Keywords

11.1 Introduction

Diabetes mellitus is a metabolic chronic disorder characterized by hyperglycaemia for a long period of time. It is a heterogeneous group of disorders that affects multiple organs, such as the kidney, eyes, nervous system, etc. Currently available and used therapeutics for the management of diabetes include biguanides, DPP-4 inhibitors, α-glucosidase inhibitors, sulfonylureas/insulinotropics and thiazolidinediones (World Health Organization Model Lists of Essential Medicines). Usage of these synthetic drugs is however associated with severe harmful effects. Besides synthetic molecules, many medicinal plant-based preparations have been found efficacious in the treatment of chronic diseases and their symptoms (Amin et al. 2009; Taur and Patil 2011; Choudhary et al. 2015; Rawat et al. 2016a, b; Brahmachari et al. 2017).

Hypertension is a key reason of mortality and morbidity and is linked with coronary heart disease, cerebrovascular disease and renal disease and significantly contributes to stroke and myocardial infarction. The threshold above which hypertension should be treated to avoid long-term complications is now 140/90 mm Hg. Hypertension is a multifactorial event, which is controlled through various factors such as neurogenic regulation, renin angiotensin system, endothelials, renomedullary vasodepression, adrenal steroids, etc. Current treatments to control high blood pressure include drugs such as calcium antagonists, angiotensin II receptor blockers, peripheral adrenergic inhibitors, angiotensin-converting enzyme inhibitors (ACEIs), β-blockers, α-2 adrenergic receptor agonists and diuretics (Kalra et al. 2010). However, intake of majority of the synthetic drugs is accompanied with adverse health outcomes and therefore does not lead to effective treatment especially when taken for prolonged duration (Marshall et al. 1976; Russell 1988; Morimoto et al. 2004).

The role of plant-based medications in the treatment of numerous ailments including chronic ones is being recognized worldwide. This was made possible through in-depth researches for understanding the mechanistic basis of the action of large number of phyto-compounds, including their target sites. Natural compounds, generally considered to be safe, have always been seen as an excellent candidate for drug discovery, which has become evident from substantial counts of drugs derived from natural sources including plants (Koehn and Carter 2005; Newman and Cragg 2016). Large numbers of traditionally used medicinal plants have been documented in classical literature and other documents, with their roles indicated in treatment of many categories of ailments such as gastrointestinal disorders (Rawat et al. 2016a, b, 2017), dengue (Singh and Rawat 2017), blood pressure (Rawat et al. 2016a, b), diabetes, obesity (Saad et al. 2017; Sudha et al. 2011), cancer (Newman and Cragg 2016), chronic inflammatory disorders, etc. With the development and advancement of technological tools, researches were conducted globally, wherein multiple biomolecules with the therapeutic efficacies have been isolated and characterized from different plant species. The outcomes of the clinical evaluation of plant-based therapeutics further confirmed their potency in human disease prevention and cure. This chapter describes several antihypertensive and antidiabetic phyto-compounds isolated from plants and evaluated for their therapeutic efficacy using in vitro as well as in vivo testing models. We found that very few of these phyto-compounds have been clinically evaluated and many preclinically validated compounds are yet to be explored in clinical trials. These phyto-molecules are the subject of further research for efficacy evaluation through clinical trials.

11.2 Applications of Plant-Derived Compounds for the Treatment of Diabetes and Hypertension

11.2.1 Antidiabetic Natural Compounds

Several plant-derived molecules have been investigated for their potential as antihyperglycaemic and their ameliorative effects on various biochemical alterations associated with diabetes at the molecular level. Common targets of some of these phyto-constituents include several intermediaries of metabolic pathways involved in maintaining glucose homeostasis in the body, viz. glycolysis, Krebs cycle, gluconeogenesis, glycogen synthesis, etc., whereas others have been found to play a functional role in the downstream signalling of insulin or function as insulinomimetics. Many researchers have reviewed the antidiabetic phyto-constituents and mechanisms of their action (Joseph and Jini 2011; Hung et al. 2012). These antidiabetic phyto-constituents have been classified into alkaloids, anthranoids, glycosides, amino acids, amines, carbohydrates, carboxylic acid derivatives, peptidoglycans, polyphenols, flavonoids and saponins (Bharti et al. 2018). Insulin therapy is an important part of diabetes treatment and is considered a must for type I diabetic patients and in many patients with type II diabetic conditions too. Secretion of insulin by pancreatic β-cells is known to regulate transport of glucose inside the cells using glucose transporter GLUT-2, through insulin-mediated signalling. Inability of pancreatic cells to secrete insulin in optimum quantity or nonresponsiveness of cells towards the insulin-insulin receptor interaction leads to non-transport of glucose inside the cells, resulting into hyperglycaemic conditions. Majority of the antidiabetic phyto-compounds have been found to have a role in triggering insulin secretion, thereby resulting in hypoglycaemia, while some also act as insulinomimetics. Recently discovered antidiabetic natural products and their mechanisms are summarized in Table 11.1.

Table 11.1 Antidiabetic phyto-compounds and their mechanisms of action
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11.2.2 Antihypertensive Natural Compounds

Numerous antihypertensive medicinal plants have been earlier documented and investigated in in vitro and in vivo models for their traditionally known biological activities. Many traditionally used antihypertensive medicinal plants have been studied in detail for their possible mode of action and pathway involved. Scientific studies highlight the significance of medicinal plants for their ameliorative effects on symptoms of the disease. Few of the plants extracts have also been tested on human subjects in multiple clinical trials and found to be effective (Rawat et al. 2016a, b). Hypotensive action has been suggested to be mediated by several modes of actions such as antagonism of Ca2+ channel, inhibition of angiotensin-converting enzyme (ACE), relaxation of myocardium or involvement of α-adrenoceptor (Rawat et al. 2016a, b). Apart from plants extracts, isolation and characterization of many phyto-compounds have also been carried out. These isolated compounds have been further explored for their role in mediating the blood pressure lowering effects. Mechanisms of action have been investigated for most of the constituents as shown in Table 11.2.

Table 11.2 Antihypertensive phyto-compounds and their mechanisms of action
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11.3 Clinical Trials on Plant-Derived Natural Therapeutic Compounds

Many phyto-constituents have been clinically tested for their effectiveness. In case of diabetes, the clinical parameters monitored were blood glucose, HbA1c, insulin after administration of test molecule. For hypertension, study parameter was reduction in mean arterial pressure, diastolic blood pressure (DBP) and systolic blood pressure (SBP).

11.3.1 Clinically Evaluated Antihypertensive Phyto-compounds

11.3.1.1 Allicin

To study antihypertensive property of allicin (from Allium sativum), a clinical trial on 100 subjects including 60 males and 40 females (25–55 years) was conducted. The study included the subjects with SBP in range of 140–150 mm and DBP <95 mm of Hg. For extraction of allicin from Allium sativum, fresh garlic cloves were crushed using water leading to 100% yield of allicin and 25 g crushed garlic was supplemented to subjects. Measurements of BP were made after 3 and 6 months. The treatment resulted in up to 5 mmHg (10%) reduction in SBP and DBP was observed (Bhardwaj et al. 2015).

11.3.1.2 Pinoresinol di-β-D-Glucoside

In a randomized placebo-controlled clinical trial, antihypertensive efficacy of Eucommia ulmoides was checked. Thirty healthy subjects (aged 18–60 years), with BP between 120–160 and 80–100 mmHg, were chosen for the study. Five hundred milligrams of aqueous bark extract of E. ulmoides (containing 8% pinoresinol di-β-D-glucoside) was administered thrice a day for 8 weeks and was found to have hypotensive action. The extract was found to act through beta-adrenergic receptors (Greenway et al. 2011).

11.3.1.3 Ginsenoside Rg3

Efficacy of ginsenoside Rg3-enriched ginseng was evaluated in a double-blind, randomized clinical trial. Twenty-three individuals including 9 males and 14 females (23–27 years) with SBP in a range of 110–116 mm Hg and DBP in a range of 68–72 mm Hg were selected. Four hundred milligrams wheat bran was used as a control along with 400 mg ginsenoside Rg3-enriched extract, which were administered to patients on two separate visits with a time gap of 7 days. After intervention, measurements of different parameters including central and branchial BP were taken at 1-h interval till 3 h. At 3 h, significant reductions in central and brachial mean arterial pressure by 4.7 mm Hg and 4.4. mm Hg, respectively, central SBP and DBP by 5 mm Hg and 3.9 mm Hg, respectively, and brachial SBP and DBP by 4.4 mm Hg and 3.6 mm Hg, respectively, were observed compared with control (Jovanovski et al. 2014). Panax quinquefolius is the main plant source for obtaining ginsenoside Rg3.

11.3.1.4 Pycnogenol

Pycnogenol from Pinus pinaster is a mixture of bioflavonoids, namely, procyanidins, taxifolin, catechin and phenolcarbonic acids. Antihypertensive effects of pycnogenol was studied in a placebo-controlled, double-blind, randomized, prospective, crossover study in mildly hypertensive patients. Eleven mildly hypertensive subjects (average age of 50 years) with SBP and/or DBP of 140–159 mm Hg and 90–99 mm Hg, respectively, were selected and supplemented with 200 mg/day of pycnogenol up to 56 days. SBP showed substantial reduction with no significant differences observed in case of DBP as compared to placebo (Hosseini et al. 2001).

11.3.1.5 Reserpine

Antihypertensive effects of reserpine have been well reported in the randomized controlled clinical trials, wherein statistically significant reduction on SBP was observed in treatment group taking 0.5 mg/day or greater of reserpine in comparison with placebo (Shamon and Perez 2009). The medicinal plant, Rauwolfia serpentina is the main source of reserpine.

11.3.1.6 Forskolin

The potential of forskolin (obtained from Coleus forskohlii), 7 beta-acetoxy-8, 13-epoxy-1 α,6 β,9 α-trihydroxy-labd-14-ene-11-one, in reducing BP was clinically evaluated in patients of dilated cardiomyopathy (DCM). Forskolin was administered at concentrations of 3 μg/kg/min and 4 μg/kg/min intravenously. At lower concentration, decline in systemic vascular resistance and diastolic pressure in left ventricular end, was observed. It also improved left ventricular function in DCM patients (Kramer et al. 1987). In another clinical trial, the antihypertensive effect of forskolin was investigated in 12 patients with congestive cardiomyopathy using the thermo-dilution catheter method. Comparative studies with dobutamine, a β-1-receptor agonist, and sodium nitroprusside, a vasodilator, were conducted. Significant reduction in SBP and DBP as well as mean pulmonary artery pressure was observed with slight increase in heart rate. Approximately 70% increase in cardiac stroke volume index was also observed (Baumann et al. 1990).

11.3.2 Clinically Evaluated Antidiabetic Phyto-compounds

11.3.2.1 Epigallocatechin Gallate

Effect of epigallocatechin (EGCG) was evaluated in obese male subjects (40–65 years), and effect on insulin resistance was evaluated. Forty-six subjects were supplemented with 400 mg EGCG, while 42 subjects were given lactose (placebo) twice daily for 8 weeks. Various parameters such as oral glucose tolerance test (OGTT) and metabolic risk factors such as waist circumference, body fat, blood pressure, body mass index, low-density cholesterol, high-density cholesterol and triglycerides were monitored before and after drug intervention. Insulin sensitivity and insulin secretion were observed to show no significant alterations. Also no substantial changes in glucose tolerance were observed. However the treatment resulted in reduction in DBP in intervention group (Brown et al. 2009).

11.3.2.2 Berberine

Antidiabetic potential of berberine was investigated in type II diabetic patients suffering with dyslipidemia. One hundred sixteen patients (age 25–70 year) were selected and administered for 3 months with per day dose of 1.0 g of berberine and the placebo. Different study parameters were analysed after 3 months. Significant reduction in plasma glucose levels, HbA1c, triglyceride, low-density lipoprotein cholesterol as well as total cholesterol was observed as compared to placebo. Both treatment and placebo groups showed increase in glucose disposal rate (Zhang et al. 2008).

11.3.2.3 Corosolic Acid

A randomized clinical trial was conducted on 10 human subjects (55–70 years) with type II diabetes with basal blood glucose levels of 140–250 mg/dl. Glucosol™, which is an extract prepared from Lagerstroemia speciosa leaves, was given at daily dosages of 32 and 48 mg for 2 weeks. The test extract was standardized to 1% corosolic acid. Administration of Glucosol™ to patients decreased blood glucose levels by 30% (Judy et al. 2003). In another double-blind, placebo-controlled, crossover study, 31 subjects (16 men and 15 women) were selected. The subjects had fasting glucose levels in the range of 110–140 mg/dl. Corosolic acid (10 mg) was administered orally, 5 min before OGTT. Lowering of glucose levels from 60 min till 120 min were observed in the treatment group (Fukushima et al. 2006).

11.4 Status of Clinically Proven Phyto-compound-Based Patents Filed Across the Globe

The clinically validated antihypertensive phyto-molecules were checked for the status of patents filed/granted on them, across the globe. Patent data was retrieved using licenced version of Derwent Innovation patent database (www.info.thomsoninnovation.com/; data accessed on 28th August 2018). Multiple patent records were found for some of the clinically proven antihypertensive phytochemicals such as reserpine, forskolin, allicin and ginsenoside, whereas very few patent applications were found for pycnogenol. In case of pinoresinol di-β-D-glucoside, no patent record was found for its application as antihypertensive. Similar searches were conducted to check the status of patents filed on clinically validated antidiabetic phyto-molecules. All the three clinically proven antidiabetic phyto-compounds, viz. EGCG, berberine and corosolic acid, were found in multiple patent applications. The numbers of patents filed on inventions encompassing role of these phyto-molecules in treatment of hypertension or diabetes is summarized in Fig. 11.1. Reserpine was observed to be used maximum numbers of times in patent applications mentioning hypertension as the treatment target. In case of antidiabetics, EGCG was used maximum numbers of times in patent applications filed across the globe.

Fig. 11.1
figure 1

Number of patents filed across the globe on clinically proven antihypertensive and antidiabetic phyto-constituents

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11.5 Conclusion and Future Prospects

Phyto-medications for the cure of numerous human ailments, including chronic ones is being globally accepted and recognized. Researchers have identified mechanistic basis of the action, including target sites, for number of phyto-compounds, useful against diabetes and hypertension. One excellent example of antidiabetic drug discovery from folklore plant source is metformin, which is globally being used to treat diabetic patients, though it has some reported side effects. However, much more efforts are needed to develop a pool of phyto-compound-based herbal medications suited to tackle hypertension and diabetes, and this can be easily achieved by targeting the traditionally used codified and non-codified medicinal plants for novel drug discovery.

Antidiabetic phyto-constituents target intermediaries of metabolic pathways involved in maintaining glucose homeostasis, downstream signalling of insulin and function as insulinomimetics. In case of antihypertensive phyto-compounds, hypotensive action has been suggested to be through antagonistic action on Ca2+ channel, ACE inhibition and α-adrenoceptor, and in some cases, the compounds have been shown to have direct relaxant effects on blood vessels. A large number of phyto-compounds have undergone preclinical validation; however, only few have been evaluated thoroughly through clinical trials. Since the plants are known to contain large number of useful compounds, researchers should also give attention on developing phyto-formulations based on whole extract and not only on pure single molecule. The non-purified plants extracts may be more useful in combating the diseases and tackling the issues of toxicity, which is generally high with single molecules. This approach may also lead to development of novel phyto-medications on fast track basis, not only as single targeted drug but also as a multifunctional therapeutics.