
Title of the research project:
Urolithiasis is still a major challenge to the Physicians, as the prevalence is increasing day by day and the relapse of the ailment is quiet high. Though the surgical treatment is considered to be ample, it only evacuates the stones and relapse cannot be prevented since the complete correction of factors influencing the formation of renal calculi, has not yet been possible in the conventional therapeutics. It is in the thirst area of medical research and also marked lacunae in this context to identify potential regime for preventing the relapse of calculi formation. A drug which can disintegrate or dissolve the stone with the potency of preventing the relapse is the need of this hour.
Urolithiasis is more prevalent in tropical countries.
Urolithiasis affects 5- 15% of population Worldwide (Moe,2006).The recurrence rates are close to 50 % (Sutherland JW,1985).The incidence is higher in developing countries including India. It has been hypothesized that the main source of dietary proteins being cereals, unlike meat in western countries, is an important etiological factor (Polinsky et al).The northern and north-western regions of India can be described as an endemic stone forming belt due to a dietary pattern rich in cereals and pulses (Teotia, et. al)
Urolithiasis is described as Kalladaippu in Siddha literatures.
In Siddha medical literatures, urological disorders are classified in to two types ( Yugi vaidhya chinthamani perunool 800)
1.
Neerinai perukkal noi
—where the urination will be in excess.
2 Neerinai arukkal noi
—where as the urine output will be reduced.
Urolithiasis is one of the major diseases in the category of ‘ Neerinai arukkal noi
’.
Patho-physiology in Siddha system:
By food, water and activities the vatha and pitha humours are vitiated. Vatha is responsible for dryness and pitha is responsible for the heat. Thus the urine is concentrated and thereby the crystal growth and aggregation takes place in the urinary passage. When Kilnokkukal a component of vayu is strong enough to expel the deposits
1

that will be washed out in urine automatically. If Kilnokkukal is not strong enough, the deposited material will not be expelled and pave way for renal stone formation.
Dryness
Indiscipline in Food and Lifestyle
Vitiated Vatha Vitiated Piththa
Heat
Concentration of Urine Crystallization of Urine
Urinary stone
This vitiated vali and azhal create the derangement in udal, uyir tathukkal. Medication is advocated towards the correction of the deranged humours.
Sindhu vallathy mezhugu and Kalladaippu kudineer are chosen as study drugs which are mentioned in Agasthiar vaidhya vallathy and Athmaraktchamirtham Ennum
Vaidhya Sarasangeeragam
, to fullfil the above aspects. These drugs are given for 45 days period orally. (45 days is equal to one mandalam , Siddha maruthuvanga churukkam)
Though these preparations are mentioned in literatures it is planned to carryout the complete standardization of these drugs by chemically, pharmacologically and toxicologically by using accepted methodologies by WHO and the department of
AYUSH.
Then clinical study will be performed followed by the guidelines given by WHO and
AYUSH for herbal and herbo-mineral drugs.
Primary Objectives
To asses the efficacy of sindhu vallathy mezhugu and Kalladaippu kudineer in urolithiasis.
Secondary objectives
2

1. To standardize the study drugs.
2. To observe the adverse effects if any
The consists of two segments
Part - A. Non- clinical studies –standardisation of the study drugs.
Part - B. Clinical studies.
Sindhu Vallathy mezhugu will be prepared as per the literature Agasthiar vaidhya vallathy 600.
Kalldaippu Kudineer will be adapted from Athmaraktchamirtham Ennum Vaidhya
Sarasangeeragam , 1968,page 349, 2.Gunapadam-Mooligai vakuppu Part-1 page 539.)
The standardization of the trial drug will be carried out at Captain Srinivasa Moorthy
Drug Research Institute for Ayurveda and Siddha, Arumbakkam, Chennai-106.
Standardisation of the study drugs.
Step –1 : Pharmacognostical standardisation
Step –2 : Preparation of the study drugs.
Step –3 : Chemical methods of testing.
Step –4 : Pharmacological standardisation.
Step –5 : Toxicological standardisation .
Step –1 :Pharmacognostical standarditation
Each raw material ingredient will be identified and authenticated by an authorized
4.
5.
6. botanist or pharmacognosist.
Sindhu vallathy mezhugu – Ingredients:
Sl.no Tamil name
1. Pazham puli
2.
3.
Cherangottai
Murungai ilai thulir
Botanical/chemical name
Tamarindus indicus
Semicarpus anacardium
Moringa olifera
Part used
Edible sap
Quantity
4parts.
Seed 4parts.
Tender leaf 3 parts
Kariuppu
Vengaram
Vediupu
Sodium chloride
Borax potassium salt
-
-
-
2 parts
3 Parts.
2 parts
3

Step –2: Sop of the trial drugs.
The trial drugs will be prepared as per the GMP guidelines of the Drugs and cosmetics act 1947.
Process:
Step-A : Cleaning and purification :
Pazham puli - one year old tamarind is taken.It is macroscopically cleaned by removing the fiber and other visible shell pieces.
Cherangottai – The head end of the seed is removed carefully, without spilling of the milky fluid in the body. The remaining portion is boiled with cow dung solution and clean with water and dried.
Murungai ilai thulir - The young tender leaf of murungai is collected and shade dried.
Kariuppu – It is dissolved in banana stem juice boil up to kulambu stage add little lemon juice and dry it.
Vengaram – Fried till completely dehydrated.
Vediuppu – Dissolve 1 part of vediuppu in 4 parts water, and boil till it dries up.
Step-B Processing :
After purification of salts and serangottai , Powder the items separately and add one by one in a mortar grind it into mezhugu consistency and store it.
Dosage:
Sundaikkai size (500mg) twice daily.
Kalladaippu Kudineer - Ingredients:
Sl.no Tamil Name
1 Nerunjil
Botanical Name
Tribulus teristris
Part used
Dried Fruits
Quantity
1part
2
3
4
Sirupeelai
Mavilangam pattai
Peramutti ver
Aerva lanata
Carateva religiosa Root
Pavonia odorata
Whole plant
Root
1part
1part
1part
Take equal quantity of each ingredient. Ground into course powder upto 40-60 mesh size.
Powder and water will be taken into 1:10 ratio and boiled and reduced to1/10 parts.
Dosage : 130 ml twice daily
4

Indication : Kalladaippu.
Step –3 : Chemical methods of testing.
This will be done as per the Protocol for testing of Ayurvedic,Siddha & Unanai
Medicines, by PLIM, Ghaziabad,Under The Department of AYUSH, Ministry of Health and family welfare , New Delhi.
Protocol for testing of Sindhu vallathy mezhugu
Sl.No
1.
2
Test
Description
Colour
Odour
Taste
Loss on drying at 105 degrees
3
4
Total –ash
Acid –Insoluble ash
5
6
7
8
PH
Total solid
Fat content
Reducing sugar
9 Total sugar
10 Identifications, TLC/HPTLC- With marker
11 Test for heavy/Toxic metals
Lead
Cadmium
Mercury
Arsenic
12 Microbial contamination
Total bacterial count
Total fungal count
13 Test for specific pathogen
E.coli
Salmonella spp
Staphylococcus areus
Pseudomonas aerugino sa
14 Pesticide residue
Organochlorine pesticides
Organophosphorus pesticides
Pyrethroids
15 Test for Aflatoxins (B1, B2, G1,G2 )
5

Protocol for testing of Kudineer Choornam.
Sl.No
1.
2
3
Test
Description
Macroscopic
Microscopic
Loss on drying at 105 degrees
Total –ash
4
5
Acid –Insoluble
Water – soluble extractive
6
7
8
9
Alcohol – soluble extractive
Particle size (40 -60 mesh for kudineer chroonam
Identifications, TLC/HPTLC- With marker
Test for heavy/Toxic metals
Lead
Cadmium
Mercury
Arsenic
10 Microbial contamination
Total bacterial count
Total fungal count
11 Test for specific pathogen
E.coli
Salmonella spp
Staphylococcus areus
Pseudomonas aeruginosa
12 Pesticide residue
Organochlorine pesticides
Organophosphorus pesticides
Pyrethroids
13 Test for Aflatoxins (B1, B2, G1,G2 )
6

Step –4 : Pharmacological standardization
Pharmacological studies will be conducted as follows:
1.
Anti- lithiatic effect on experimental animals
2.
Diuretic effect
3.
Changes in electrolytes
4.
Relaxation of smooth muscle
5.
Analgesic effect
Step –5 : Toxicological standardization.
This will be done as per the guidelines for toxicity investigation of herbal medicine by
WHO. As the duration of study is 45 days the drug administration period for the toxicity study is decided for 3 months.
Male and female albino rats of 10 numbers in each sex will be used for the study.
Three different dose levels will be used. It will be observed for general signs, body weight and food and water intake and hematological examinations, renal and hepatic function tests etc.
Pilot study:
A pilot study will be conducted to validate the study protocol.
(As per the guideline for GCP accepted by AYUSH, Adapted from the ICH.)
Study population
Chennai city population is used for this study.
Study centers
Clinical studies will be conducted at National Institute for Siddha, Chennai -47 and
Central Research Institute for Siddha, Arumbakkam,Chennai-106. Patients who are attending the OPD and IPD of the above hospitals will be included.
Study design
The study will be an Open, non-randomized and non-comparative Phase –I (with normal individuals) and Phase-II (with urolithiasis patients) clinical study.
Primary end Point
7

It is defined as the expulsion of stones, the effects on reduction in the number and size of stones.
Dosage/ Dosage regimen/Route of administration/Frequency of administration.
Sindhuvallathy mezhu -500 mg capsules twice daily per orally.
Kalladaippu kudineer -130 ml decoction twice daily per orally will be given.
Expected duration of subject participation
45 days ( one mandalam is 45 days as per Siddha maruthuvanga churukkam ).
Patients who are ambulant and able to follow the instructions will be treated in OPD.
Patients who are not ambulant and not able to follow the instructions will be treated as in- patients.
Follow up
A ll the OPD/IPD patients will be followed up every 15 th
day till the end of treatment period. Clinical examination will be done to evaluate symptomatically. X Ray- KUB and/or Ultra –sound, laboratory investigations will be done at the starting and the end of
45 th
day and when ever required based on the clinical conditions.
Case report form
CRF proforma is enclosed. Form –A in the annexure
Selection and withdrawal of subjects:
Subject Inclusion criteria
Patients above 18 years, of either sex, diagnosed ultrasonographically or radiographically with visible calculi of larger then 5mm size, with or without any symptoms will be included in the study.
Subject Exclusion criteria
Patients’ falls under the following criteria will be excluded from the study
 severe pain not responding to pain killers
 severe obstruction requiring immediate surgery with stones

Existing renal failure Conditions

Bilateral stones with severe obstruction

Pregnant and lactating women

Children below 18 years

Patients with known hepatic and cardiac diseases.

Subjects those who are not willing to give informed consent.
8


Women those who are planning for pregnancy during the study period.
Sample size :
Phase –I - 20 normal individuals to asses the safety of the drugs .
Phase –II - 50 subjects with urolithiasis to asses the safety and efficacy.
Withdrawal criteria.
The occurrence of any adverse events either reported or observed the intervention will be stopped. Patients will be allowed to withdraw from the study if they experience serious discomfort during the study or any serious clinical events requiring specific treatment.
The follow-up on withdrawn subjects.
Efforts will be made to ascertain the reason for dropout. The non-compliance will not be regarded as treatment failure.
Treatment of subjects
Name the drugs/ Dose/ Dosing schedules
Sindhu vallathy mezhu - 500 mg twice daily
Kalladaippu kudineer – 130 ml twice daily .
Route of administration
Oral route
Mode of administration
Sindhu vallathy mezhugu- 500mg in gelatin capsules.
Kalladaippu kudineer – decoction
Treatment period including follow-up period
45 days treatment period and follow up period 3 months.
Procedures for monitoring subject compliance
Medicine intake chart:
Medicine intake chart will be given to all the participants to mark an entry of the intake of medicine for 45 days. The template of the chart is attached.
Form - F in the annexure.
9

Assessment of efficacy parameters
Siddha parameters : changes in symptoms ,Envagai thervu , change in Naadi nadai ,
Neerkuri and neikuri. Form-D in annexure.
Laboratory investigations : Form –C in annexure.
Blood
–TC, DC, ESR , Hb, blood sugar, BUN., Serum calcium, Phosphate, potassium, chloride, creatinine, Magnesium, and uric acid, Cholesterol.
Urine
–
Albumin, sugar, deposits, PH, Specific gravity, culture and sensitivity,
24 hours urine collection for Volume, Calcium Oxalate, uric acid, phosphate, sodium, potassium, magnesium, ammonium, chloride, sulfate and creatinine.
Ultrasonogram and/or X-ray KUB.
Recording and timing of parameters.
All the parameters will be assed on day one and day 45. On Day 15 th
& 30 th
interim clinical assessment will be performed or as when required. Form – B in annexure.
Specification of efficacy parameter
Primary outcomes :
Expulsion of stones, Change in the number and size of the stones.
The effect on the prevention of stone forming factors with in the study period.
Secondary outcome measures:
Relief from symptom score, reduction in pain score, Changes in other investigatory parameters.
Specification of safety parameter
Liver Functions, Serum creatinine, sodium, potassium levels to asses the electrolyte balance.
Timings and methods of safety parameter:
On every follow-up visit of patients with routine laboratory procedures. The neikuri will be done on the first urine .
10

All adverse events reported by the patients with information about severity, date of onset, duration and action taken regarding the study drug will be recorded. The relation of AE to study medication is defined as “unrelated’ (a reaction that does not follow a known response pattern to the study drug), “possible” (Follows a known response pattern to the study drug could have been produced by patients clinical state), “Probable” (Follows a known response pattern to the study drug, that could not be reasonably explained)
Form-G in annexure.
Follow-up of subjects after adverse events
Follow –up of the subjects after adverse events depending upon the nature of the event in accordance to the general physician or by the concerned specialist.
Time line:
2
3
Sl.no Proposed work
1 Literature collection
Preparation of drugs.
Standardization of drug.
Period of study
2 months
1 month
3-9 months
4
5
6
7
Pilot study.
Patient enrollment.
Data cleaning and analysis.
Manuscript writing.
9-12 months
13-30 months.
30-32 months.
33-36 months.
Statistics
Descriptive statistics will be used for the analysis. The data obtained from the study will be analyzed with SPSS 11.0 and epiinfo 6.1. Analysis will be done according to intention to treat principles. Changes in various parameters like envagaithervu, naadi nilai, neerkuri, various baseline parameters of urine and blood investigations, Change in radiological/ sonographical measurements to the values after the 45 th day will be analyzed using “paired t test”. He minimum level of significance will be fixed at 95% confidence limit and a 2-sided p value of <0.05 will be considered significant.
11

Source of funding:
The proposal will be applied for funding under the Extra- mural research scheme,
Department of AYUSH, ministry of Health and Family Welfare, New Delhi.
12