INTRODUCTION:

Siddha system of medicine is an ancient system of medicine native to Tamilnadu. The so called Siddhars by their intuitive power and spiritual power found curative medicines to a number of ailments afflicting the community. Their medicines are still in use and they are being subjected to pharmacovigilance. WHO defines Pharmacovigilance as the science of detection, assessment, understanding and prevention of adverse drug effects or any other possible drug related problems^1,2.

Pharmacovigilance have gained importance in recent years. In their time, the Siddhars might have also noticed the adverse drug reactions when they first started administering the Siddha medicines. They therefore suggested antidotes in such cases³. Siddha text books are replete with such details. Hence the belief of the lay man that all the Siddha drugs are without side effects is unfounded. The pharmacovigilance helps the medical practitioners to make safe use of the drugs. For instance, the latex of Exacoecaria agallocha (Thillaipaal) a medicinal plant, when smelt causes angio neurotic oedema. Sulphur, a mineral drug is not a highly toxic substance, but if improperly purified and irregularly prepared and consumed over a long period would cause toxic effects.

The review paper by Manjunath Ajanal et al have discussed about the adverse drug reactions of AYUSH drugs⁴. The qualitative, quantitave drug over dose results in adverse drug reactions. The results of one of the previous research studies reveal that over usage of Commiphora mukul, curd, Piper longum, salt, alkalis and administration of single flavoured items resulted in disorders like impotency, dryness of mouth, refractive error, lean, fainting and diarrhea^5,6. A type A augmented drug reaction was reported by Hasmuc R Jadav et al in his case report ⁷.The previous research article by Gunvor S Fosnes et al has concluded that constipation and diarrhea ae the common adverse reactions⁸. The challenges faced by Siddha drugs in pharmacovigilance was discussed by Meena et al in 2013.

Karpoora Chindhamani Mathirai, a Siddha herbo- mineral formulation is sourced from the text Anuboga Vaidhya Navaneedham Part 4. KCM is indicated for vatha diseases, mudakkuvayu (Rheumatoid arthritis), all types of fever and arthritis. Uthiravatha Suronitham, which can be equated to Rheumatoid arthritis in modern science is one of the 80 vatha diseases mentioned by sage Yugi. This paper analyses the Karpoora Chindhamani Mathirai vis- a- vis pharmacovigilance. This paper will help the young researchers to uncover the unnoticed dose related adverse reactions of many drugs. The objectives of the study are:

1) To find out the therapeutic efficacy of KCM on Uthiravatha Suronitham (Rheumatoid arthritis).

2) To study the safety aspects of KCM.

MATERIALS AND METHODS:

The study is carried out in National Institute of Siddha (NIS), Tambaram sanatorium, Chennai, India in 2009.

With due permission, 40 patients of normal built with body weight ranging from 50-75 and age between 18 to 60 years with Uthiravatha Suronitham disease (20 inpatients and 20 out patients) from the Department of Sirappu Maruthuvam, National Institute of Siddha were included in the open clinical trial. They were prescribed KCM – 60mg twice daily for 40 days. The challenges faced were reported to the research committee of NIS. The ingredients of the trial drug is listed in table1.

Table 1: Ingredients of Karpoora Chindhamani Mathirai:

S.No	Ingredient	Quantity
	Purified Hydrargyrum subchloride -Rasakarpooram(Calomel)	17 ½ G
	Purified Myristica fragrans,Houtt (Nutmeg) – Sathikai	17½G
	Purified Croton tiglium seeds - Naervalam (Croton seeds)	35G
	Aloe vera juice - Katralai	Required quantity.
	Acacia indica (gum acacia) powder - Karuvael pisin	3 ½ G.

Purification process of raw drugs and toxicity:

All raw drugs possess two extreme qualities like therapeutic effect and toxic effect. The word “Suddhi” means “to get rid of impurities”. Suddhi is a unique process of detoxification ie, the raw drugs lose their undesirable toxic effects. In Siddha system, all the raw drugs will be purified individually as mentioned in the literatures before including in medicine preparation. The process of purification of drugs are variable according to the medicine that is to be prepared. Purification process of raw drugs aims at purification and concentration of the raw drugs. The processes like cleaning, frying, soaking and grinding with herbal juices until impurities are removed are generally involved. Purification process have a direct implication on the adverse drug reactions.

Step 1: Purification of raw drugs:

Purification of Calomel⁹:

The poultice made of betel leaf (Piper betel) and pepper (Piper nigrum) each 8.7 grams is taken in an earthen pot and dissolved in 1.3 lit of water. Calomel 35gms is tied with a cloth and immersed in the liquid from the cross bar and heated. When the water is reduced to ¾ of its volume calomel is taken out, washed with water and dried to get it in purified form.

Purification of Nutmeg:

The outer cover is removed and then fried in ghee.

Purification of Croton seeds¹⁰:

Croton-35 G, Indian gooseberry fruit juice, Bringaraja leaf juice, Cow dung each 85G is taken in a vessel and its mouth is closed with a cloth. Croton seeds are placed over the cloth. The vessel is heated for 3 hours (1samam).Then its tip is removed and the seeds are dried in shade. This procedure is again repeated twice. Then it is fried in cow’s ghee

Purification of Aloe gel:

It is soaked in water for three days and then used.

Step 2: Method of preparation¹¹:

Method:

Croton seeds and Nutmeg are added to powdered Rasa karpooram and then grounded. Then Aloe vera juice is added to the above mixture in small quantities as and when required. This mixture is grounded for 6 hours. Finally powder of gum acacia is added and grounded. This paste is rolled into pills of 130 mg weight and dried in shade. These dried pills are preserved in a clean wide mouthed glass bottle.

Dosage:

1 tablet (twice a day after food).

Adjuvant:

Ghee.

The brand used was Aavin ghee purchased from authorized Aavin dealers.

Indications:

This medicine is indicated for all types of fever, pain, arthritis and rheumatism

· Initial dose of 130 mg in morning and night after food was given for 5 patients. 3 patients (60% of cases) had diarrhea alone. The remaining 2 patients (40% of cases) had diarrhea associated with nausea and vomiting. The dose related adverse reaction was reported to the research committee of National Institute of Siddha. The medicine was discontinued and Acorus calamus with honey was given. After giving the antidote the diarrhea, vomiting and nausea was reduced^{12,13 .}This was the dechallenging done. So, the dose was adjusted as 60 mg twice a day, i.e, morning and night after food for 40 days. This dose was given for 40 patients. Out of 40 patients diarrhea , nausea and vomiting was reported as follows

· Diarrhea- 10 patients

· Nausea-4 (25% of cases) vomiting-5 patients (12.5% of cases)

RESULTS AND DISCUSSION:

The drug Karpoora Chindhamani Mathirai administered to Uthiravatha Suronitham patients resulted in reduction of joint swelling, pain and stiffness. Vomiting and nausea are the adverse drug reactions noted which were reduced on reducing the drug dosage. This paper discusses only the ADR reported of the internal medicne. The therapeutic efficacy in Uthiravatha Suronitham is not dealt in detail here. A search was conducted from classical books of Siddha and electronic data base such as Google scholar, Pubmed and Pubmed Central on the following search terms ‘ Pharmacovigilance, adverse drug reaction of AYUSH drugs, Kapoora Chindhamani Mathirai, etc’. In a prospective survey study for 1 year in an Ayurvedic hospital, 54 adverse drug reactions were reported. The overall incidence of ADR in the patient population was 1.14%. Out of this 25.00% was related to the herbal formulations and 11.53% were of mineral or herbo-mineral formulations. The commonly affected organ systems were gastrointestinal system 24 (46.15%) and skin 15 (28.84%)¹⁴.

Regarding the pharmacovigilance perspective in pilot trial, out of 5 patients all had diarrhea. Two patients (40%) had nausea and vomiting along with diarrhea, 3 (60%) of them had only diarrhea. The medicine was stopped and the dosage reduced in keeping with the patient’s condition. The symptoms reported might be due to Croton tiglium seeds. The adjusted dose in 40 patients ended up with diarrhea in 10 patients (25%), nausea in 4 (10%) and vomiting in 5 (12.5%) patients. The purgative action of croton seeds is supported by the work of N.R.Pillai¹⁵. Saputera et al 2006 has also confirmed the presence of alkaloids, flavonoids, saponins and 8 fatty acids were identified by GS-MS analysis. The purgative action of Croton tiglium is dose dependent. Hence properly purified croton seeds in specified dose can be used therapeutically. The Acorus calamus ash is used to reduce the croton seeds toxicity. The reactions observed in the current study can be compared with the type of augmented adverse reactions that are related to the main pharmacological effect of the drug (Type A). Previously a type A augmented drug reaction was reported by Hasmuc R Jadav et al in his case report. The drug Karpoora Chindhamani Mathirai is proved to be non-toxic up to the dose of 2000mg/kg/po in acute toxicity and safe up to the dose of 12.5mg/kg/po in repeated oral toxicity¹⁶. The drug KCM did not cause diarrhea or vomiting in preclinical studies, but clinically when the drug is administered to patients it resulted in diarrhea and vomiting as discussed above.

The previous studies by the author Meena et al have proven that the drug is a very effective analgesic, anti-inflammatory and antipyretic agent. This gives an evidence based support for the use of the drug KCM for Uthiravatha Suronitham and other arthritis and fever. The physicochemical characterization of this drug was carried out. It has been stated that the FTIR analysis demonstrated the existence of nitro compounds, carboxylic acids, alcoholic and phenolic compounds as the key components. The quantitative ICP analyses revealed the presence of heavy metals like Arsenic, Cadmium and Lead in KCM. They were below the detection limit and, sodium, potassium, Calcium, Phosphorous and Sulphur were in essential nutritional concentration. Thanigaivelan et al have reported that the quantity of Mercury was in above 100 ppm (above the permissible limit laid by WHO). But he also made a mention that in the clinical practice, KCM does not produce any toxic manifestations on prescribed dose and duration as per Siddha text. While, continuous administration of KCM beyond 40 days and at high dosage beyond 130 mg pill per time may produce adverse reactions due to ingestion of higher concentration of Hg¹⁷. This is reflected in the present study also. The drug safety is very important and is clearly explained by the Siddhars in their texts. The author Abdulla Sayubu has given a note that the dose of the medicine has to be adjusted according to the disease and body condition of the patients¹⁸. Hence we can say the dose mentioned as 130 mg caused ADR in 60% cases and the same reduced when the dose is adjusted. The findings support the literature evidence. In 2006 a similar type A adverse drug reactions with reference to Aconitum ferox and latex Calotropis gigantea are reported by Gangier J et al. Abdominal pain, vomiting and diarhoea are the toxic manifestations with these herbs¹⁹. The results of the present study is an added data to the previous studies on Karpoora Chindhamani Mathirai. So, this paper adds to the knowledge that there is some degree of risk in using Karpoora Chindhamani Mathirai if the instructions given in classics are not strictly adhered. Type A augmented drug reaction was the expected ADR in the use of KCM.

CONCLUSION:

Adverse drug reactions are the vital part of drug pharmacology. ADRs are anticipated to occur with administration of any drug. Formulations from Siddha system of medicines are not exempted from this. The ADR reported cannot to be attributed to a single raw drug of KCM as this is a compound formulation. As mentioned in classics, reducing the dose of the trial drug by conducting pilot trial have however reduced the percentage of adverse drug reaction in the clinical trial. A trial for longer duration is necessary to study the type a – acute/ augmented-dose related ADR in near future.

CONFLICT OF INTEREST:

The concept was presented as an e-poster in a conference in Sri Ramachandra University. The toxicity and pharmacological activity of the drug Karpoora Chinthamani Mathirai is already published. A single case study on Uthiravatha Suronitham with Karpoora Chinthamani Mathirai and an external oil published.

ACKNOWLEDGEMENTS:

The authors express their sincere thanks to the Director, National Institute of Siddha.

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Received on 21.11.2017 Modified on 20.12.2017

Research J. Pharm. and Tech 2018; 11(5):1877-1880.

DOI: 10.5958/0974-360X.2018.00348.7