A herb is a plant or part of a plant that can be used for its scent, flavour and therapeutic properties, a product made from plants and used solely for internal use is called a herbal supplement. These natural products claim to maintain and improve health, however the safety of them remains controversial, they claim to have similar affects to a prescription drug, however they are not subject to the same level of testing, manufacturing, labelling standards and regulations. Many prescription drugs or over the counter medicines contain plant products however, usually only purified ingredients and are regulated by the Food and Drugs Administration (FDA), herbal supplements will contain entire plants or plant parts.
These herbal products are not required to be standardized, therefore batch to batch consistency is not guaranteed. Their safety, like other drugs, will depend on the dose, chemical makeup, how they are prepared and how they react within an individuals body including interactions with any other drugs or medicine being taken concomitantly.
Therefore, the authenticity of these drugs is highly important from a consumers point of view to ensure their safety and that they perform as expected.
There is a growing awareness of herbal medicines for the use of prevention and treatment of Cardiovascular Disease (CVD), a general term used for conditions affecting the heart and blood vessels (nhs.uk, 2019). Cardiac related diseases are recognised as one of the main causes of death and disability in the UK and the number 1 cause of death globally, an estimated 17.
9 million people died from CVDs in 2016, representing 31% of global deaths (World Health Organisation, 2017). There are lots of risk factors which increase the likelihood of developing the disease, high blood pressure (HBP) being one of the most prevalent, meaning your BP is consistently higher than the recommended level, causing damage to the blood vessels (Bhf.org.uk, 2019). In 2003, HBP was the greatest attributor to the burden of CVD accounting for 42.1% of CVD total burden (The Heart Foundation, n.d.). Generally, hypertension is a systolic blood pressure (SBP), ? 140 mm HG, this is the highest level you BP reaches when the heart contracts and pumps blood through the arteries, or a diastolic blood pressure (DBP) ? 90 mm Hg, the lowest level your BP reaches as the heart relaxes between beats, or both. A decrease of as little as 3 mm Hg in SBP decreases the mortality rate of stoke by 8% and heart disease by 5%. (Banerjee and Maulik, 2002)
This review will look at herbal medicines associated with hypertension and their efficacy and consistency of therapeutic action towards lowering BP in an attempt to reduce the chance of an individual developing CVD. Medical trials and case studies alone are weak pieces of evidence due to the wide range of preparations and methods used from study to study, comparison and evaluation of findings will allow a wider conclusion to be drawn together regarding the main question surrounding herbal medicines, Are they beneficial to health, simply a placebo or detrimental to health?.
The outcome of this investigation is expected to be beneficial for consumers with the intention of using herbal medicines as a treatment/prevention. The conclusions drawn will provide a level of confidence and trust in the effectiveness of herbal-based products available as an alternative to regular prescribed medicines and confirming that their claims are not in fact fraudulent.
My interest in herbal products started building a few years ago when I became more aware of my own mental and physical health, I began exploring and using different products such as vitamins and supplements for hair, skin, digestion and weight loss along with adopting lifestyle changes such as a healthy diet and regular physical exercise. My personal use brought about questions such as How accurate are the product claims, Are they actually beneficial to my health? and therefore, Are they worth the money or just a scam?.
The use of plants and herbal products as therapeutic agents is culturally ubiquitous, and archaeological evidence shows they have been used since early history (Heinrich et al., 2012). This long history of use of herbal medicines shows their importance to consumers, however the acceptance and recognition of these products by pharmacists carries a large responsibility within their profession of ensuring safety of their patients and their health, and the lack of research behind most of these medicines makes this acceptance difficult (Edwards et al., 2012). Nonetheless, the use of herbal medicines is growing whether accepted by health care professional or not, the use of products and supplements has increased tremendously over the past three decades with ? 80% of people relying on them for some form of preliminary healthcare (Ekor, 2013). Thus showing the importance of investigating their effectiveness to ensure that the end results are meeting the claims behind the supplement.
In 2006 Rahman and Lowe stated that diets rich in fruits, vegetables and spices are associated with a lower risk of human diseases, including CVD, this is believed to be down to these foods containing phytochemicals with anti-inflammatory properties, conferring health benefits, one source of these being garlic (Allium Sativum). Although commonly known for its uses as a food flavouring agent, there is lots of scientific literature that supports the proposal that garlic consumption has multiple beneficial cardiovascular effects including lowing blood pressure, inhibition of platelet aggregation, lowering of cholesterol and triglyceride levels and protection of the elasticity of the aorta. (Walden and Tomlinson, 2011; Banerjee and Maulik, 2002; Joseph et al., 2014; Lawson 1998). The reason for these medicinal benefits is down to its chemical constituents. Garlic is rich in sulfer-containing compounds, alliin being the most abundant in whole garlic, however their composition and ratios can be altered depending on the type of processing and length of ageing (Watson and Preedy, 2013), for example a review conducted in 2013 stated that 10 and 30 mg/g of alliin is present in fresh and dry garlic, respectively (Gebreyohannes, 2013). Depending on the needs, garlic is used in different forms such as aged, powdered, raw, tablet and oil extracted from the cloves and marketed (Watson and Preedy, 2013). All literature explored, including journals, articles and online web pages have attributed the organosulfer compounds to the health benefits and medicinal properties of garlic. It is very evident that there is a large agreement that Allicin is thought to be the principal bioactive compound present in aqueous garlic extract responsible for these health benefits, however it is not present in garlic until tissue damage occurs (Yun et al., 2014). Processing garlic (chopping or crushing) causes the allinase enzyme to be activated and act on alliin to give rise to allicin (Banerjee and Maulik, 2002). The enzyme alliinase, responsible for this conversion, becomes inactive below a pH of 3.5 and is heat sensitive and therefore heat-treated preparations of garlic contain alliin. It is thought that 0.45mg allicin is equivalent to 1mg of alliin (European Scientific Cooperative on Phytotherapy, 1997; Barnes, Anderson and Phillipson, 2007).
Considering these health benefit claims multiple researchers from various disciplines have conducted reviews in the effort to discover the medicinal value of garlic on human health. The majority of studies looked at the use of garlic for other benefits as well as CVD, such as its antioxidant effect and treatment of neurological and malignant diseases. (Yun et al., 2014; Gebreyohannes, 2013; Lawson, 1998), however this review will stay focussed specifically on hypertension due to time constraints????
One of the more recent reviews by Hyung Yun and others , found evidence to support garlics pharmaceutical effect on cancer development, neurological diseases as well as cardiovascular disorders. Specifically looking at its effect on blood pressure, the review looked at 15 studies carried out between the years 2000 and 2010, using different preparations of garlic, doses and duration of trial. However, this review also discussed in vast detail the functional compounds of garlic and their contents in garlic from different origins, something that with the limitation of time and as it was not further discussed or linked into the discussion of garlics effect towards HT, is unnecessary to consider within this thesis. A review by Rahman and Lowe  looked at the correlation between garlic consumption and progression of CVD by analysing both in vitro and in vivo studies published since 1993. They concluded that garlic can reduce parameters associated with CVD, however mixed results were obtained on its antihypertensive effects. They explained that the importance of standardization in garlic preparation when used in clinical trials and that the duration of trials must be sufficient. Therefore, trials of varied length will be included and preparation used will be noted to see if these are contributing factors to the effect on hypertension, however dosage will still be the main focus as this is expected to be more (larger/more important) factor. In addition, the tables included in this review lacked detail regarding each trial and were difficult to understand, they mainly focussed on the preparation used and the number of trials which showed BP lowering effects, whereas reviews conducted by H. Yun  and Banerjee and Maulik  had clear tables with dose, duration, preparation and effect for each trial included. This layout will be used to exhibit findings for this thesis to allow effortless and simple comparison.
There is a lot of variety present for effective dose of Garlic in published literature, and for some reviews, no dosage values are reported at all. This is due to the different effects preparations of garlic have on the final supplement and therefore different doses appear to be required for each type of supplementation. Banerjee and Maulik  show that an effective dose of Kwai supplements was 600mg/d, whereas H. Yun  shows 1g/d of garlic cloves had the same blood pressure lowering effect and 3 out of 15 trials included that showed garlic to have no significant effect on BP all showed similarities, using a dose of 900-1000mg/d of garlic in tablet form. Therefore, to draw accurate conclusions between effectiveness of supplements used in trials with doses available to consumers, preparations will be discussed and compared to dosages on sale individually.
Most published reviews only briefly touch on the adverse effects of garlic as it generally possesses little risk in terms of safety, its main adverse effect being breath odour. Although not all side effects of garlic are known, consumption over a short period of time is thought to be moderately safe and mostly excessive consumption causing problems (Gebreyohannes, 2013). However as with any medication, this is strongly reliant on the preparation and dose being taken. A review was conducted by Ekor in 2013 discussed the toxicity and adverse affects of common herbal medicines and briefly touched on garlic, stating that effects such as burning sensation in the gastrointestinal tract, nausea, diaphoresis, and lightheadedness have been reported as associated with garlic extract, a review by Xiong et al.  reports gastrointestinal discomforts in 3 trials, however suggests easy methods of alleviation to be advised for patients in future trails. On the other hand, majority of trials have shown no adverse effects when using garlic supplements (Schwingshackl et al., 2016).
For some patients as an attempt to control blood pressure, various drugs need to be taken concurrently, thus increasing risks of side effects. It is believed by some researchers that CoQ10 supplementation will reduce the need to consume multiple antihypertensive drugs (Garrido-Maraver et al., 2014; Langsjoen et al., 1994b). Existing literature states that the exact mechanism of the enzyme is unknown, but most researchers agree on one theory, that it reduces peripheral resistance via sustaining levels of nitric oxide within vascular muscle (Pepe et al., 2007).
An article from 2015 by Dr David Mantle talks in more detail about what Coenzyme Q10 (CoQ10) is and its 3 functions related to cardiovascular function; its cell membrane protecting antioxidant abilities, its effect involved in genes inflammation and lipid metabolism and most relevant to hypertension, supplying cardiac cells with energy. CoQ10 is a naturally occurring lipid-soluble antioxidant produced within the body, also known as ubiquinone due to its ubiquitous distribution within all body tissues, but in highest concentration in the heart. It occurs in cells in two similar structures, ubiquinone (when oxidised) and ubiquinol (when reduced). A review article from 2018 compares the distribution of both these forms in bodily tissues, showing highest concentrations of ubiquinone in the heart (Zozina et al., 2018). Its primary function is as an essential intermediate of the electron transport system in the mitochondria. Adequate amounts are necessary for cellular respiration and ATP production and therefore is vital in the mechanism of supplying cells with energy (Garrido-Maraver et al., 2014). Therefore, it is very important for tissues with a high energy requirement, such as cardiac muscle, due to the higher number of mitochondria within their cells making them particularly reliant on maintaining adequate tissue CoQ10 levels for normal functioning. About 25% of the required amount of CoQ10 can be obtained from the diet and the rest is manufactured in the liver, this can become problematic with increasing age as the bodys capacity to produce CoQ10 decreases with age, optimal production being around mid-twenties. Therefore, dietary supplements of CoQ10 provide a simple mechanism to maintain adequate levels in the body. Langsjoen and Langsjoen,  state that optimum improvement in heart function requires a plasma CoQ10 level of at least 3 µg/ml.
A meta-analysis conducted by Sander et al.,  identified 11 trials using CoQ10 for dealing with hypertension and reiterated the theory that CoQ10 augments the relaxation of the vascular smooth muscle by preventing the reaction of nitrogen oxide (NO) with superoxide preserving the NO in the endothelium. It is widely discussed that increased oxidative stress initiates and propagates HT and CVD (Houston, 2014; Garrido-Maraver et al., 2014). In blood vessels, there is a positive correlation between oxidative stress and the production of the superoxide radical (O2?-). This reduces the ability of the endothelium cells to induce relaxation of smooth muscles, inducing vasoconstriction and thus increased blood pressure. A study carried out on 11 mild to moderate hypertensive males observed increased oxidative damage was present in patients with essential hypertension (Koska et al., 1999) and a clinical study demonstrated that supplementation of 300mg/d significantly improved endothelium dependent vasodilation (Tiano et al., 2007). Numerous other studies have investigated these claimed benefits of CoQ10 supplementation for improving cardiovascular function via enhanced energy production and therefore improved contractility of cardiac smooth muscle resulting in lower blood pressure. In addition to Sander 2006, two other meta-analysis reported CoQ10 had significant antihypertensive effects on patients with hypertension in clinical trials (Mortensen, 2003; Rosenfeldt et al., 2007) and a more recent meta-analysis carried out in 2017 found that CoQ10 supplementation has the potential to improve systolic BP, however no effect on diastolic BP was observed.
Langsjoen et al., [1994a] carried out a study summarizing 8 years of research treating 242 patients suffering from various forms of CVD. CoQ10 was taken in conjunction with their usual medical regimes. This study confirmed that CoQ10 is safe and effective adjunctive treatment for CVDs. Since this study, numerous other trials have exhibited CoQ10s usefulness towards CVD conditions and also more specifically HT, with the exception of one review in 2016, a meta-analysis of two randomised control studies was conducted and results showed an average reduction in both SBP and DBP, however they authors concluded that the change was not significant enough to say that CoQ10 had antihypertensive effects. However, as discussed in their limitations, the number of patients studied was small and therefore more studies were needed for a certain conclusion to be drawn of CoQ10s effect on BP (Ho et al., 2016). One meta analysis included 11 trials and another included 17, and both managed to reach reasonable conclusions, therefore, to answer the questions posed by this review, a minimum of 11 trials will be reviewed per supplement to ensure findings are based on a satisfactory amount of data to be deemed reliable.
In addition, most published literature has looked at broader effects of CoQ10 on human health than set out for this review, their investigations included the effect of CoQ10 on other CVD parameters such as serum lipoproteins and plasma fibrogen levels, myocardial infarction, and other conditions; metabolic diseases, neurological diseases, and diabetes (Fotino, Thompson-Paul and Bazzano, 2012; Tabrizi et al., 2018). However, this review will just focus on the symptom of hypertension and the supplements ability to reduce SBP and/or DBP due to the limitation of time available and considering the .
In 2014 J Garrido-Maraver published a journal on CoQ10 therapy and stated that a dose of 90-200mg/d is recommended, however this can vary depending on the person or condition being treated (Garrido-Maraver et al., 2014). A meta analyses conducted in 2017 found from the trials they included that a dose of 10-150mg/d of CoQ10 supplements resulted in significant decrease in SBP compared to doses of ? 150 mg/day. Another review of 13 studies found that 100mg/d for 12 weeks improved blood flow from the heart by reducing BP. (Fotino, Thompson-Paul and Bazzano, 2012). The majority of published literature that acknowledges dosage used, with a positive effect on HT, fall in agreement with the values of 10-200mg/d, however, one review said the dosage could be increased up to 300mg/d (Maladkar, 2016). Therefore, to confirm these allegations, trails using doses that lie within this range will be included, however, if available, outlier doses will also be investigated. This will allow the min and max dosages above to be confirmed or new ones to be established in light of new research.
Most published literature have shown CoQ10 as being devoid of any side effects, a safety assessment of CoQ10 was carried out by Hidaka. T in 2008 stated that it is highly safe to use as a dietary supplement as it has low toxicity and does not induce severe side effects in humans. The assessment calculated that based on various clinical trial data the acceptable daily intake (ADI) is 12mg/kg/day and the observed safety level (OSL) for CoQ10 is 1200mg/day/person. The only side effects reported were gastrointestinal effects such as abdominal discomfort, nausea, vomiting, diarrhoea, and anorexia, however nothing significant that necessitated stopping therapy (Hidaka et al., 2008). This literature shows that safety of CoQ10 supplementation is not necessary to focus on during this thesis unless the observed safety level of 120mg is exceeded or specific side effects are observed.