2MBBS, Post Graduate trainee, Internal medicine, Jinnah Hospital, Karachi
3MBBS, Research Fellow, Department of Neurology.
4MBBS, Women Medical Officer, Department of ENT, Civil Hospital, Karachi
5MBBS, House Officer, Jinnah Hospital, Karachi
6DPT, Baqai Medical University
7MBBS, M.Phil, Assistant Professor Department of Physiology Al Tibri Medical College Karachi
Objective: To assess the improvement in clinical features in dengue patients having silymarin treatment as compared to the placebo, along with conservative therapy.
Methods: A randomized controlled trial was conducted Ziauddin hospital, Clifton, Karachi. 92 dengue patients, aged 18 to 70 years, were included in the study and were equally divided into two groups, A and B, which received silymarin and placebo respectively, along with the symptomatic dengue treatment. The clinical features assessed included nausea, vomiting, bodyache, headache, retro-orbital pain, rashes, petechial haemorrhoids, facial flushing, conjunctivitis and hepato splenomegaly. The data were analyzed using SPSS version 20.0. Chi-square test and independent samples t-test were used for inferential analysis whereas the significance level was set at 0.05.
Results: The study results revealed that none of the liver enzymes were found to significantly decrease after the use of Silymarin in the treatment group as compared to the placebo group (p>0.05 for all). Moreover, none of the clinical features studied were found to be significantly different in both study groups (p>0.05 for all).
Conclusion: The study results revealed that none of the clinical features studied significantly improved in the treatment group as compared to the placebo group after Silymarin treatment. Further evaluation of the potential benefits of Silymarin therapy in the treatment of dengue infection is recommended.
Key words: Treatment; Dengue Infection; Clinical Trial; Silymarin; Clinical Features
As liver is a susceptible organ in dengue infection, the present study was therefore designed to assess the improvement in clinical features in dengue patients having silymarin treatment as compared to the placebo, along with conservative therapy.
Variables |
Group A Mean +S.D |
Group B Mean + S.D |
p-value |
Age (years) |
38.39±17.08 |
36.32±13.93 |
0.527 |
Duration of Fever (days) |
3.30±1.28 |
3.84±1.46 |
0.061 |
Hemoglobin (gm %) |
13.89±1.87 |
13.92±3.04 |
0.957 |
Pack Cell Volume (%) |
42.10±5.13 |
41.17±4.68 |
0.364 |
Total Leucocytes Count (x103 cells /cumm) |
3.62±1.55 |
3.78±1.68 |
0.644 |
Platelets (x106 cells /cumm) |
79.00±44.04 |
84.60±45.50 |
0.55 |
Sodium (mEq/L) |
134.89±3.42 |
137.13±3.35 |
0.002 |
Potassium (mEq/L) |
3.68±0.38 |
3.70±0.44 |
0.763 |
Urea (mg/dl) |
19.26±7.53 |
19.41±6.67 |
0.919 |
Creatinine(mg/dl) |
0.87±0.23 |
0.87±0.22 |
0.925 |
Serum Billirubin Direct (mg/dl) |
0.20±0.12 |
0.25±0.18 |
0.172 |
Serum Billirubin Indirect (mg/dl) |
0.251±0.14 |
0.42±0.42 |
0.011 |
Alanine Transaminase (U/L) |
132.76±178.03 |
107.32±93.86 |
0.394 |
Gamma GultamylTransferase (U/L) |
87.86±59.55 |
89.39±103.85 |
0.931 |
Alkaline Phosphates (U/L) |
79.54±37.05 |
66.65±28.42 |
0.064 |
Clinical Features |
Group A |
Group B |
P-value |
|||
N |
% |
N |
% |
|||
Nausea and vomiting |
Yes |
37 |
80.40% |
28 |
60.90% |
0.247 |
No |
9 |
19.60% |
18 |
39.10% |
||
Bodyache |
Yes |
46 |
100.00% |
44 |
95.70% |
0.45 |
No |
0 |
0.00% |
2 |
4.30% |
||
Headache |
Yes |
38 |
82.60% |
36 |
78.30% |
0.397 |
No |
8 |
17.40% |
10 |
21.70% |
||
Retro Orbital Pain |
Yes |
26 |
56.50% |
28 |
60.90% |
0.416 |
No |
20 |
43.50% |
18 |
39.10% |
||
Rash |
Yes |
36 |
78.30% |
40 |
87.00% |
0.205 |
No |
10 |
21.70% |
6 |
13.00% |
||
Petechiae |
Yes |
1 |
2.20% |
2 |
4.30% |
0.5 |
No |
45 |
97.80% |
44 |
95.70% |
||
Facial Flushing |
Yes |
31 |
67.40% |
36 |
78.30% |
0.174 |
No |
15 |
32.60% |
10 |
21.70% |
||
Infected Conjunctiva |
Yes |
22 |
47.80% |
26 |
56.50% |
0.266 |
No |
24 |
52.20% |
20 |
43.50% |
||
Hepatomegaly |
Yes |
0 |
0.00% |
1 |
2.20% |
0.5 |
No |
46 |
100.00% |
45 |
97.80% |
||
Splenomegaly |
Yes |
0 |
0.00% |
0 |
0.00% |
0.5 |
No |
46 |
100.00% |
46 |
100.00% |
Clinical Features |
Group A |
Group B |
P-value |
||||
n |
% |
n |
% |
||||
Bodyache |
1st Day |
Yes |
46 |
100.00% |
45 |
97.80% |
0.5 |
No |
0 |
0.00% |
1 |
2.20% |
|||
5thDay |
Yes |
0 |
0.00% |
0 |
0.00% |
0.5 |
|
No |
46 |
100.00% |
46 |
100.00% |
|||
Headache |
1st Day |
Yes |
39 |
84.80% |
36 |
78.30% |
0.296 |
No |
7 |
15.20% |
10 |
21.70% |
|||
5thDay |
Yes |
0 |
0.00% |
0 |
0.00% |
>0.999 |
|
No |
46 |
100.00% |
46 |
100.00% |
|||
Anorexia |
1st Day |
Yes |
43 |
93.50% |
46 |
100.00% |
0.121 |
No |
3 |
6.50% |
0 |
0.00% |
|||
5thDay |
Yes |
0 |
0.00% |
1 |
2.20% |
0.5 |
|
No |
46 |
100.00% |
45 |
97.80% |
The study results revealed a significant difference only in the mean serum levels of sodium and indirect bilirubin in both study groups (p< 0.05 for both). Furthermore, none of the liver enzymes were found to significantly decrease after the use of Silymarin in the treatment group as compared to the placebo group(p>0.05 for all).Moreover, none of the clinical features studied were found to be significantly different in both study groups (p>0.05 for all).
Literature regarding potential benefit of bio flavonoids in the treatment of liver diseases is equivocal. A systematic review in 2001 reported Silymarin to have metabolic and cell-regulating effects such as carrier-mediated regulation of cell membrane permeability, inhibition of the 5-lipoxygenase pathway, scavenging of reactive oxygen species of the R-OH type and action on DNA-expression. In spite of this, no unambiguous conclusion can be drawn regarding the value of silymarin in the treatment of liver diseases (20).
Same is true for the role of silymarin in the treatment of dengue infection about which the heterogeneity of data prevents any decisive conclusions. Powers CN &Seltzer WN in 2016 reported that polyphenolic compounds, flavonoids, Chalcones, and other phenolics were the most strongly docking ligands for dengue virus protein targets as assessed by a virtual screening analysis of phyto chemical structures (21). Likewise, in a computer aided analysis of phytochemicals as potential dengue virus inhibitors in Pakistan, Qadir I et al., in 2017reported that five out of nine phytochemicals tested in the analysis proved to be novel dengue virus inhibitors out of which three were from silybummarianum(22).
On the other hand, Zindi K et al., in 2001 reported that among the various bioflavonoids studied only quercetin showed significant anti dengue virus type 2 inhibitory activities with other bioflavonoids showing minimal to no inhibition of viral activity (23).
The study results did not show any significant improvement in any of the studied clinical features of dengue infection in the treatment group given silymarin. Unfortunately, to the best of author’s knowledge, there is virtual silence in the literature about any potential benefits of silymarin, or any silybummarianum derived phytochemical for that matter, in the context of improvement in the clinical features of dengue infection. A meaningful comparison of the relevant study findings therefore could not be made as a thorough literature search did not reveal any pertinent published data.
- HO. Dengue and Severe Dengue. 2018;
- Humayoun MA, Waseem T, Jawa AA, Hashmi MS, Akram J. Multiple dengue serotypes and high frequency of dengue hemorrhagic fever at two tertiary care hospitals in Lahore during the 2008 dengue virus outbreak in Punjab, Pakistan. International Journal of Infectious Diseases. 2010; (14):54-59.
- Malavige GN, Fernando S, Fernando DJ, Seneviratne SL. Dengue viral infections. Postgraduate medical journal. 2014; 80(948):588-601. doi: 10.1136/pgmj.2004.019638
- Thein S, Aung MM, Shwe TN, Aye M, Zaw A, Aye K, et al., Risk Factors in Dengue Shock Syndrome. The American journal of tropical medicine and hygiene. 2013; 56(5):566-72. doi: 10.4269/ajtmh.1997.56.566
- Tang JW, Khanani MR, Zubairi AM, Lam WY, Lai F, Hashmi K, et al., A wide spectrum of dengue IgM and PCR positivity post‐onset of illness found in a large dengue 3 outbreak in Pakistan. Journal of medical virology. 2008; 80(12):2113-2121. doi:10.1002/jmv.21290
- HO EMRO. Dengue Fever. Dengue Guidelines.
- whqlibdoc.who.int/publications/2009/9789241547871_eng (accessed June 2015)
- Gibbons RV, Vaughn DW. Dengue: an escalating problem. Bmj. 2012; 324(7353):1563-1566.
- Ashley EA. Dengue fever. Trends in Anesthesia and Critical Care. 2011 Feb 1; 1(1):39-41.
- Oishi K, Saito M, Mapua CA, Natividad FF. Dengue illness: clinical features and pathogenesis. Journal of infection and chemotherapy. 2007; 13(3):125-133. doi: 10.1007/s10156-007-0516-9
- Pal T, Dutta SK, Mandal S, Saha B, Tripathi A. Differential clinical symptoms among acute phase Indian patients revealed significant association with dengue viral load and serum IFN-gamma level. Journal of Clinical Virology. 2014; 61(3):365-70. doi: 10.1016/j.jcv.2014.09.003
- Banerjee A, Paul UK, Bandyopadhyay A. Diagnosis of dengue fever: roles of different laboratory test methods. International Journal of Advances in Medicine. 2018; 5(2):395-399.doi:10.18203/2349-3933.ijam20181076
- Kumar A, Pandit VR, Shetty S, Pattanshetty S, Krish SN, Roy S. A profile of dengue cases admitted to a tertiary care hospital in Karnataka, southern India. Tropical doctor. 2010 Jan; 40(1):45-51. doi: 10.1258/td.2009.080376
- Kumar K, Singh PK, Tomar J, Baijal S. Dengue: epidemiology, prevention and pressing need for vaccine development. Asian Pacific Journal of Tropical Medicine. 2010; 3(12):997-1000.
- Waggoner JJ, Abeynayake J, Sahoo MK, Gresh L, Tellez Y, Gonzalez K et al. Comparison of the FDA-approved CDC DENV-1-4 Real-Time RT-PCR with a laboratory-developed assay for dengue virus detection and serotyping. Journal of clinical microbiology. 2013; 5(0):1359-73. doi: 10.1128/JCM.01359-13
- Jaweria A, Naeem F, Malik M, Javaid F, Ali Q, Ahmad S et al. Dengue Fever: Causes, Prevention and Recent Advances. Journal of Mosquito Research. 2016 Nov 17; 6(29): 11-5. doi: 10.5376/jmr.2016.06.0029
- Schrieber SJ, Wen Z, Vourvahis M, Smith PC, Fried MW, Kashuba AD et al. The pharmacokinetics of silymarin is altered in patients with hepatitis C virus and nonalcoholic fatty liver disease and correlates with plasma caspase-3/7 activity. Drug Metabolism and Disposition. 2008; 36(9):1909-16. doi: 10.1124/dmd.107.019604
- Pradhan SC, Girish C. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian Journal of Medical Research. 2013; 124(5):491-504.
- Abenavoli L. Role of silymarin to treat fibrosis development in non-alcoholic fatty liver diseasehepr_823 668. Hepatology Research. 2011 Jun 1; 4(1):668-9.
- Solhi H, Ghahremani R, Kazemifar AM, Yazdi ZH. Silymarin in treatment of non-alcoholic steatohepatitis: A randomized clinical trial. Caspian journal of internal medicine. 2014; 5(1):9-12.
- Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs. 2001; 61(14):2035-63.
- Powers CN, Setzer WN. An In-Silico Investigation of Phytochemicals as Antiviral Agents Against Dengue Fever. Combinatorial Chemistry & High Throughput Screening. 2016; 19(7):516.
- Qaddir I, Rasool N, Hussain W, Mahmood S. Computer-aided analysis of phytochemicals as potential dengue virus inhibitors based on molecular docking, ADMET and DFT studies. Journal of vector borne diseases. 2017; 54(3):255.
- Zandi K, Teoh BT, Sam SS, Wong PF, Mustafa MR, AbuBakar S. Antiviral activity of four types of bioflavonoid against dengue virus type-2.Virology journal.2011 ;( 1):560. doi: 10.1186/1743-422X-8-560