realgar-containing medicines have been reported rarely.[34] Long-term arsenic toxicity can be observed in fatty liver which is liver is a most important target organ of the body. In humans, after long-term use of realgar may reason of fatty liver, but no dysfunction and liver fibrosis were observed.[35] Niu Huang Jie Du Pian a Chinese traditional medicine after long-term use skin lesions, liver and kidney damage were caused.[36] Bioavailability and bioaccessibility of realgar are very poor. In another study, after administration of realgar only 0.6% of realgar was free into simulated gastric juice[37] and bioaccessibility of realgar was found to be 0.6% into the simulated gastric juice which is low as 0.6%, consistent with another finding.[38] After administration of Niu Huang Jie Du Pian a traditional Chinese medicine is used as a tablet in each tablet 7% ± 1% of arsenic contain in the form of realgar.[39] Taken these collectively explanation indicates that when realgar is applied therapeutically, the absorptive uptake transversely the gastrointestinal tract probable a potential problem. Above finding result possibly raises a question about the low bioavailability of realgar: the mild toxicity of realgar is due to the less bioavailability or its low toxic nature? In recently, different nanosized realgar particles were prepared to improve the bioavailability because of unprocessed realgar. To evaluate the untreated realgar powders available commercially; the slighter realgar particles did get better the bioavailability as manifested by total arsenic content has been an increase in the urinary excretion.[40],[41] However, the systemic pharmacokinetic study of nanosized realgar has not been achieved.
| Pharmacology | | |
After oral administration (150 mg/kg) of realgar for 5 weeks in experimental rats showed that just a small portion of arsenic was absorbed and reached the blood (45 mg/mL), lung (5.4 mg/g), spleen (5.2 mg/g), and liver (2.9 mg/g).[42] To conquer the low solubility and poor bioavailability, nanoparticles of realgar have been prepared by cryogrinding with polyvinylpyrrolidone and SDS, along with arsenic solubility can greatly be increased compared with untreated realgar powder. In vitro and in vivo study nanoparticles of realgar show significant increases in bioavailability. In experimental rats, it has been observed that at a dose of 50 mg/kg p.o., 70% nanoparticles and untreated realgar 25% increase in urinary improvement of arsenic.[40] After external treatment nanocrystallized realgar gives suitable therapeutic effects for the patients of skin cancer or skin metastasis by inhibiting A431 proliferation.[43]1 H-NMR spectra and pattern recognition analyses from realgar after intragastrical administration (1 g/kg body weight) treated animals showed that higher dose and long-term use of realgar produce toxicity.[44] By 3-(4, 5-dimethylthiazol-2-diphenyl-tetrazoliumbromide assay, nanoparticles of realgar could significantly restrain the proliferation of HL-60 cells in a dose-dependent manner and the IC50 value was 5.67 μM. These results recommended that such in the development of apoptotic induction membrane toxicity induced by realgar might participated a significant role and could be measured as one of fundamental mechanisms of the cytotoxicity of realgar.[45] By suppressing angiogenesis nanoparticles of realgar may provide a less toxic agent for anti-neoplasia.[46] Realgar is much less toxic than arsenite and arsenate.[32] The LC50 of realgar ranged from 250 to1500 μM, both cinnabar and realgar are much less toxic than well-known mercurial and arsenicals.[47] Effect of sizes is much more influenced NPs as well as its activities and bioavailability.[48] In vitro cytotoxic effects of NPs on human ovarian and cervical (HeLa) cancer cell lines were examined. IC50 values were found to be most sensitive cancer cell lines less than 1 μM after treatment with realgar. In vivo study suggested that a significant increase in urinary improvement of arsenic was observed in albino rats after a single oral administration of realgar particle suspension which is prepared by the cryogrinding method.[40] In vitro cytotoxic effects of realgar were performed on K562 and fresh chronic myelogenous leukemia (CML) mononuclear cells. Realgar significantly inhibits these cell lines. This finding result also recommended that realgar may be a useful agent for the treatment of CML.[49] Treatment with nanoparticles of realgar is considerably low cell viability compared with untreated realgar particles. These results recommended that nanoparticles of realgar are superior to untreated realgar particles for their cytotoxic as well as inhibition of cell proliferation and improved effects of oxidative stress, which may provide a possibility for its treatment in tumor therapy.[50] Processed realgar was evaluated for their antiproliferative activities using different cancer cell lines K-562, HL-60, ARH-77, and U-266. All the processed realgar exhibited antiproliferative activities with IC50 values ranging from 0.39 to 4.82 μg/mL against different cancer cell lines K-562, HL-60, ARH-77, and U-266.[25] Ardraka Shodhita Manahshila was evaluated for sedative-hypnotic activity in albino rats using spontaneous motor activity and diazepam-induced sleeping time model. Through the reduction of spontaneous motor activity and potentiating the diazepam-induced sleeping time Shodhita Manahshila shows sedative-hypnotic activity in albino rats.[51]
| Conclusion | | |
These outlooks discuss mineral realgar used in traditional medicines. The bioavailability of realgar is low; though, arsenolite is high. Pharmacologic facts show that the use of realgar in traditional medicines may be most wanted in some cases, but the therapeutic basis in the most case remains to be completely acceptable. Realgar is much less acutely cardiovascular toxic than arsenic trioxide. In current period, accumulative facts have suggested that realgar is a potent anticancer agent to treat malignant hematologic diseases; our information is still incomplete about who plays the most essential role. Is it the little amount of insoluble arsenic sulfide or soluble arsenic, or arsenic metabolites in the body? This plan can be achieved by increasing a sensitive and definite analytical technique for speciation of realgar. Nanoparticle size of realgar could potentially change its bioavailability, toxicity, and pharmacology profile positively or negatively, that demanding additional studies.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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