Safety and efficacy of Labisia pumila containing products.
In folk medicine, Labisia pumila (kacip fatimah) has a very wide usage. L. pumila is consumed by a new mother to regain body strength, delay fertility, and contract the birth channel. In Malaysia, water decoction of the root or whole plant is traditionally consumed by the Malay women for induction and facilitation of labor, as well as for the treatment of flatulence, dysentery, dysmenorrhea, gonorrhea, and sickness in the bones. 
Product registration information obtained by National Pharmaceutical Control Bureau (NPCB) states that the active ingredients of this product are L. pumila (kacip fatimah) extract and also Croton caudatum (manjakani) extract without mentioning any specific chemical compound. Referring to the packaging, L. pumila extract is 40 mg, C. caudatum extract is 10 mg, and excipient is 450 mg for each 500 mg capsules. As highlighted by the product name, the major active component is L. pumila extract. The main chemical constituents of L. pumila are flavonoids (kaempferol, myricetin, naringin, and rutin) and phenolics compound (gallic acid and pyrogallol). 
Generally, flavonoids are absorbed by small intestine ranges from 0% to 60% of the dose and elimination half-life range from 2 to 28 h. Absorbed flavonoids undergo extensive first-pass Phase II metabolism in the small intestine epithelial cells and in the liver. Metabolites conjugated with methyl, glucuronate, and sulfate groups are the predominant forms present in plasma. This review summarizes the key differences in absorption, metabolism, and pharmacokinetics between the major flavonoids present in the diet. For each flavonoid, the specific metabolites that have been identified so far in vivo are indicated. These data should be considered in the design and interpretation of studies investigating the mechanisms and potential health effects of flavonoids. 
In a study involving four healthy males and four healthy females, kaempferol, from a relatively low dose (9 mg), was absorbed from endive with a mean maximum plasma concentration of 0.1 [micro]M, at a time of 5.8 h, indicating absorption from the distal section of the small intestine and/or the colon. Although a 7.5-fold interindividual variation between the highest and lowest maximum plasma concentration was observed, most individuals showed remarkably consistent pharmacokinetic profiles. This contrasts with profiles for other flavonoids that are absorbed predominantly from the large intestine (e.g., rutin). An average of 1.9% of the kaempferol dose was excreted in 24 h. Most subjects also showed an early absorption peak, probably corresponding to kaempferol-3-glucoside, present at a level of 14% in the endive. Kaempferol-3-glucuronide was the major compound detected in plasma and urine. Quercetin was not detected in plasma or urine indicating a lack of phase I hydroxylation of kaempferol. Kaempferol is absorbed more efficiently than quercetin in humans even at low oral doses. The predominant form in plasma is a 3-glucuronide conjugate, and interindividual variation in absorption and excretion is low, suggesting that urinary kaempferol could be used as a biomarker for exposure. 
Another study was conducted to characterize the bioavailability of cranberry flavonoids and phenolics acids from cranberry juice cocktail (CJC) in 10 healthy adults with body mass index (BMI) 18.5-29.9, and age 50-70 years.  After 2 days, blood samples were collected at specified time points before and up to 24 h after beverage consumption. Marked variation in the maximal plasma concentration (Cmax) and time to reach Cmax (Tmax) of these cranberry bioactives such as myricetin with 18.3 ng/mL at 2 h, quercetin with 0.4 [micro]g/mL at 8 h, and kaempferol with 18.4 ng/mL at 2 h, respectively. These data suggest that different phenolic constituents in CJC are absorbed and metabolized at different locations in the gastrointestinal tract. 
From few studies conducted above, it can be concluded that each flavonoid and phenolics compound have its characteristics pharmacokinetics property. For its pharmaceutical actions, discussion should be done in deeper as a study in humans is less or none compare to studies conducted in rats.
COMPLIANCE TO MALAYSIAN ADVERTISEMENT BOARD REGULATIONS
Medicinal products have potential for beneficial as well as harmful effects and if it is used incorrectly, it may cause a serious health problem. Therefore, all advertising and promotion of medicinal products must be responsible and ethical to ensure public are protected and safe from any misleading and confusing information provided. Advertisement of medicinal product is regulated in Malaysia and guidelines have been provided by Malaysian Advertisement Board (MAB) for references. General principles on advertising related to this product are as discussed in the coming paragraph.
According to MAB guidelines 4.3, advertising to the public is only allowed for a product which is registered with drug control authority (DCA). Through NPCB registry, this product is registered and allowed to be advertised on any mean of advertising method after approved by MAB. 
However, according to MAB guidelines 4.14, Kementerian Kesihatan Lembaga Iklan Ubat (KKLIU) number must be clearly displayed together with the name, address, and contact number of the advertiser on every page which has been approved by MAB, which seems to be lacking in the product's page. The absence of KKLIU number indicates that the advertisement does not getting any approvals from MAB. 
In terms of product claims, advertisement should not contain any claims either directly or indirectly referring to the list of diseases or health condition as mention in MAB guidelines 4.4. In the product's page, it mentions that the product can be used for the prevention of cancer, infertility, and few other indications, which is not allowed by MAB. The use of these indications is only allowed if approved by MAB and indications approved by DCA. Medicinal products such as traditional products are very unlike to use these specific indications. 
According to MAB guidelines 4.9, advertisements should not contain any statement or visual presentation which, whether directly or by implication, is likely to mislead the consumer about any product. In the page, the picture of ovarian tumor fibroma was placed in one of the windows related to the product. 
According to MAB guidelines 4.13, approved advertisement by MAB shall not be advertised in the same space as with product advertisement which does not require MABs approval such as food, medical device, and cosmetic products. In the page, there is food product (Butterfly Tea) being placed in the page. 
An online search was conducted using the criteria described in Table 1.
RESULTS AND DISCUSSION
Efficacy and safety
In Malaysia, for the purpose of registration, the efficacy of traditional product is not tested. The concern is to test on the safety of the product so public are protected from the flooding of traditional product in the market.
A randomized, placebo-controlled study was designed to look at the safety profile of L. pumila water extract on postmenopausal women. The study duration was 6 months, and all participants were required to come for visit every 2 months. During each visit, participants were asked regarding any side effects of medication or occurrence of per vaginal bleeding. Vital signs, BMI, and waist-hip ratio were measured on every visit. On visit 4 or last visit, all blood investigations, chest X-ray, electrocardiogram, and pap smear were repeated. As a conclusion, we found that L. pumila water extract was safe for consumption. 
A study on the effect of L. pumila on the skin as topical application has been conducted. Extract of L. pumila was first analyzed for their antioxidant activities using 2,2-diphenyl-1-picrylhydrazyl. The 50% free radical scavenging activity (FSC50) of L. pumila extract was determined to be 0.006%, which was equal to that produced by 156 [micro]M ascorbic acid. Treatment with L. pumila extract markedly inhibited the tumor necrosis factor alpha production and the expression of cyclooxygenase-2. Decreased collagen synthesis of human fibroblasts by ultraviolet B was restored back to normal level after treatment with L. pumila extract. On the other hand, the enhanced matrix metalloproteinase-1 (MMP-1) expression upon UVB irradiation was downregulated by L. pumila extract in a dose-dependent manner. Furthermore, treatment of normal keratinocytes with L. pumila extract attenuated UVB-induced MMP-9 expression. These results collectively suggest L. pumila extract has tremendous potential as an anti-photoaging cosmetic ingredient. 
As further search for the efficacy and safety data on L. pumila, there is not much information available regarding clinical test conducted in human. Most studies were conducted in laboratory using rat, and the available information cannot be extrapolated in human. Animals may process herbal products differently from humans; thus, results are not necessarily reliable. It is important that the plant materials of herbal medicines being clinically evaluated in randomized, double-blind studies to examine the evidence-based benefits to consumers. 
Potential risk to general public
Living active kacip fatimah phyto plus capsules and other products classified under traditional product are flooding Malaysian market. These products are sold in many places and easily available to the public including those registered and also those are not registered with NPCB.
The influence of folk's medicine, especially herbal in the daily living of Malaysia is very prominent and can be one of the main reasons for any herbal product to be marketed easily in Malaysia. The risk came when public assuming all herbal base products are safe and can be consumed without any cautions. This is where unregistered and adulterated traditional product plays their role by taking advantages to public.
Adulterated products are very dangerous because most of it is mixed with steroids and sildenafil. These two chemical constituents are mostly found in adulterated product because the demand for it. Public will use that certain product repeatedly because the relieving effect of steroid and improving sexual function by sildenafil and the herbal is just to mask the product and trick public to buy their product.
RECOMMENDATIONS AND CONCLUSIONS
According to MAB Guidelines on advertising of medicines and medicinal products to general public, all medicinal products need to get approval before it can be advertised. The product itself must be registered prior application to MAB. Other class of product such as food and medical device does not have to get approval from MAB.
It is very important to educate public on how to identify approved product advertisement to avoid manipulation from irresponsible party by being able to identify KKLIU number. Furthermore, to check the validity of the KKLIU number, cross-check can be done through pharmaceutical services division website at www.pharmacy.gov.my.
Medicinal product advertisement with MAB approved indicates that product information as well as product safety upon use is approved by Ministry of Health and can be used without worry by public. In addition, public also needs to play their role by seeking doctor's advice before using any medicinal products even though the advertisement is approved by MAB because this is another issue to be discussed.
Currently, the market has been flooded with many medicinal products in traditional or herbal form with various claims. Some of it made high claims too such as to treat infertility and even cancer. Guidelines and act prohibit such claims on traditional products unless approved by DCA. Ministry plays their role by enforcing advertisement act to protect public. On the other hand, public also needs to be aware and take notice on the KKLIU number and also product registration number before using any medicinal product, especially traditional product.
Financial support and sponsorship
This work was supported by Research Acculturation Grant Scheme: RAGS/1/2014/SKK07/UITM//7. The authors would like to express their gratitude to Ministry of Higher Education and Universiti Teknologi MARA (UiTM), Malaysia for financial support for this research.
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Conflicts of interest
There are no conflicts of interest.
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[3.] DuPont MS, Day AJ, Bennett RN, Mellon FA, Kroon PA. Absorption of kaempferol from endive, a source of kaempferol-3-glucuronide, in humans. Eur J Clin Nutr 2004; 58:947-54.
[4.] McKay DL, CY, CA, JB. Pharmacokinetics of flavonoids and phenolic acids from cranberry juice cocktail in humans. Faseb J 2010.
[5.] Malaysian Advertisement Board MoHM. Guideline on Advertising of Medicines and Medicinal Products to General Public; 2015.
[6.] Nik Hussain NH, Kadir AB. Clinical trial on the effects of Labisia pumila (kacip fatimah): Among Post Menopausal Women. 2011.
[7.] Choi HK, Kim DH, Kim JW, Ngadiran S, Sarmidi MR, Park CS. Labisia pumila extract protects skin cells from photoaging caused by UVB irradiation. J Biosci Bioeng 2010; 109:291-6.
[8.] Nik Hussain NH, Kadir AA. Potential role of Labisia pumila in the prevention and treatment of chronic diseases. J Food Res 2013; 2.
Muhammad Syafiq Saleh (1), Shazwani Shaharuddin (1), Md. Moklesur Rahman Sarker (2), Long Chiau Ming (1,3)
(1) Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, (2) Faculty of Pharmacy, Lincoln University College, Petaling Jaya, (3) Vector-borne Diseases Research Group (VERDI), Pharmaceutical and Life Sciences CoRe, Universiti Teknologi MARA, Shah Alam, Selangor, Malaysia
Address for correspondence:
Dr. Long Chiau Ming, Level 11, FF1 Building, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia.
Table 1: Search criteria and results Parameters Action/results Key words used Labisia pumila, kacip fatimah Years searched 2000-2015 Total numbers of articles reviewed 10 Relevant full-text article reviewed 2 Relevant abstract reviewed 4
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|Author:||Saleh, Muhammad Syafiq; Shaharuddin, Shazwani; Sarker, Moklesur Rahman; Ming, Long Chiau|
|Publication:||Archives of Pharmacy Practice|
|Date:||Jan 1, 2016|
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