96 J Contemp Med Sci | Vol. 5, No. 2, March–April 2019: 96–100 Original The efficacy of traditional formulation on quality of life and fatigue in multiple sclerosis patients: a randomized double-blind placebo-control clinical trial F. Namjooyan,a R. Ghanavati,b N. Majdinasab,c and H. Rezaei Zadehd aPharmacognosy Department, School of Pharmacy, Jundishapur University of Medical Sciences, Ahvaz, Iran. bTraditional Pharmacy, School of Pharmacy, Jundishapur University of Medical Sciences, Ahvaz, Iran. cNeurology Department, School of Medicine, Jundishapur University of Medical Sciences, Ahvaz, Iran. dTraditional Medicine, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran. *Correspondence to Rahil Ghanavati (email: rahil_ghanavati@yahoo.com). (Submitted: 04 December 2018 – Revised version received: 26 January 2019 – Accepted: 23 February 2019 – Published online: 26 April 2019) Objective According to effects that cinnamon, ajwain and Iranian borago shows in involving mechanisms in MS and MS animal model, we decided to survey the effect of traditional formulation on MS patient by clinical trial. Methods In a double blind randomized clinical trial study, 60 patients with MS observed. They take formulation 15 cc per day, fill the MSQOL-54, and fatigue questionnaires every month. The data were analyzed with 18th version of SPSS, independent t-test and repeated measure tests. The P-value for tests was 0.05. Results The mean quality-of-life and fatigue of patient with MS were significantly changed during 3 months. Conclusion Most patients with MS had better quality-of-life during 3 month and get less tired. In some patient tremor and pain reduce. Because of good result and revenue of formulation, it seems to be useful for MS patient. Keywords quality of life, fatigue, multiple sclerosis Introduction Multiple sclerosis (MS) is a chronic inflammatory autoim- mune demyelinated disease of central nervous system (CNS) that could be disabling and fatal. MS attack to myelinated axons in CNS and destroy it. This disease generally occurs at the age of 20–40 years. The key of pathologic mechanism of MS shows a breakdown in immunologic tolerance or a periph- eral infection and following a demineralizing inflammation attack to CNS. Start of this pathologic process represents the complex interference of genetics and environment that is not understand completely. In MS, neurologic symptoms (visual, sensory and motor) occur because of neurodegenerative pro- cess. In CNS there are lesions with penetrated specific inflam- matory cells and demyelinated. The cause of neurodegenerative process is unknown. One possibility is a chronic infection in CNS. Various kinds of neurotropic micro-organisms in MS are known although there is no definitive evidence for the reasons. The grade of MS is wildly different and unpredictable. In sev- eral patients MS initially diagnosis with reversible neurologic disorder episodes that is often followed by progressive neuro- logic attack. In 2013 almost 2.5 million patients in the world affected with MS that 50% of them, need help for walking after 15 years of disease onset. Women twice the men affected with MS, and northern Europe people are in higher risk for MS.1–3 Using complementary and alternative medicine (CAM), for chronic disease such as MS is an important issue for patients. CAM’s methods use in addition or instead of conven- tional medicine. In summary, CAM is wildly described as a positive cure without major defeat and without or with low adverse effect by patients. CAM is part of varied medical system which is not considered as a conventional medicine and include mind–body practice and manipulative, traditional medicine and modern medical system. Unani medicine is a part of traditional medicine that is according to Harrison’s book” Unani medicine is a western Indian medical system that is derived from Iranian medicine and initially use in Muslim country and also called hikmet”.4–6 Moreover traditional Persian medicine (TPM), is an ancient temperament medicine with thousands years history. This kind of medicine is thought in traditional and comple- mentary medicine and traditional pharmacy faculty in Iran. Recently use of herbal medicine as CAM in cure disease is increased.7,8 In TPM one categories of disorders generally called Khaddar, that similar point of them is sensory disorders. Khaddar is any kind of sensory deficiency or invalidity, which may be associated with motor symptoms. This sensory dis- order is painful, like creeping sensation, having a prickly sen- sation or sense of ant walking on the skin. According to these definitions, it seems that Khaddar is similar to hypesthesia and paresthesias.9–13 Ajwain or Trachyspermum ammi belong to Apiaceae that is wildly grown in Iran, Egypt, Pakistan, Afghanistan, India and some part of Europe. This plant is known as zenyan or nankhah in medicine and pharmaceutical references of TPM. Ajwain’s seeds are wildly prescribed by traditional Iranian physician’s foe several disorders. Because of its various chem- ical constituents, this seeds have numerous pharmacologic effects. Ajwin’s seed has stimulant, carminative, diuretics, analgesic, antimicrobial, antiviral, antiulcer, antihypertensive, and antitussive, and bronchodilator, antiplatelet and hepato- protective properties.14,15 Iranian borago or Echium amoenum is belonging to Bor- aginaceae family that is a 2 year or perennial herb. This plant is endemic of north of Iran and Caucasus. Iranian borago is one of the important medicinal herbs in TPM. E. amoenum has different effect such as pain relief, anti-inflammatory, anti- oxidant, and analgesic, antianxiety, sedative and anticonvul- sant. This plant commercially cultivated for the seed’ oil which ISSN 2413-0516 F. Namjooyan et al. 97J Contemp Med Sci | Vol. 5, No. 2, March–April 2019: 96–100 Original The efficacy of traditional formulation on quality of life and fatigue in multiple sclerosis patients is prepared from seed. The leaves and flower are also used as drug. They are used for fever, cough and depression. Seed’s oil is used for skin disorder such as eczema, seborrhea dermatitis and neuro dermatitis. Also it is used for rheumatoid arthritis, alcoholism, obsessive compulsive disorder, pain and swelling and preventing cardiovascular disease.16 Cinnamon is prepared from inner bark of an ever green tree which is endemic of Sri lanka and south of India. Its scien- tific name is Cinnamomum verum or Cinnamomum zeylan- icum. Cinnamon bark is wildly used as a spice and flavoring agent.17,18 In addition to home uses of cinnamon, in ayurveda, cinnamon is used for respiratory digestion and women dis- ease. Almost all part of cinnamon tree such as bark, leaves, flower, fruits and root have home and medicinal application. The essential oil which is prepared from roots bark, bark and leaves is significantly different in chemical constituents. So it is suggested that they have different pharmacologic effect. In vitro, in vivo and clinical studies all over the world demon- strated numerous beneficial effect for cinnamon, such as anti-inflammatory, antibacterial, reduce cardiovascular dis- ease, increase cognitive function and reduce risk of colon cancer.18 The aim of this study is evaluate the efficacy of a tradi- tional formulation on quality-of-life and fatigue of MS patients. Materials and Methods Two part of ajwain and one part of Iranian borago were soaked in water for 24 h and one part of cinnamon was soaked in water for 72 h then were distilled to yield the drug. Drug and placebo were gave to patients 15 cc per day for 3 months. This study was a 3-month, double-blind study of parallel group of patients with multiple sclerosis and was taken in Khuzestan MS association in Iran from July 2018 to November 2018. Sixty adult patient (20–50 years old), who were member of MS association were eligible to participate. Patient were required proved MS disease according to clinical examination and disease history, Expanded Disability Status Scale score 2–5.5,19 had a regular drug therapy and no change in drugs for last 4 weeks. A neurologist examined all patients. Patients with any of the following conditions were not qualified for the study: history of drug or alcohol abuse, preg- nancy or lactation during the last 12 months, renal or liver failure, and steroid therapy during last 2 months, another neu- rologic disease except MS, cardiovascular disease, or infection and sensitivity to cinnamon. This trial is in accordance with the Helsinki Declaration of 1975. The Ethics committee of Ahvaz Jundishapur Univer- sity of Medical Sciences (ethics No. IR.AJUMS.REC.1397.063) approved the protocol. The patients authorized the testimonial and were informed that they could withdraw from the trial any time they want. A written consent was obtained from all par- ticipants. The measurements that include quality-of-life score, fatigue score, and cognition were monitored by filling stand- ardized and validate questionnaire MSQL-54, fatigue severity score, and California Verbal Learning Test score respectively. All measures were done at baseline and monthly after the treatment started. We used block method for randomization. The investi- gator provided with a randomization code for each available medication. All randomization codes were opened at the end of the study. Patients were randomized to receive drug or pla- cebo in 1:1 ratio. Drug and placebo were not visually identi- fied. All participants were supposed to take four capsules per day (every 6 h). Results Of total 60 patients, who enrolled into the trial, 30 patients were assigned to either drug or placebo group. During follow-up, nine patients were dropped out. Three for disease progression, one for moving to another city, one for drug sen- sitivity, and five for lack of compliance in follow-up. Finally, 51 patients completed full 3 months of study period. Basic demographic data are presented in Table 1. There were no sig- nificant differences between the two group’s participants. After 3 months follow-up of all participants, our study, demonstrate that for patient’s fatigue score, the difference between two groups was not significant (P-value: 0.353, f: 1.0464), but interaction difference between drug and pla- cebo group in four levels was significant (P-value <0.001, f: 126.393). Mean ± SD score of drug and placebo group and 95% confidence interval were shown in Table 2. Results showed that fatigue in the drug group was decreased from baseline 15.74%, 23.49% and 40.65% at the end of 1st, 2nd and 3rd month respectively. While in placebo group, fatigue was increased from baseline 15.91%, 32.15% and 43.92% respectively (Fig. 1). Quality-of-life questionnaire is divided into two parts, physical and mental quality-of-life. For physical quality-of-life score in the cinnamon group increased more than placebo group. According to Mauchly’s test, due to lack of sphericity, for comparison between levels and their interactions with drugs used Greenhouse-Geisser was used. The difference Table 2. Fatigue score Mean ± SD 95% Confidence interval Down bound Upper bound Drug Baseline 3.729 ± 0.027 3.355 4.103 1st month 3.142 ± 0.033 2.684 3.600 2nd month 2.853 ± 0.032 2.684 3.307 3rd month 2.213 ± 0.32 1.765 2.661 Placebo Baseline 3.520 ± 0.028 3.121 3.919 1st month 4.186 ± 0.035 3.658 4.635 2nd month 4.652 ± 0.035 4.168 6.135 3rd month 5.066 ± 0.034 4.588 5.543 Table 1. Demographic data for patients participated in this study Drug Placebo P-Value Gender (m/f ) 10/16 9/16 ns Age (mean ± SD) years 46 ± 1.52 48 ± 1.78 ns Level of education Under diploma 6 8 ns Diploma 12 10 ns Higher diploma 8 7 ns 98 J Contemp Med Sci | Vol. 5, No. 2, March–April 2019: 96–100 The efficacy of traditional formulation on quality of life and fatigue in multiple sclerosis patients Original F. Namjooyan et al. between two groups was significant (Greenhouse-Geisser, p-value <0.001, f: 11630), and interaction difference between drug and placebo group in four levels was significant (p-value <0.001, f: 41.988). Mean ± SD score of drug and placebo group and 95% confidence interval were shown in Table 3. Results showed that physical quality-of-life in the drug group was increased from baseline 5.29%, 10.69% and 14.63% at the end of 1st, 2nd and 3rd month respectively. While in placebo group, physical quality-of-life was decreased from baseline 0.38%, 2.66% and 12.83% respectively (Fig. 2). For mental quality-of-life score in the cinnamon group increased more than placebo group. According to Mauchly’s test, due to lack of sphericity, for comparison between levels and their interactions with drugs used Greenhouse-Geisser was used. The difference between two groups was significant (Greenhouse-Geisser, p-value <0.001, f: 14.805), and interac- tion difference between drug and placebo group in four levels was significant (p-value <0.001, f: 75.600). Mean ± SD score of drug and placebo group and 95% confidence interval were shown in Table 4. Results showed that mental quality-of-life in the drug group was increased from baseline 14.37%, 31.31% and 48.88% at the end of 1st, 2nd and 3rd month respectively. While in placebo group, mental quality-of-life was decreased from baseline 2.15%, 8.77% and 16.97% respectively (Fig. 3). For overall quality-of-life score in the cinnamon group increased more than placebo group. According to Mauchly’s test, due to lack of sphericity, for comparison between levels and their interactions with drugs used Greenhouse–Geisser was used. The difference between two groups was significant (Greenhouse–Geisser, p-value <0.001, f: 20.622), and interac- tion difference between drug and placebo group in four levels was significant (p-value <0.001, f: 93.881). Mean ± SD score of drug and placebo group and 95% confidence interval were shown in Table 5. Results showed that quality-of-life in the drug group was increased from Fig. 1 Fatigue score curve. Table 3. Physical quality-of-life score Mean ± SD 95% Confidence interval Down bound Upper bound Drug Baseline 79.280 ± 0.171 76.917 81.643 1st month 83.480 ± 0.162 81.241 85.719 2nd month 87.760 ± 0.161 85.563 89.984 3rd month 90.880 ± 0.171 88.518 93.242 Placebo Baseline 81.818 ± 0.182 79.299 84.337 1st month 81.500 ± 0.172 79.114 83.886 2nd month 79.636 ± 0.171 77.266 82.007 3rd month 78.318 ± 0.182 75.800 80.836 Fig. 2 Physical quality-of-life score curve. Table 4. Mental quality-of-life score Mean ± SD 95% Confidence interval Down bound Upper bound Drug Baseline 50.080 ± 0.312 45.751 54.409 1st month 57.280 ± 0.257 53.721 60.839 2nd month 65.760 ± 0.287 61.790 69.730 3rd month 74.560 ± 0.281 70.675 78.445 Placebo Baseline 54.909 ± 0.334 50.249 59.524 1st month 53.727 ± 0.275 49.933 57.522 2nd month 50.091 ± 0.306 45.859 54.323 3rd month 45.591 ± 0.300 41.450 49.732 Fig. 3 Mental quality-of-life score curve. Table 5. Overall quality-of-life score Mean ± SD 95% Confidence interval Down bound Upper bound Drug Baseline 141.76 ± 2.95 135.81 147.712 1st month 152.68 ± 2.37 147.90 157.46 2nd month 162.56 ± 2.45 157.63 167.48 3rd month 173.52 ± 2.44 168.60 178.44 Placebo Baseline 159.04 ± 3.15 152.70 165.39 1st month 152.40 ± 2.53 147.31 147.50 2nd month 145.81 ± 2.60 140.56 151.06 3rd month 139.36 ± 2.60 134.122 144.60 F. Namjooyan et al. 99J Contemp Med Sci | Vol. 5, No. 2, March–April 2019: 96–100 Original The efficacy of traditional formulation on quality of life and fatigue in multiple sclerosis patients baseline 8.81%, 18.67% and 27.89 at the end of 1st, 2nd and 3rd month respectively. While in placebo group, overall quality-of-life was decreased from baseline 1.09%, 5.12% and 9.37% respectively (Fig. 4). Discussion Although the etiology of MS is poorly understood, it is becoming clear that widespread inflammation, loss of regula- tory T cells (Tregs), hyperactivity of autoimmune Th1 and Th17 cells, breakdown of blood–brain barrier and blood– spinal cord barrier, and loss of neuroprotective molecules in the CNS are critical for the manifestation of demyelinating pathology in MS.20 Sodium Benzoate (NaB) is one the direct metabolites of cinamic acid which is find in cinnamon. Human body could metabolize cinnamon to NaB. Studies showed that NaB effec- tively inhibited infiltration of monoulcer and demyelinated cells into spinal cord of experimental autoimmune encephalomy- elitis (EAE), the animal model of MS, mice. Following NaB sup- press the expression of pro-inflammatory molecules and normalized the expression of myelin in CNS. In addition, NaB showed that it could change differentiation of myelin basic pro- tein-primed T cells from Th1 into Th2 mode. NaB increase the number of regulatory T cells and reduce the expression of var- ious contact molecules. Thus, altogether this evidence showed that NaB in multiple steps modulate encephalitogenic T cells so it could be an important therapeutic agent in MS.21 On the other hand, studies showed that cinnamon and its metabolite cin- namon increase neutropic factors (NF) in CNS. NaB is a FDA-approved drug against urea cycle disorder in human and increase the level of brain derived NF (BDNF) and neurotro- phin-3 (NT-3) in CNS. Oral use of cinnamon increases the level of NaB and after that level of NF in CNS of mice. NaB induce activation of protein kinase A (PKA), so cAMP response ele- ments binding (CREB) will be activated. Thus with oral use of cinnamon PKA activate and the level of phospho-CREB in mice CNS will be increased. This result shows that cinnamon and NaB has neurotropic property.22,23 Increase and maintenance of regulatory T cells (Tregs) during inflammation process could have therapeutic effect in autoimmune disease. NaB increase Tregs and protect mice against EAE.24,25 Fig. 4 Overall quality-of-life score curve. Ajwain is evaluated for its anti-inflammatory effect. Both ethanolic and aqueous total extract of ajwain in animal models significantly show anti-inflammatory effect.26 Anti- oxidant effect of ajwain is evaluated with hexachlorocy- clohexane extract and showed that in animal model oral extract of ajwain reduce hepatotoxicity induce free radicals stress.26,27 It is well defined that nitric oxide has an important role in inflammatory process and chronic disease such as MS. Nitric oxide toxicity increase when it react with super- oxide radicals. In vitro studies show that aqueous and etha- nolic extract of ajwain inhibited nitric oxide.26,28 In addition ajwain seed oil is effective in neurologic pain.27 Clinical trial shows that using ajwain product in curing neuropathy pain in MS patients was useful.29 In summary, we have demonstrated that this drug could improve quality-of-life and fatigue of MS patients through suggested mechanisms. Thus this drug may have therapeutic value in MS and other demyelinating conditions. 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