BENEFICIAL THERAPEUTIC EFFECTS OF NIGELLA SATIVA AND/OR ZINGIBER OFFICINALE IN HCV PATIENTS IN EGYPT
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EXCLI Journal 2013;12:943-955 – ISSN 1611-2156
Received: July 31, 2013, accepted: October 28, 2013, published: November 11, 2013
Original article:
BENEFICIAL THERAPEUTIC EFFECTS OF NIGELLA SATIVA
AND/OR ZINGIBER OFFICINALE IN HCV PATIENTS IN EGYPT
Adel Abdel-Moneim1, Basant M Morsy2, Ayman M Mahmoud1*, Mohamed A Abo-Seif3,
Mohamed I Zanaty2
1
Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University,
Egypt
2
Biochemistry Division, Chemistry Department, Faculty of Science, Beni-Suef University,
Egypt.
3
Department of Internal Medicine, Faculty of Medicine, Beni-Suef University, Egypt
* Corresponding author: Ayman M Mahmoud; Physiology Division, Zoology Department,
Faculty of Science, Beni-Suef University, Salah Salim St., 62511, Beni-Suef, Egypt.
E-mail: ayman.mahmoud@science.bsu.edu.eg; aymano911@yahoo.com
Tel.: +201144168280
ABSTRACT
Hepatitis C is a major global health burden and Egypt has the highest prevalence of hepatitis
C virus (HCV) worldwide. The current study was designed to evaluate the beneficial thera-
peutic effects of ethanolic extracts of Nigella sativa, Zingiber officinale and their mixture in
Egyptian HCV patients. Sixty volunteer patients with proven HCV and fifteen age matched
healthy subjects were included in this study. Exclusion criteria included patients on interferon
alpha (IFN-α) therapy, infection with hepatitis B virus, drug-induced liver diseases, advanced
cirrhosis, hepatocellular carcinoma (HCC) or other malignancies, blood picture abnormalities
and major severe illness. Liver function enzymes, albumin, total bilirubin, prothrombin time
and concentration, international normalized ratio, alpha fetoprotein and viral load were all as-
sessed at baseline and at the end of the study. Ethanolic extracts of Nigella sativa and Zingi-
ber officinale were prepared and formulated into gelatinous capsules, each containing 500 mg
of Nigella sativa and/or Zingiber officinale. Clinical response and incidence of adverse drug
reactions were assessed initially, periodically, and at the end of the study. Both extracts as
well as their mixture significantly ameliorated the altered viral load, alpha fetoprotein, liver
function parameters; with more potent effect for the combined therapy. In conclusion, admin-
istration of Nigella sativa and/or Zingiber officinale ethanolic extracts to HCV patients exhib-
ited potential therapeutic benefits via decreasing viral load and alleviating the altered liver
function, with more potent effect offered by the mixture.
Keywords: Hepatitis C, Nigella sativa, Zingiber officinale, viral load
INTRODUCTION hepatocellular carcinoma (HCC) (Alter,
2007; Lavanchy, 2011). It has been shown
Hepatitis C virus (HCV) infection often
that there is an alarming increase in the in-
is conducive to chronic hepatitis due to the
cidence of HCC in HCV patients in Egypt
low viral clearance rate, leading to liver cir-
(Anwar et al., 2008). According to the
rhosis (LC) and subsequent progression to
943EXCLI Journal 2013;12:943-955 – ISSN 1611-2156
Received: July 31, 2013, accepted: October 28, 2013, published: November 11, 2013
World Health Organization (WHO) there ti-cancer, anticlotting, anti-inflammatory,
are 130-170 million people infected with and analgesic activities (Chrubasik et al.,
the hepatitis C virus, corresponding to 2- 2005; Ali et al., 2008).
2.5 % of the world’s total population Nigella sativa (N. sativa) is used as a
(WHO, 2013). Egypt has the highest preva- food condiment in the Middle East, and its
lence of HCV worldwide (15 %) and the seeds/oil have been shown to possess anti-
highest prevalence of HCV-4 (67 %) with a inflammatory, antiviral and antineoplastic
predominance of subtype 4a (55 %) (Ngu- activity in various in vitro and in vivo stud-
yen and Keeffe, 2005; Elkady et al., 2009; ies (Zaher et al., 2008). There are many re-
Khattab et al., 2011, WHO, 2013). ports of its biological activities including:
The standard therapy, which is based on immunopotentiation, antitumor, anti-
a combination of pegylated interferon alpha inflammatory, analgesic, antihypertensive,
(IFN-α) and ribavirin (McHutchison et al., antidiabetic, respiratory stimulation, anti-
1998), results in highly variable outcomes, bacterial, antifungal, anticestode and
is very expensive and has severe side ef- antinematode effects (Ali and Blunden,
fects that are difficult to endure for the pa- 2003; Al-Naggar et al., 2003).
tients (Di Bisceglie and Hoofnagle, 2002; To date, studies addressed the use of
Calland et al., 2012). Therefore, the estab- ethanolic extracts of Z. officinale, N. sativa
lishment of a new treatment modality with- and their mixture in HCV patients are
out serious adverse effects is desirable scanty. Hence, we sought to evaluate the
(Vermehren and Sarrazin, 2011). efficacy, safety, and tolerability of Z. offici-
Medicinal plants have been found to nale and N. sativa extracts, individually and
play a major role in managing human dis- in combination, as an alternative therapy in
eases. Historically, numerous important the management of HCV patients.
modern drugs have been developed from
molecules originally isolated from natural MATERIALS AND METHODS
sources (Lee, 2000; Balunas and Kinghorn, This was a prospective, single-armed,
2005). The search for new bioactive mole- self-controlled pilot study, conducted at the
cules in plants in key therapeutic areas such Hepatology Unit, Gastroentrology Depart-
as immunosuppression, infectious diseases, ment, Beni-Suef University Hospital, Beni-
cancer and metabolic disorders is still an Suef University, Egypt.
active part of pharmaceutical research
(Newman and Cragg, 2012). About 40 new
Patients
drugs launched on the market between 2000 Sixty volunteer patients with proven
and 2010, originate from terrestrial plants, chronic HCV who were selected from ad-
terrestrial microorganisms, marine organ- mitted patients at the Hepatology Unit, Be-
isms, and terrestrial vertebrates and inver- ni-Suef University Hospital, with fifteen
tebrates (Brahmachari, 2011). age-matched healthy controls were included
Ginger (Zingiber officinale) is a well- in this study.
known and widely used herb, which con- Inclusion criteria included all patients
tains several interesting bioactive constitu- diagnosed with HCV and negative for
ents and possesses health-promoting prop- HBV. Exclusion criteria included patients
erties (Ajayi et al., 2013). From its origin in on IFN-α therapy; infection with HBV or
Southeast Asia and its spread to Europe, it hepatitis immunodeficiency virus; drug-
has a long history of use as herbal medicine induced liver diseases; advanced cirrhosis;
to treat a variety of ailments including vom- HCC or other malignancies; blood picture
iting, pain, indigestion, and cold induced abnormalities such as anemia (hemoglobin
syndromes (White, 2007). More recently, it concentration of 10 g/dl or less), leucopenia
was reported that ginger also possessed an- (white blood cells 1.500/µl or less) and
944EXCLI Journal 2013;12:943-955 – ISSN 1611-2156
Received: July 31, 2013, accepted: October 28, 2013, published: November 11, 2013
thrombocytopenia (platelets count 80.000/µl Clinical and laboratory assessment
or less); major severe illness such as renal All eligible patients and controls were
failure, congestive heart failure, respiratory subjected to the following at enrollment and
failure or autoimmune disease; or non- after 1 month therapy: (1) Full clinical as-
compliance to treatment. Informed consent sessment with an emphasis on hepato-
was obtained from all patients, and the in- and/or splenomegaly, jaundice, palmar ery-
stitutional ethical committee approved the thema, flapping tremors, spider naevi, low-
study protocol, which conformed with the er-limb edema, and ascites; (2) Laboratory
ethical guidelines of the 1975 Declaration investigation of liver functions including
of Helsinki. aspartate aminotransferase (AST) and ala-
nine aminotransferase (ALT) were assayed
Extract preparation according to the method of Schumann and
N. sativa seeds and Z. officinale rhi- Klauke (2003) using reagent kit purchased
zomes were purchased from the local herb- from Noble Diagnostic (Egypt); lactate de-
alist in Egypt. The seeds and rhizomes were hydrogenase (LDH) was determined ac-
authenticated by a specialist of Plant Tax- cording to the method of Teitz (1986) using
onomy in Botany Department, Faculty of reagent kit purchased from Human (Ger-
Science, Beni-Suef University, Egypt. Both many); alkaline phosphatase (ALP) was
were cleaned, dried, mechanically pow- assayed according to the International Fed-
dered, extracted with 96 % ethanol and eration of Clinical Chemistry (IFCC, 1980)
evaporated with rotary evaporator to render using BioSystem (Spain) commercial kit,
the extract alcohol free. The extracts were gamma glutamyl transferase (γGT) assay
made into soft gelatin capsules, each con- was performed according to Persijn and van
taining 500 mg of N. sativa and/or Z. offici- der Slik (1976) using kits from Reactivos
nale extracts. The above procedures were GPL (Spain); albumin was assayed accord-
undertaken in the Arab Company for Phar- ing to the method of Webster (1974) using
maceuticals & Medicinal Plants (Mepaco- kits of Diamond Diagnostic (Egypt); total
Medifood), Enshas EL Raml, Sharkeiya bilirubin, was determined using reagent kit
Factory, Sharkeiya, Egypt. purchased from Diamond Diagnostic
(Egypt), according to the method of Kaplan
Treatment protocol (1984) and prothrombin time (PT), pro-
Included patients and controls were thrombin concentration (PC) and interna-
classified into five groups each comprising tional normalized ratio (INR) were deter-
fifteen patients as follows; Group 1 served mined according to the method of Wanger
as healthy subjects; Group 2 (HCV) served and Dati (1998) using kits supplied by Sie-
as HCV control; Group 3 (HCV+N) re- mens Healthcare Diagnostic (USA) and (3)
ceived a capsule containing 500 mg N. sati- Serum α-fetoprotein (AFP) was assayed
va extract twice daily; Group 4 (HCV+G) according to Forest and Pugeat (1987) us-
received a capsule containing 500 mg Z. ing kits purchased from VIDAS bio
officinale extract twice daily and Group 5 Merieux (France) and quantitative real time
(HCV+NG) received a capsule containing polymerase chain reaction (qRT-PCR) for
500 mg of each extract twice daily. Patients HCV using Roche Amplicor HCV monitor
were followed up weekly throughout the version 2.0 (Roche Diagnostics, Branch-
study period for assessing treatment adher- burg, NJ), with lower detection limit < 50
ence, tolerability and incidence of adverse IU/ml.
reactions.
Statistical analysis
The data were statistically analyzed us-
ing SPSS v.16. Results were expressed as
945EXCLI Journal 2013;12:943-955 – ISSN 1611-2156
Received: July 31, 2013, accepted: October 28, 2013, published: November 11, 2013
Mean ± Standard error (SE) and all statisti- mixture seemed to be more effective in re-
cal comparisons were made by means of ducing serum AFP levels.
one-way ANOVA test followed by Dun-
can’s multiple range test post hoc analysis.
A P value less than 0.05 was considered
significant.
RESULTS
The effects of N. sativa, Z. officinale
and their mixture on viral load of control
and treated patients were depicted in Figure
1. After one month treatment with N. sativa
and/or Z. officinale ethanolic extracts, pa- Figure 2: Serum AFP in healthy, HCV control
tients exhibited a significant (PEXCLI Journal 2013;12:943-955 – ISSN 1611-2156
Received: July 31, 2013, accepted: October 28, 2013, published: November 11, 2013
Figure 3: Serum liver enzymes of healthy, HCV control and HCV treated patients; (a) ALT, (b) AST,
(c) γGT, (d) LDH and (e) ALP. Data are expressed as mean ± SE, means which share the same su-
perscript symbol(s) are not significantly different, PEXCLI Journal 2013;12:943-955 – ISSN 1611-2156
Received: July 31, 2013, accepted: October 28, 2013, published: November 11, 2013
Table 1: Albumin, total bilirubin, PT, PC and INR in healthy, HCV and HCV treated patients
Albumin Total Bilirubin PT PC INR
(g/dl) (mg/dl) (Sec) ( %)
Healthy 4.57 ± 0.09a 0.21 ± 0.03c 12.86 ± 0.06b 95.68 ± 0.65c 1.05 ± 0.01b
HCV Control 3.69 ± 0.09b 0.83 ± 0.08a 13.69 ± 0.19a 88.61 ± 1.47d 1.13 ± 0.02a
HCV + N 4.32 ± 0.11a 0.37 ± 0.07bc 11.93 ± 0.24d 105.94 ± 2.89a 0.95 ± 0.02d
HCV + G 4.29 ± 0.11a 0.46 ± 0.05b 12.49 ± 0.24cb 99.75 ± 2.35cb 1.01 ± 0.03bc
HCV + NG 4.47 ± 0.08a 0.42 ± 0.06b 12.17 ± 0.14cd 102.68 ± 1.55ab 0.98 ± 0.02cd
F-Prob. PEXCLI Journal 2013;12:943-955 – ISSN 1611-2156
Received: July 31, 2013, accepted: October 28, 2013, published: November 11, 2013
potent inhibitors of nitric oxide (NO) syn- zymes are considered the most sensitive
thesis in activated macrophages as reported markers of liver injury as they are found in
by Li et al. (2011). The antioxidant activity the cytoplasm of liver cells, thus damage of
of [6]-gingerol against linoleic acid autoxi- these cells lead to their rapid leakage into
dation and phospholipids peroxidation has the blood circulation (Ramaiah, 2007). The
been demonstrated earlier (Ippoushi et al., present investigation showed a significant
2003). In addition, it has been found to pro- increase in serum ALT, AST, LDH, γGT
tect against cellular damages induced by and ALP activities and total bilirubin levels
peroxynitrite (Ippoushi et al., 2003). It pro- of untreated HCV patient as compared to
tected DNA from lipopolysaccharide- healthy subjects. The significantly elevated
induced oxidation damage in rats (Ippoushi liver enzymes could be attributed to viral-
et al., 2007). In the study conducted by Du- induced hepatocellular damage. On the oth-
gasani et al. (2010), [6]-shogaol has exhib- er hand, administration of N. sativa, Z. of-
ited the most potent antioxidant properties, ficinale and their mixture greatly improved
compared to [6]-gingerol, [8]-gingerol and the altered serum liver enzymes and this
[10]-gingerol. The recorded antioxidant ef- may be mediated through their hepatopro-
ficacy of [6]-shogaol can be attributed to tective effects.
the presence of α,β-unsaturated ketone moi- In consistent with our results, a recent
ety (Dugasani et al., 2010). Moreover, the study by Barakat et al. (2013) showed that
contained phenolic compounds of ginger, N. sativa seed oil potentially alleviated se-
such as gingerol and shogoal, possess anti- rum liver marker enzymes in Egyptian
oxidant (Jeyakumar et al., 1999), anti- HCV patients. They also revealed that N.
cancer (Shukla and Singh, 2007), anti- sativa oil administration was tolerable, safe,
inflammatory (Hudson et al., 2006; Habib decreased viral load, and improved oxida-
et al., 2008), anti-angiogenesis (Huang et tive stress and clinical condition. Mallikar-
al., 2000) and anti-artherosclerotic proper- juna et al. (2008) demonstrated that oral
ties (Coppola and Novo, 2007). Further- administration of 200 mg/kg ginger etha-
more, the phagocytic activity of blood leu- nolic extract along with country-made liq-
kocytes was increased in rainbow trout fed uor significantly alleviated the elevated se-
with plant extracts containing food, espe- rum AST, ALT and ALP activities as well
cially 1 % ginger (Dügenci et al., 2003). as tissue lipid peroxide levels in experi-
Zhou et al. (2006) demonstrated that the mental animals. Moreover, Lebda et al.
volatile oil of ginger influences both cell- (2012) reported that rabbits fed with basal
mediated immune response and non- diet supplemented with 2 % ginger powder
specific proliferation of T lymphocyte, and and ginger extract; hot and cold for 30 days
may exert beneficial effects in a number of showed significant decrease of serum AST,
clinical conditions, such as chronic inflam- ALT, ALP and γGT activities as compared
mation and autoimmune diseases. Hence, with control group. Furthermore, many
the observed antiviral potential of N. sativa studies had addressed the potent hepatopro-
and/or Z. officinale was mediated through tective effect of ginger extract in induced
their antioxidant, immunomodulatory and hepatotoxicity (Mallikarjuna et al., 2008;
anti-inflammatory efficacies. El-Sharaky et al., 2009; Motawi et al.,
The role of liver enzymes in the as- 2011).
sessment of chronic hepatitis C remains Serum albumin is the most abundant
important due to the fact that the majority plasma protein (Don and Kaysen, 2004) and
of clinical indexes estimating the degree of is essential for maintaining oncotic pressure
liver fibrosis are based on liver transami- of the vascular system (Quinlan et al.,
nases (Giannini and Testa, 2003; Forns et 2005). Serum albumin and prothrombin
al., 2004; Lackner et al., 2005). These en- time can be considered useful tools, alone
949EXCLI Journal 2013;12:943-955 – ISSN 1611-2156
Received: July 31, 2013, accepted: October 28, 2013, published: November 11, 2013
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