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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 2  |  Page : 77-94

Homoeopathic pathogenetic trial of Cuprum aceticum: A multicentric, double-blind, randomized, placebo controlled trial


1 D. P. Rastogi Central Research Institute of Homoeopathy, Noida, India
2 Central Research Institute of Homoeopathy, Jaipur, Rajasthan, India
3 Regional Research Institute of Homoeopathy, Gudivada, Andhra Pradesh, India
4 Homoeopathic Drug Research Institute, Lucknow, Uttar Pradesh, India
5 Central Council for Research in Homoeopathy, New Delhi, India

Date of Submission27-May-2020
Date of Acceptance02-Jun-2021
Date of Web Publication29-Jun-2021

Correspondence Address:
Dr. Ashish Mahajan
Central Research Institute of Homoeopathy, Sector- 26, Pratap Nagar, Jaipur - 302 033, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijrh.ijrh_54_20

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  Abstract 


Background: Although the symptomatology of Cuprum metallicum is quite vast, its other salts have fragmentary proving. Thus, homoeopathic pathogenetic trial for Cuprum aceticum (Cu acet.) was taken up. Objective: To elicit the pathogenetic response to Cu acet. in homoeopathic potencies on healthy human provers. Materials and Methods: A multi-center, double-blind randomized, placebo controlled, trial was conducted at three centers of Central Council for Research in Homoeopathy. Proving was conducted on 50 relatively healthy provers selected after conducting the Pretrial Medical Examination. All the provers were given placebo during the first phase of the trial. In the next two phases, Cu acet. was administered in 6 C and 30 C potencies, in the intervention group (n = 34); and placebo in the placebo group (n = 16), after randomization. The proving data so generated on Cu acet. were compiled and analyzed at the proving-cum-data processing cell. Results: Out of 34 provers who were on actual drug trial, only 12 provers manifested symptoms. Twenty-six and 20 symptoms were manifested in 6C and 30C potency, respectively. Conclusion: The pathogenetic response elicited during the proving trial expands the scope of use of the homoeopathic medicine C. aceticum. The symptoms generated in this trial will carry more value when verified clinically.

Keywords: Cuprum aceticum, Double blind, Drug proving, Homoeopathy, Pathogenetic effect, Placebo, Verdigris


How to cite this article:
Mehra P, Mahajan A, Vichitra AK, Rajakumar BS, Singh JP, Banoth K, Arya BS, Khurana A, Manchanda RK, Padmanabhan M. Homoeopathic pathogenetic trial of Cuprum aceticum: A multicentric, double-blind, randomized, placebo controlled trial. Indian J Res Homoeopathy 2021;15:77-94

How to cite this URL:
Mehra P, Mahajan A, Vichitra AK, Rajakumar BS, Singh JP, Banoth K, Arya BS, Khurana A, Manchanda RK, Padmanabhan M. Homoeopathic pathogenetic trial of Cuprum aceticum: A multicentric, double-blind, randomized, placebo controlled trial. Indian J Res Homoeopathy [serial online] 2021 [cited 2021 Oct 27];15:77-94. Available from: https://www.ijrh.org/text.asp?2021/15/2/77/319611




  Introduction Top


Cuprum aceticum (Cu acet.) is commonly known as acetate of copper. It is seen that cuprum and its salts are used for medical properties since ancient times. The book De Materia Medica by Dioscorides (first century A. D.) describes the use of verdigris (made by exposing metallic copper to vinegar steam to form copper acetate) in combination with copper sulfate as a remedy for bloodshot eyes, inflamed eyes, “fat in the eyes,” and cataracts.[1] Copper was also employed in ancient India and Persia to treat lung diseases. The tenth century book, Liber Fundamentorum Pharmacologiae describes the use of copper compounds for medicinal purposes in ancient Persia. Powdered malachite was sprinkled on boils, copper acetate and copper oxide were used for diseases of the eye and for the elimination of “yellow bile.” In 1885, the French physician, Luton, reported on using copper acetate in his practice to treat arthritis patients. For external application, he made a salve of hog's lard and 30% neutral copper acetate. For internal treatment, he used pills containing 10 mg of copper acetate.[2]

Quoting from the Allen's Encyclopedia of Pure Materia Medica, “

;Dr. Samuel Hahnemann, in his Fragmenta, 1805, gives symptoms under the heading of “Cuprum vitriolatum” and in 1824 contributed to Franz's collection in the Archiv. f. Hom., where “Cu acet.” is directed to be used. Franz's collection also includes symptoms by Franz, Fr. H-n, Herrmann, and Ruckert, as well as various poisoning cases contributed by Dr. Hahnemann.”[3]

Although the symptomatology of Cuprum metallicum is quite vast in homoeopathic materia medica, its other salts have fragmentary provings.

Homoeopathic drug proving is not only an integral part, but the first step to find out the pathogenetic effect of a drug substance. Hence, this proving was conducted to assess the therapeutic effect of Cu acet.

Description

Details and chemical properties of cuprum acetate are as follows:

Copper (II) acetate monohydrate (Cu [II] acetate) is odourless and efflorescent. It is soluble in alcohol and slightly soluble in ether and glycerol. Cu (II) acetate has many applications, as a fungicide, insecticide, catalyst for organic reactions, as well as applications in electrolysis and electroplating.[4]

Cu (II) acetate is used in the biochemical applications such as DNA extraction. Cu (II) complexes have been evaluated for anticancer, antibacterial, and antifungal activities. These are known to cleave DNA; however, increased efficiency is seen in the presence of an oxidizer (often hydrogen peroxide).[5]


  Materials and Methods Top


Study design and study setting

A multicenter prospective, randomized, double blind, placebo controlled study with allocation ratio of verum: placebo as 70:30 was conducted at three institutes of the Central Council for Research in Homoeopathy (CCRH): Dr. D. P. Rastogi Central Research Institute of Homoeopathy, Noida, Regional Research Institute of Homoeopathy, Gudivada and Homoeopathic Drug Research Institute, Lucknow. Proving Master was Research Officer of the Council, having post graduate degree in Homoeopathy whereas, Honorary Consultants were the experts of various specialties of modern medicine engaged in the examination of volunteers/provers. Medical experts constituted both of them.

Participants

Selection of provers

Applications were invited from 15 to 20 volunteers (from each center) of both sexes and age 18 years and above through a notice placed on the notice board of the institutes and homoeopathic colleges. The volunteers of non-homoeopathic background were also considered for the study. Pretrial medical examination (PME) was then conducted for 76 volunteers after getting written informed consent from them, 05 of which were from the non-homoeopathic background. Detailed physical, pathological, and radiological examinations were conducted by the medical experts to ensure the health status of the volunteers before enrolment into the study. For the pathogenetic drug trial of Cu acet, a total of 50 volunteers were enrolled as provers.

Inclusion and exclusion criteria

Volunteers of both sexes with age more than 18 years, certified as healthy by the medical experts, found capable of carefully recording the facts, subjective, and objective symptoms generated by the drug during proving and those who had not taken any homoeopathic medicines in the last 2 months were included in the study.

Volunteers suffering from any acute or chronic disease, color blindness, anxiety or hysteria, having any addictions, undergoing any kind of medical treatment, undergone surgery in last 2 months, women during pregnancy, puerperium or lactating, and those who had participated in another clinical or proving trial during the last 6 months were excluded from the study.

Sample size

Sample size was determined as per the Drug Proving Protocol of the Council,[6] according to which there should be at least 15 provers at each center, 30% of whom shall act as control. Therefore, 50 provers were enrolled at three centers for this trial. 34 provers were under verum group and 16 were under placebo group.

Randomization and blinding

Provers were randomized in two groups using stratified randomization technique for each center, Group I: Homoeopathic medicine group and Group II: Placebo group. Random numbers were generated with the help of computer-based software available at www.randomizer.org,[7] and the random code for the provers along with the information about the group allocation was kept at CCRH headquarters. The decoding of the group was done after the compilation of the symptoms produced in both the groups.

Both homoeopathic drug and placebo were dispensed in identical form, visually indistinguishable from each other, from Nodal Office of Drug Proving Programme at Dr. D. P. Rastogi Central Research Institute (Homoeopathy), Noida. Provers, Proving Master and the Programme Officer were investigators and kept blinded to the group allocation and also to the identity of the drug. All the provers were assigned code numbers and coded drugs of different potencies were supplied in separate glass phials bearing code numbers of the respective prover.

Intervention

Homoeopathic group

Homoeopathic dilutions of Cu acet. in 6C and 30C potencies in 100 ml sealed bottles were procured from a Good Manufacturing Practices certified Homoeopathic Drug manufacturer, Hahnemann Publishing Company Private Ltd., Kolkata, India. Globules of number 30 were medicated with these dilutions at the proving-cum-data processing cell at Nodal office of Drug Proving.

Placebo group

Placebo consisted of nonmedicated globules (number 30) moistened with nonmedicated dispensing alcohol (unsuccussed) and was therefore indistinguishable from verum in appearance, taste, and color.

Duration of study

Proving period: 1 year (2014–2015).

Ethics and consent

The Council's 18th Ethical Committee approved the study protocol on June 19, 2014. Proving Masters with experience in drug proving were sensitized about the protocol. Written informed consent was received from all the volunteers prior to enrolment in the study, after providing the detailed information about the trial.

All procedures were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2013.[8]

Procedure

Study was conducted in three phases at each of the centers. In each phase, 12 doses of drug or placebo as per randomization were administered, divided in four doses/day for 3 days (if no symptom arises).

Phase-I: Placebo phase. All the provers were given Placebo in Phase I. It is useful in generating prover's response to placebo in both the groups, and therefore, symptoms generated by the prover in this stage act as control for subsequent phases.

Phase-II: In the 2nd phase, the verum group received the drug in 6C potency and Placebo group received optically identical placebo.

Phase-III: In the 3rd phase, the verum group received the drug in 30C potency and Placebo group received optically identical placebo.

At each study center, a Proving Master supervised the volunteers enrolled in the study. After receiving the informed consent, PME, the baseline characteristics equivalent to Homoeopathic interview and the findings with respect to all the systemic examination and laboratory investigations (Complete Blood Count, Blood Sugar Fasting, Lipid Profile, Liver Function Test, Kidney Function Test, Urine (routine and microscopy), Stool (routine and microscopy), electrocardiogram, Chest X-ray PA view and ultrasonography whole abdomen and pelvis) were filled in the pro forma. The volunteers were instructed to take four globules of the coded drug four times a day for a maximum period of 3 days. Orientation training programs were conducted for the staff, faculty and students of homoeopathic medical colleges to educate them about the process of drug proving and safety of proving substance before the initiation of the study. However, as it was a double-blind study, names of proving substance were not disclosed. The provers were asked to note down daily the details of their feelings/changes in mental and/or physical state, after taking the coded drug in “Prover's Day Book Proforma”©.

If sign(s)/symptoms(s) appeared

  • The provers were asked to stop taking the drug/placebo as soon as they felt any change or any sign(s) and/or symptoms(s) developed during the trial
  • The provers noted down the sequence of the appearance of new sign(s) and/or symptoms(s), their progress and the number of doses after which such sign(s) and/or symptoms(s) appeared, with date, time of onset and duration for which they persisted
  • Any change in normal routine of the prover in respect of daily habits pertaining to diet, living conditions etc., any treatment taken was also noted in the Prover's Day Book Proforma.


After disappearance of sign(s) and/or symptom(s) produced by the drug, the volunteer had to wait for a further period of 30 days (wash out period) before starting the next phase following the same dose schedule as stated above.

The symptoms recorded in “Prover's Day Book Proforma” were verified by the Proving Master and completed through further interrogation with the provers in respect to their location(s), sensation(s), modalities and concomitants, extension of symptoms, causation, clinicopathological findings and other treatment taken, if any, in “Symptoms Elaboration Proforma.”

During the course of proving, the provers were referred for specific laboratory investigation(s) to rule out any pathological cause of appearance of symptom(s). Since laboratory tests were performed to identify any correlation between the subjective and objective changes during the course of proving, the expert opinion of the honorary consultant(s) was obtained, wherever needed.

If no sign(s)/symptoms(s) appeared

The provers noted down “No Symptom” with date and time of intake of the respective dose of the drug/placebo in “Prover”s Day Book Proforma.”

Before commencing the administration of subsequent potencies (subsequent Phase) of the drug, the provers remained on a wash out period of 30 days and started taking next potency following the same procedure as mentioned above, till completion of all the doses/appearance of symptom. The same procedure was followed for the 3rd phase. After the completion of trial of all potencies, the provers underwent Terminal (Post Trial) Medical Examination (TME), following the same manner as done during PME.

On completion of all the phases of the drug proving, the compilation of data recorded in “Prover”s Day Book Proforma,” “Symptoms Elaboration Proforma,” “Pathological Report Sheets” and “TME sheets,” was done by the Drug Proving-cum-Data Processing Cell of the Council. After decoding, the sign(s) and/or symptom(s) generated by the provers kept on the drug were separated from those generated by the provers kept on placebo.

Management of adverse effects

A vial of medicated globules of Camphora 30C was sent with each quota to each center as “Antidote.” As per recommendation by a group of experts, Camphora 30C was used as an antidote. In case of prolonged or intensely disturbing symptoms, antidote was to be used by the Proving Master after consulting the medical expert.

Proving symptoms

The sign(s) and/or symptom(s) generated by verum (drug) or control (placebo) on each prover are noted down for each phase, number of doses after which each of the signs or symptoms appeared and the duration for which they persisted. The sign(s) and/or symptom(s) generated by verum group are separated from those generated by provers of control group. The sign(s) and/or symptom(s) which were produced by the placebo in control and verum group provers are not taken into consideration.

Statistical analysis

The consolidated standards of reporting trials[9] and Red Hot guidelines[10] were adhered to report the outcome of the trial. The compiled data of proving symptoms and the changes in the laboratory investigations were analysed using IBM Statistical Package for the Social Sciences (SPSS) version 20, USA for Windows was used for all the data analysis.

Comparisons between Homoeopathy and placebo groups were performed at baseline to assess randomization effect using independent “t-test” for the continuous variable and “Chi-square test” for the categorical variables. Further “descriptive analysis” was done for the data with respect to the pathogenetic effect (signs and/or symptoms) produced during trial.

To distinguish placebo effect and nocebo effect, intra and inter prover analysis was done in both the groups.

Pathogenetic effects

Pathogenetic effects (Proving symptoms) are defined as all changes in state of health and laboratory findings reported by the provers during the Homoeopathic Pathogenetic Trial and recorded in the final report. The incidence of pathogenetic effects per prover is defined as the total number of findings observed in verum group of the trial divided by the total number of provers.[11]

Pathogenetic effects were deduced from:

  1. Comparison of symptoms developed in the placebo phase with symptoms during intervention phases (intra-prover comparison)
  2. Comparison of symptoms developed by provers on control (for all phases) with provers on actual drug trial (inter-prover comparison).



  Results Top


From three drug proving centers where the study was conducted, a total of 76 volunteers were screened and 50 apparently healthy volunteers were enrolled as provers. Of 50 provers, 34 were on verum and 16 were on placebo. [Figure 1] shows the flowchart of the number of volunteers who underwent screening, enrolled, randomized in two groups and number of provers who developed symptoms during the trial. The baseline information in both the groups was comparable (P ≥ 0.05) and well matched as shown in [Table 1].
Table 1: Baseline information

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Figure 1: Flow chart of study participants

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Out of 50 enrolled provers, 42 provers underwent the TME. 06 provers dropped out from the verum group while 02 provers dropped out from placebo group. The descriptive data analysis was done for remaining 42 provers as per protocol.

During the pathogenetic trial, out of 34 provers who were in verum group, only 12 (35%) provers reported symptoms consequent upon the administration of the drug. In the placebo group, five (31%) provers produced the symptoms. The symptoms developed after the administration of both the potencies, i.e., 6C and 30C. Out of 46 symptoms which were produced by the provers of verum group in the 2nd and 3rd phases, 26 symptoms were produced in 6C potency [Table 2] while 20 symptoms were produced in 30C potency [Table 3]. In 6C potency, majority of symptoms developed after the administration of 10–12 doses while in 30C potency symptoms developed after administration of 4–5 doses only.
Table 2: Symptoms produced with 6C potency of Cu acet.

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Table 3: Symptoms developed by 30C potency of Cu acet.

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The following proving symptoms appeared in both 6C and 30C potency:

  1. Loquacity (talking about irrelevant things), did not want to be interrupted, if interrupted feels like hitting
  2. Bursting pain in the frontal region of the head
  3. Stitching pain in right lower molar
  4. Gripping, colicky pain in the abdomen
  5. Dry cough
  6. Stitching pain in lower extremities especially calf muscles
  7. Fever.


Loquacity, stitching pain in right lower molar, stitching pain in lower extremities especially calf muscles and fever symptoms are reported by the same prover in both 6C and 30C potency. They were reported singularly by different provers in the verum group only. They were not observed in the placebo group or the placebo phase of the verum group.

Analysis was also done considering the physical built, physical generals and mental generals of the provers in the verum group who have produced symptoms but no significant similarities were found in these provers, which could have been considered the constitutional symptoms. Further, inter-group analysis considering the above parameters were done in the provers who have produced symptoms in the verum group and control group but no distinct similarities or dissimilarities were found.

A comprehensive qualitative symptom profile of intervention group, control group, and former homoeopathic proving symptoms found in the literature [Table 4] reflect that:
Table 4: Qualitative symptom profiles of intervention group, control group, and former Homoeopathic drug proving symptoms

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  • Symptoms were generated in intervention group and were placed in regional spheres (following the Schema Repertory of the Homoeopathic Materia Medica by J. T. Kent[12]) of Mind, Vertigo, Head, Eyes, Nose, Mouth, Throat, Abdomen, Rectum, Cough, Back, Extremities, Sleep and Skin in the present study and were found to have striking similarities to the symptoms present in the homoeopathic literature[3],[13],[14]
  • In addition to the above, symptoms were also generated in intervention group in regional spheres of teeth, stomach, fever, and generalities.


A brief summarization of the main symptoms observed which are also mentioned in the homoeopathic literature is as follows:

  1. Anger and attacks of rage
  2. Violent pain in the frontal region of the head
  3. Eyelids swollen
  4. Dryness of mouth with thirst for cold water
  5. Sore throat
  6. Colicky, gripping pain in the abdomen and diarrhea
  7. Dry cough with tearing/throbbing pain in the head
  8. Pain in nape of neck, aggravation (agg.) looking upward or bending head backward
  9. Pain and cramp in the extremities especially calf muscles
  10. Complete sleeplessness in 6C and sleepiness in 30C potency.


The incidence of pathogenetic effects in this study has been found to be 1.35.

Placebo symptoms developed during the trial are placed in [Table 5].
Table 5: Placebo symptoms developed during the trial

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  Discussion Top


In the present study, when the symptoms generated in the verum group, placebo group and the earlier proving symptoms available in the homoeopathic literature were compared, it was found that marked mental symptoms were elicited in this proving and many symptoms were similar to those mentioned in the literature. Characteristic symptoms were produced related to head, eye, mouth, abdomen, rectum, cough, back and extremities, sleep and fever with marked modalities, and associated symptoms. Well-defined skin symptoms with finer details were observed in comparison with a few vague symptoms mentioned in the homeopathic literature.

Certain symptoms developed during the proving trial were quite similar to those found in previous literature. Thus, it can be considered as a characteristic for this drug. However, there have been additional findings as well in a few of these symptoms which need to be clinically verified. A few symptoms which are overlapping in both the groups could be due to the nocebo effect or due to confounding factors such as alteration in weather, food or regimen. Although adequate efforts were made to rule out such effects by proper record keeping, these can't be ruled out completely. The pathogenetic findings of this drug need further verification by using it for therapeutic purposes in the patients reporting with similar symptoms.

In one of the articles, Dr. Teut[15] has mentioned that 'placebo proving occasionally seem to produce similar symptoms to the proving symptoms, thus casting further doubt on the use of this medium in proving' and has attributed it to nocebo effect. A nocebo response is explained as subject's own negative expectations and/or negative suggestions from therapists/clinical staff in the absence of any treatment. Nocebo phenomena are generally explained by Pavlovian conditioning and expectations induced by verbal information and suggestions. In this trial also nocebo phenomenon can be considered and apart from the individual's own perception, this can be attributed to the discussion which usually takes place among the students of homoeopathic colleges who are the participants in the study. This poses a limitation as it is difficult to keep a check on them for not discussing or sharing the experiences. The massive number of symptoms developed in the control group could be considered because of such discussions among the students.

There are certain other limitations in the study apart from the nocebo effect; like no defined parameters for the classification of characteristic symptoms and less number of provers which may be addressed in future studies.


  Conclusion Top


The pathogenesis of the Cu acet. found in this study has produced symptoms which were already noted in the homoeopathic literature and there are many symptoms which are new. These signs and symptoms need to be subjected to clinical verification study for confirming their therapeutic utility. This will further enhance the scope and utility of this drug by the profession.

Financial support and sponsorship

Nil.

Conflicts of interest

None declared.



 
  References Top

1.
A Brief History of the Health Support Uses of Copper. Available from: https://www.purestcolloids.com/history-copper.php [Last accessed on 2019 Nov 19].  Back to cited text no. 1
    
2.
Medical Uses of Copper in Antiquity. Available from: ttp://www.copper.org/publications/newsletters/innovations/2000/06/medicine-chest.html [Last accessed on 2019 Nov 19].  Back to cited text no. 2
    
3.
Allen TF. The Encyclopaedia of Pure Materia Medica, Vol. 1, Reprint New Delhi: M/s B. Jain Publishers Ltd.;1986. p.160-3.  Back to cited text no. 3
    
4.
Verma PN, Indu V. Encyclopaedia of Homeopathic Pharmacopoeia, Vol.1, 3rd ed, New Delhi: M/s B. Jain Publishers Ltd.;2007. p.292-3.  Back to cited text no. 4
    
5.
Copper (II)acetate monohydrate | CAS 6046-93-1 | SCBT - Santa Cruz Biotechnology[Internet]. Available from:https://www.scbt.com/p/copper-ii-acetate-monohydrate-6046-93-1. [Last accessed on 2021 Jun 18].  Back to cited text no. 5
    
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Khurana A, Manchanda R, Mittal R, Taneja D, Haselen R. Homoeopathic drug proving: Randomised double-blind placebo-controlled trial. Indian J Res Homoeopath 2015;9:3-11.  Back to cited text no. 6
    
7.
Available from: http://www.randomizer.org. [Last assessed on 2014 Nov 3].  Back to cited text no. 7
    
8.
WMA Declaration of Helsinki- Ethical Principles for Medical research involving Human subjects. Available from: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ [Last assessed on 2020 May 26].  Back to cited text no. 8
    
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Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869. doi: 10.1136/bmj.c869. PMID: 20332511; PMCID: PMC2844943.  Back to cited text no. 9
    
10.
Dean ME, Coulter MK, Fisher P, Jobst KA, Walach H. Reporting data on homeopathic treatments (RedHot): a supplement to CONSORT. J Altern Complement Med. 2007;13:19-23. doi: 10.1089/acm.2006.6352. PMID:17309373.  Back to cited text no. 10
    
11.
Dantas F, Fisher P, Walach H, Wieland F, Rastogi DP, Teixeira H et. al. A systematic review of the quality of homeopathic pathogenetic trials published from 1945 to 1995. Homeopathy 2007;96: 4-16.  Back to cited text no. 11
    
12.
Kent JT. Repertory of the Homoeopathic Materia Medica. New Delhi: B. jain Publishers; 2009.  Back to cited text no. 12
    
13.
Clarke JH. A Dictionary of Practical Materia Medica, Vol.-I, B. Jain Publishers New Delhi. Reprint Edition 2009, Pp. 56-59.  Back to cited text no. 13
    
14.
Hering C. The Guiding Symptoms of Our Materia Medica. Vol.-I, B. Jain Publishers New Delhi. Republished edition 1971. Pp. 119-25.  Back to cited text no. 14
    
15.
Teut M, Dahler J, Hirschberg U, Luedtke R, Albrecht H, Witt CM. Homeopathic drug proving of Okoubaka aubrevillei: a randomised placebo-controlled trial. Trials 2013;14:96. https://doi.org/10.1186/1745-6215-14-96.  Back to cited text no. 15
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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