|Ahead of print publication
Therapeutic potential of Sameera Pannaga Rasa (an arsenical compound formulation): A Versatile Kupipakva rasayana
Vikas Kumar, Swapnil Y Chaudhari, Prashant Bedarkar, BJ Patgiri
Department of Rasa Shastra and Bhaishajya Kalpana, IPGT and RA, GAU, Jamnagar, Gujarat, India
|Date of Submission||11-Nov-2019|
|Date of Decision||12-Feb-2020|
|Date of Acceptance||22-Apr-2020|
Department of Rasa Shastra and Bhaishajya Kalpana, IPGT and RA, GAU, Jamnagar - 361 008, Gujarat
Source of Support: None, Conflict of Interest: None
Kupipakwa Rasayanas are unique, widely prescribed, and highly therapeutic pharmaceutical preparations in ayurvedic therapeutics prepared in Kachkupi (glass bottle). Sameera Pannaga Rasa (SPR) is one such an arsenical compound formulation first cited in Rasa Chandanshu classic. It contains Parada (Hg), Gandhaka (S), Somala (As2O3), Haratala (As2S3), and Manahshila (As2S2) as integral components. Much diversity was seen in Rasa classics regarding its ingredients and duration of heating required for its preparation. Considering this, many studies have been carried out at different centers of India. The aim of the present study was to compile such available research works and relevant information from different Rasa classics and published literature from different databases to provide brief information about pharmaceutical, analytical, pharmacological, and clinical studies. Screening of literature revealed that Manahshila is not an ingredient of SPR in Rasa Chandanshu but added in recent treatises such as Ayurveda Aushadhi Guna Dharma Shastra and Ayurvedic Formulary of India. Totally seven references are found pertaining preparation of Sameer Pannaga Rasa in ayurvedic classics. It is recommended in the management of Tamaka Shwasa (bronchial asthma), Sandhivata (osteoarthritis), Amavata (rheumatoid arthritis), neurological disorders, etc.
Keywords: Arsenic, Ayurveda, Kupipakva, Rasashastra, Sameera Pannaga Rasa
|How to cite this URL:|
Kumar V, Chaudhari SY, Bedarkar P, Patgiri B J. Therapeutic potential of Sameera Pannaga Rasa (an arsenical compound formulation): A Versatile Kupipakva rasayana. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2021 Feb 28]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=308718
| Introduction|| |
Ayurveda is one among widely practiced ancient medical system in Indian subcontinent since about 5000 years BC. It comprises utilization of drugs originated from natural resources including metals and minerals in the treatment or prevention of different disease conditions. These formulations are being therapeutically used successfully without any noticeable ill effects. As, these medicines are being used for over a long period, this is ultimate proof for their nontoxic beneficial effects. However, there are many concerns raised on safety aspects of ayurvedic formulations due to the mere presence of heavy metals in it., Few toxicity reports were published due to the administration of ayurvedic drugs, but toxicity may be noticed due to noncompliance of code of conduct of classical pharmaceutical and treatment procedures. Ayurvedic classics also provided cautionary measures in preparation and use of metals and minerals.
Arsenicals are a group of minerals comprising Haratala (arsenic trisulfide), Manahshila (arsenic disulfide), and Somala (arsenic trioxide) mentioned with wide range of therapeutics.
Sameera Pannaga Rasa (SPR) is one such arsenical compound formulation in the Ayurveda first mentioned in Rasa Chandanshu.
It is a Kupipakva preparation containing Shuddha Parada (processed mercury), Shuddha Gandhaka (processed sulfur), Shuddha Somala (processed arsenic oxide), Shuddha Haratala (processed arsenic trisulfide) and Shodhita Manahshila (processed arsenic disulfide) as integral ingredients. Different Rasa classics documented SPR with or without Manahshila. In Kupi, SPR is found on both sides, i.e., Galastha and Talastha. It has been used in a number of diseases with suitable Anupanas. Considering this diversity, different methods of preparations, and therapeutic efficacy of SPR, the current work is planned to compile relevant references regarding SPR from different Rasa classics and published literature from different databases to provide brief information about pharmaceutical, analytical, pharmacological, and clinical studies.
| Materials and Methods|| |
Relevant information of SPR through different Rasa classics and published literature are screened to compile brief information about its pharmaceutical, analytical, pharmacological, and clinical aspects.
| Preparation and Usage of Sameera Pannaga Rasa|| |
Screening of Rasa classics revealed that different pharmaceutical ingredients are used in the preparation of SPR. Manashila was not added in ancient texts, but in later period, it was an integral component in the SPR. References pertaining to ingredients and proportion of SPR are summarized in [Table 1]. Important information related to Bhavana, method of preparation, duration of heating and dose, etc., are provided in [Table 2]. Therapeutic indications available in Rasa classics are summarized in [Table 3].
|Table 2: Description of different preparation methods of Sameera Pannaga Ras in different texts|
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|Table 3: Indications of Sameera Pannaga Ras as described in classical texts|
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| Recent Researches|| |
Trial to develop standard manufacturing procedure of Sameer Pannaga Rasa with evaluation of its safety and efficacy in Tamaka Shwasa (bronchial asthma) was done in 2011. SPR was prepared with and without Manashila in Valuka Yantra and Electrical Muffle Furnace. Analytically, Galastha SPR prepared without Manashila is chemically HgS, whereas SPR with Manashila is HgS along with microlevel of As2O3. Talastha SPR without Manashila was some complex compound of arsenic which was not detected, whereas microlevel of As2O3 and elemental sulfur along with some other compound of arsenic was found in SPR with Manashila. No mortality and gross behavioral changes were observed in acute toxicity study with all the samples. Talastha SPR without Manashila has shown significant anti-inflammatory activity, anti-histamine, bronchodilatory, and antitussive activities in experimental animals. All the drugs were used clinically in 52 patients of Tamaka Shwasa. Talastha SPR without Manashila and Galastha SPR with Manashila has shown significant results in relieving signs and symptoms of Tamaka Shwasa.
| Published Researches|| |
Neuroprotective effects of Sameerpannag Ras Mixture (SPR, Pravala Pishti, and Guduchi Satva in ratio of 1:2:4) on the neurobehavioral dysfunction and associated neuroinflammation, induced by transient internal carotid artery occlusion (ICAO) in mice model, were evaluated in one study. Sameerpannag Ras Mixture was administered at the dose of 40 mg/kg body weight by oral gavages for 3 and 7 days, respectively, twice a day, after the induction of ICAO for 90 min followed by reperfusion. Sameerpannag Ras Mixture significantly reduced neurological deficit Score and improved the motor coordination at different time intervals post-ICAO. Standardized response mean (SRM) group showed marked improvement in the ischemia-induced neurobehavioral deficits by attenuating ischemia-induced neuroinflammatory response at both gene and protein levels.
| Osteoarthritis (Sandhivata)|| |
Fifteen patients having signs and symptoms of Sandhivata (osteoarthritis) were randomly selected for the clinical trial and administered with SPR 60 mg twice a day with Nagavallidala (Piper betel Linn.) or warm water. The efficacy of drug was evaluated on subjective parameters such as Visual Analog Scale for pain, tenderness, and edema. Therapy showed a maximum effect on edema with relief percentage of 66.66%, followed by morning stiffness 57.14%, restriction of flexion 56.25%, and Visual Analog Scale of pain improvement of 51.28% with statistically significant P < 0.001. Analysis of the data generated during the study showed that all the patients had better quality of life after taking the medicine.
| Rheumatoid Arthritis (Amavata)|| |
A randomized single-blind clinical trial was conducted on 80 cases of Amavata (rheumatoid arthritis) who were selected and given SPR and Vardhmana pippali ksheerapaka in which all cases, whichever completed the treatment, got highly significant (P < 0.001) improvement in their signs and symptoms with least adverse effects and toxicity.
A case of Bell's palsy was successfully treated with SPR with some adjuvant medicines. Sameer Pannaga Rasa has also shown good results in patients with hemiplegia (Pakshawadha). It acts as a stimulant (Uttejaka) upon nerve centers of the central nervous system.
| Discussion|| |
In the process of Kupipakva preparation, many alchemical principles work. Mercury and sulfur are the elements, mostly used in preparation of various Kupipakva preparations due to their high chemical reactivity. Chemistry: SPR is identical with red sulfide of mercury and contains arsenic in combination with mercuric sulfide., In many processes, mercury has been used to form an intermediate product, which could increase the surface reactivity of the metal or mineral with other chemicals. Sulfur facilitates the formation of respective sulfide. In these cases, mercury and sulfur have acted as promoters for the final chemical reaction. Most of the chemical reactions occurring in Kupipakwa Rasayana preparations are heterogeneous kinetics, i.e., reaction between solid-gas or solid-liquid, and it is known that the rate of such reactions is proportional to the interfacial area. During such reactions, first of all, a surface layer of the chemical is readily formed (chemical rate controlled), and afterward, the rate of reaction is controlled and becomes slow. The ancient ayurvedic scholars were conscious of these facts and overcame this problem first by increasing the primary surface area and second by removing the chemical layer formed on the metal particles and thus exposing new metallic surface. These conditions were achieved by intermittent trituration. In solid-solid reaction, trituration increased the chemical rate kinetics. Sublimation is the chemical process involved in most of the Kupipakwa Rasayana preparation, in which a solid directly converts into vapor and condensing the vapor into solid state having the same composition. It must be remembered that all the Kupipakwa Rasayanas are not pure chemical compounds, rather cocktail of many trace elements. Those make the product therapeutically more potent and less toxic. The drugs used for levigation (Bhavana Dravyas) may add trace elements to the final product.
The concentration of elements varied in Galastha and Talastha SPR. Mercury is found less in Talastha SPR than Galastha, while sulfur and arsenic are more in Talastha than Galastha SPR. X-ray diffraction revealed that Galastha preparation is HgS and As2O3, while in Talastha, cocktail of many elements including sulfur, As2O3, and other unrecognizable compounds. LD50 in all the animal groups has been found as slightly toxic drug (0.5–5 g) which can be considered in humans is 250 g as per the Paget and Barnes table which is more than therapeutic dose (60 mg/kg) ranging from even more than 400 times. As the main ingredients of SPR are arsenic and mercury, so it is predictable in maximum tolerable dose or LD50 dose. Inflammation includes three phases, namely acute, subacute, and chronic. In acute inflammation, due to change in small blood vessels, fluid and granulocytic cells accumulate at the site of injury. This reaction often triggers a systemic response such as fever, leukocytosis, protein catabolism, and altered hepatic synthesis of acute-phase proteins such as C-reactive protein. Airway inflammation is one of the distinct features observed in asthma and is one of the most important contributors to discomfort of patients. SPR was evaluated against carrageenan paw edema to determine anti-inflammatory activity, especially against acute inflammation. The development of carrageenan-induced edema is biphasic; the first phase is attributed to the release of histamine, 5-hydroxytryptamine, and kinins, while the second phase is release of prostaglandins.
Talastha SPR has shown better inhibition which was almost equal to that of standard anti-inflammatory drug phenylbutazone. The observed effect may be due to inhibition of phlogistic mediators, antagonizing their interaction with their respective receptors, or it may be due to general mechanism like increasing the membrane stability in the cell.
SPR Ubhayastha reduced the number of cough reflexes more significantly, which is almost nearer to the effect of central cough suppressants – Recodex in sulfur dioxide gas-induced coughing in mice. Talastha SPR without Manashila (SPRT) has produced moderate anti-spasmodic activity against histamine-induced contraction in guinea-pig ileum. In bronchodilatory activity among the four different samples, Ubhayastha SPR with Manashila (SPRMU) produced good antagonism. The next best results were with the Ubhayastha SPR without Manashila (SPRU) – this clearly shows that addition of Manashila increases the toxicity potential without imparting any significant therapeutic activity. The Manahshila-containing formulations Talastha SPR with Manashila (SPRMT) and SPRMU were more toxic and less therapeutically active in comparison to SPR without Manahshila; hence, they should be preferred, especially the Talastha sample. In this study, it was observed that SRM significantly attenuated the interleukin (IL)-6 expression, the molecule reported to be a potent mediator of inflammation, on day 3 itself post-ICAO. However, on day 7 post-ICAO, SRM-treated mice showed a significant attenuation in tumor necrosis factor-alpha and p65 expression too at both gene and protein levels.
A double-blind randomized clinical trial was performed in 52 patients with classical signs and symptoms of Tamaka Shwasa. The patients were given SPR in dose of 30 mg twice a day with Nagavallidala as Sahapana for 28 days with follow-up of 14 days. The overall results were significant to highly significant in all cardinal symptoms and significant results on objective parameters.
Considering the aggravated Vata and depleted Kapha, use of Vataghna, Ushna, Vatanulomaka drugs are the first line of treatment in Sandhigata Vata. However, in Vegavastha, drugs exhibiting quick control over vitiated Vata and depleted Kapha are required. Vagbhata emphasizes that a drug acts by its Rasa, Vipaka, Virya, Guna, and Prabhava. Normally, the effect of Rasa is least and Prabhava is most dominant, provided all are present in equal proportions. The dynamics of Sameer Pannaga Rasa is helpful in breaking the pathogenesis of Sandhigata Vata. In osteoarthritis, one of the main factors is IL-1, which is a potent pro-inflammatory cytokine that, in vitro, is capable of inducing chondrocytes and synovial cells to synthesize MMPs. Stent-based As2O3 delivery effectively inhibited expression of inflammation-associated proteins such as monocyte chemoattractant protein-1 and IL-6, in agreement with the Western blotting results. This shows the anti-inflammatory and anti-IL effect of arsenic compounds, which helps in breaking the pathology of osteoarthritis. In Sameer Pannaga Rasa, juice of Tulsi leaves (Ocimum sanctum) is used as Bhavana Dravya. Some studies have proved that extract of Ocimum sanctum inhibits the arsenic-induced toxicity. Thus, Ocimum may help in nullifying possible adverse drug reactions. In the study, Nagavallidala (Piper betel) was taken as Sahapana. Some studies showed that it contains active analgesic principle that acts as both centrally and peripherally. Hence, the extract can be used to manage acute as well as chronic pain.
Lower motor neuron facial palsy occurs due to various reasons and presents with facial weakness, sagging down of face, and disappearance of face creases. The idiopathic facial palsy is called Bell's palsy. It is caused due to the vitiation of Vata Dosha, which results in symptoms such as deformity unilateral of face, difficulty in speech and laughing, tremors of the head, difficulty in movements of eyes, loosening of teeth, loss of voice, loss of hearing, loss of touch sensation of the face, or one half of the body. While spitting, it goes to one side, drooping of the eyelid of one side of the face, pain over the head and neck region, or one half of the body or of the face. As the disease is caused purely by Vata, which is cold, dry, rough, etc., in property, the medicated sudations which are unctuous, hot, etc., (the opposite qualities for Vata) are beneficial. Drugs such as SPR are known to mitigate Vata.
| Conclusion|| |
SPR is a Kupipakva arsenical mercurial preparation which has been prepared having difference in composition and in temperature periods as per different Rasacharyas. It has been indicated in various Vata and Kaphaja ailments, especially Tamaka Shwasa, Amavata, and neurological disorders, and also proved in different studies. SPR has been proved as a potent anti-inflammatory medicine. In spite of arsenical-mercurial preparation, SPR is proved safe medicine on account of different toxicological studies and having large LD50.
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[Table 1], [Table 2], [Table 3]