JP2022535128A - Compositions for Prostaglandin Transporter Inhibition and Related Therapeutic Uses - Google Patents

Abstract

The present invention provides a garlic extract standardized to contain not less than 0.3% w/w S-allylcysteine, not less than 2% w/w for use as a prostaglandin transporter inhibitor. of nitrates, 0.1%-5% w/w thymoquinone, about 0.01%-10% w/w thymohydroquinone, about 20%-95% w/w /w fatty acids, Nigella sativa extract standardized to contain about 0.001% to 3% w/w α-hederin or hederagenin, and 3% w/w arjunoglucosides. Disclosed is a composition comprising a Terminalia arjuna extract standardized to The present invention also discloses the use of the aforementioned compositions in the therapeutic management of hypertension and cardiovascular complications.

Description

The present invention generally relates to compositions comprising botanical extracts. More particularly, the invention relates to compositions and related therapeutic uses for prostaglandin transporter (PGT) inhibition.

Prostaglandins (PGs) are naturally occurring unsaturated fatty acids involved in mediating various pathophysiological processes and homeostatic functions in different organs. PG is derived from arachidonic acid by the action of cyclooxygenase isoenzymes. There are mainly four ubiquitously produced bioactive PGs: prostaglandin E2 (PGE2), prostacyclin, which acts as an autocrine and paracrine mediator in the body and maintains homeostatic functions. (PGI2), prostaglandin D2 (PGD2) and prostaglandin F2α (PGF2α) (Ricciotti et al., Prostaglandins and Inflammation, Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;31:986-1000). PGs play a major role in regulating many disease states in the body, including inflammation. The biological roles of PGs are well documented in the scientific literature, some of which are specified herein below:
1. Ricciotti et al., Prostaglandins and Inflammation, Arteriosclerosis, Thrombosis, and Vascular Biology, 2011; 31:986-1000.
2. Harris et al., Prostaglandins as modulators of immunity, Trends in Immunology, 2002; 23(3):144-150.
3. Wand and DuBois, Prostaglandins and Cancer, Recent advances in basic science, http://dx.doi.org/10.1136/gut.2004.047100.
4. Anderson et al., Prostaglandins: Effects on blood pressure, renal blood flow, sodium and water excretion, Kidney International, 1976;10(3):205-215.
5. Klien et al., Prostaglandins: Stimulation of Bone Resorption in Tissue Culture, Endocrinology, 1970; 86(6):1436-1440.

PG also plays a role in ovulation, mucus secretion in the GI tract, vasodilation and angiogenesis, apart from its role in inflammation. PG triggers its function by triggering a cascade of signals upon binding to its transporter in the cell membrane. Member 2A1 of the solute carrier organic anion transporter family, also known as prostaglandin transporter (PGT), is a member of the 12-transmembrane organic anion-transporting polypeptide superfamily of transporters. The encoded protein is responsible for prostaglandin uptake in numerous tissues and organs, including brain, colon, heart, kidney, liver, lung, ovary, pancreas, placenta, prostate, musculoskeletal, small intestine, spleen and vascular endothelium. and involved in mediating clearance. PGTs are now increasingly becoming targets for the development of drugs to reduce the adverse effects caused by PG uptake into cells and related clinical conditions. In their publication entitled Development of a High-Affinity Inhibitor of the Prostaglandin Transporter, J Pharmacol Exp Ther. 2011;339(2): 633-641, Chi et al. -(2-(2-azidoethoxy)ethoxy)ethyl)-4-((4-((2-(2-(2-benzamidoethoxy)ethoxy)ethyl)amino)-6-((4-hydroxyphenyl) Amino)-1,3,5-triazin-2-yl)amino)benzamide (T26A) is disclosed. Non-steroidal anti-inflammatory drugs (NSAIDs) are also known to inhibit PG production and action. However, these synthetic drugs have high side effects and there is a need for safe and natural alternatives that mitigate the effects of PG by inhibiting PGT. Active molecules derived from plants are now widely used to treat numerous diseases and disorders. However, no plant-based compositions for inhibiting or blocking PGT have been reported. The present invention solves the above problems by disclosing natural plant-based compositions for inhibition of PGT and providing related therapeutic effects.

The main object of the present invention is an effective dose of garlic (Allium sativum) extract, beet (Beta vulgaris) extract, Nigella sativa extract and Terminalaria arjuna for use as PGT inhibitors. (Terminalia arjuna) extract.
Another object of the present invention is to disclose a method for therapeutic management of hypertension using a composition comprising garlic extract, beet extract, Nigella sativa extract and Terminalaria arjuna extract. .
Another object of the present invention is to disclose a method for conferring cardioprotection in a mammal using a composition comprising garlic extract, beet extract, Nigella sativa extract and Terminalaria arjuna extract. is.
The present invention solves the above objectives and achieves further related advantages.
The present invention provides natural plant-based compositions for use as prostaglandin transporter inhibitors.

More particularly, the present invention provides a garlic extract standardized to contain 0.3% w/w or more S-allylcysteine, 2% w/w, for use as a PGT inhibitor. Beet extract standardized to contain above nitrates, 0.1%-5% w/w thymoquinone, about 0.01%-10% w/w thymohydroquinone, about 20%-95% w/w fatty acids, Nigella sativa extract standardized to contain about 0.001% to 3% w/w α-hederin or hederagenin, and 3% w/w arjunoglucosides. Disclosed is a composition comprising an effective dose of a Terminalia arjuna extract standardized to contain

The present invention also provides garlic extract standardized to contain 0.3% w/w or more S-allylcysteine, beet extract standardized to contain 2% w/w or more nitrates. 0.1%-5% w/w thymoquinone, about 0.01%-10% w/w thymohydroquinone, about 20%-95% w/w fatty acid, about 0.001%-3% Composition comprising Nigella sativa extract standardized to contain w/w α-hederin or hederagenin and Terminalaria arjuna extract standardized to contain 3% w/w arjunoglucosides Disclosed are methods for the therapeutic management of hypertension in mammals using products.

In another aspect, the invention provides a garlic extract standardized to contain 0.3% w/w or more S-allylcysteine, 2% w/w or more nitrates. 0.1%-5% w/w thymoquinone, about 0.01%-10% w/w thymohydroquinone, about 20%-95% w/w fatty acid, about 0.001 Nigella sativa extract standardized to contain %-3% w/w α-hederin or hederagenin, and Terminalaria arjuna extract standardized to contain 3% w/w arjunoglucosides. Disclosed is a method for conferring cardioprotection in a mammal using a composition comprising an agent.
Other features and advantages of the invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the invention.

FIG. 2 is a graphical representation showing the effects of formulations on PGE2 metabolism in MDCK cells, analyzing extracellular PGE2 expression in culture medium. FIG. 4 is a graphical representation showing the effects of formulations on PGE2 metabolism in MDCK cells, analyzed for intracellular PGE2 expression in cell lysates. FIG. 4 is a graphical representation showing plasma PGT expression levels in rats treated with different concentrations of the formulation. FIG. 4 is a graphical representation showing the expression of nitric oxide levels in rats treated with different concentrations of formulations. FIG. 4 is a graphical representation showing systolic BP in rats treated with different concentrations of formulation. FIG. 3 is a graphical representation showing diastolic BP in rats treated with different concentrations of formulations. FIG. 3 is a graphical representation showing heart rate in rats treated with different concentrations of formulations. Figure 2 is a graphical representation showing mean arterial pressure in rats treated with different concentrations of formulations. Figure 2 is a graphical representation showing AST levels in rats treated with different concentrations of formulations. Figure 3 is a graphical representation showing LDH and CK-MB levels in rats treated with different concentrations of formulations.

The present invention will be described in detail along with respective preferred embodiments for better understanding and to enable those skilled in the art to demonstrate or practice the invention.
In a preferred embodiment, the present invention discloses a plant-based composition consisting of garlic extract, beet extract, Nigella sativa extract and Terminalaria arjuna extract. In a related aspect, the garlic extract is standardized to contain 0.3% or more S-allylcysteine. In another related aspect, the beet extract is standardized to contain no less than 2% nitrates. In yet another related aspect, the Nigella sativa extract comprises 0.1%-5% w/w thymoquinone, about 0.01%-10% w/w thymohydroquinone, about 20%-95% w/w /w fatty acids, and about 0.001% to 3% w/w α-hederin or hederagenin. In another aspect, the Terminalaria arjuna extract is standardized to contain 3% w/w arjunoglucosides. In another preferred embodiment, the composition is used as a prostaglandin transporter inhibitor. In yet another preferred embodiment, the composition is used for therapeutic management of hypertension. In a further preferred embodiment, the composition is used as a cardioprotectant. In another related aspect, the composition is formulated with a pharmaceutically/nutraceutical acceptable bioavailability enhancer, antioxidant, excipient, adjuvant, diluent or carrier, It is administered in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewable tablets, drops or edibles.

In another preferred embodiment, the present invention provides a method for inhibiting the prostaglandin transporter in mammalian cells, comprising 30-60% w/ w garlic extract, 10-30% w/w beet extract, 5-15% w/w Nigella sativa extract and 10-30% w/w Terminalaria arjuna extract. A method is disclosed that includes the step of contacting. In a related aspect, the garlic extract is standardized to contain 0.3% or more S-allylcysteine. In another related aspect, the beet extract is standardized to contain 2% or more nitrates. In yet another related aspect, the Nigella sativa extract comprises 0.1%-5% w/w thymoquinone, about 0.01%-10% w/w thymohydroquinone, about 20%-95% w/w /w fatty acids, and about 0.001% to 3% w/w α-hederin or hederagenin. In another aspect, the Terminalaria arjuna extract is standardized to contain 3% w/w arjunoglucosides. In a related aspect, the prostaglandin is selected from the group comprising prostaglandin E2 (PGE2), prostacyclin (PGI2), prostaglandin D2 (PGD2) and prostaglandin F2α (PGF2α). In another related aspect, the mammalian cells are human cells.

In another preferred embodiment, the present invention provides 30-60% w/w garlic extract, 10-30% w/w beet extract, 5 A composition comprising ˜15% w/w of Nigella sativa extract and 10-30% w/w of Terminalaria arjuna extract is disclosed. In a related aspect, the garlic extract is standardized to contain 0.3% or more S-allylcysteine. In another related aspect, the beet extract is standardized to contain 2% or more nitrates. In yet another related aspect, the Nigella sativa extract comprises 0.1%-5% w/w thymoquinone, about 0.01%-10% w/w thymohydroquinone, about 20%-95% w/w /w fatty acids, and about 0.001% to 3% w/w α-hederin or hederagenin. In another aspect, the Terminalaria arjuna extract is standardized to contain 3% w/w arjunoglucosides. In a related aspect, the prostaglandin is selected from the group comprising prostaglandin E2 (PGE2), prostacyclin (PGI2), prostaglandin D2 (PGD2) and prostaglandin F2α (PGF2α).

In yet another preferred embodiment, the present invention is a method for therapeutic management of hypertension in a mammal comprising 30-60% w/w garlic extract, 10-30% w/w beet extract 5-15% w/w Nigella sativa extract and 10-30% w/w Terminalaria arjuna extract is administered to a mammal to reduce symptoms of hypertension. A method is disclosed that includes the step of causing. In a related aspect, control of hypertension is effected by inhibiting/blocking the prostaglandin transporter. In another related aspect, the symptom of hypertension is selected from the group comprising elevated systolic and diastolic blood pressure, elevated mean arterial pressure, elevated heart rate and reduced nitric oxide levels. In another related aspect, the effective dose of the composition is 50-400 mg/kg body weight. In another aspect, the mammal is a human. In another related aspect, the composition is formulated with a pharmaceutically/nutraceutical acceptable bioavailability enhancer, antioxidant, excipient, adjuvant, diluent or carrier, It is administered in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewable tablets, drops or edibles.

In yet another preferred embodiment, the present invention provides 30-60% w/w garlic extract, 10-30% w/w beet extract for the therapeutic management of hypertension and related conditions in mammals. , discloses a composition comprising 5-15% w/w Nigella sativa extract and 10-30% w/w Terminalaria arjuna extract. In a related aspect, control of hypertension is effected by inhibiting/blocking the prostaglandin transporter. In another related aspect, the symptom of hypertension is selected from the group comprising elevated systolic and diastolic blood pressure, elevated mean arterial pressure, elevated heart rate and reduced nitric oxide levels. In another related aspect, the effective dose of the composition is 50-400 mg/kg body weight. In another aspect, the mammal is a human. In another related aspect, the composition is formulated with a pharmaceutically/nutraceutical acceptable bioavailability enhancer, antioxidant, excipient, adjuvant, diluent or carrier, It is administered in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewable tablets, drops or edibles.

In another preferred embodiment, the present invention is a method for therapeutic management of cardiovascular complications in a mammal comprising 30-60% w/w garlic extract, 10-30% w/w w of beet extract, 5-15% w/w of Nigella sativa extract and 10-30% w/w of Terminalaria arjuna extract is administered to a mammal to effect cardiovascular A method is disclosed that includes the step of causing symptomatic relief of a systemic complication. In a related aspect, management of cardiovascular complications is effected by inhibiting/blocking the prostaglandin transporter. In another related aspect, the symptoms of cardiovascular complications are selected from the group comprising elevated systolic and diastolic blood pressure, elevated mean arterial pressure, elevated heart rate and elevated levels of cardiac markers. . In another related aspect, the cardiac marker is selected from the group comprising aspartate aminotransferase, lactate dehydrogenase and creatine kinase. In another related aspect, the effective dose of the composition is 50-400 mg/kg body weight. In another aspect, the mammal is a human. In another related aspect, the composition is formulated with a pharmaceutically/nutraceutical acceptable bioavailability enhancer, antioxidant, excipient, adjuvant, diluent or carrier, It is administered in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewable tablets, drops or edibles.

In another preferred embodiment, the present invention provides 30-60% w/w garlic extract, 10-30% w/w for the therapeutic management of cardiovascular complications and related conditions in mammals. beet extract, 5-15% w/w Nigella sativa extract and 10-30% w/w Terminalaria arjuna. In a related aspect, management of cardiovascular complications is effected by inhibiting/blocking the prostaglandin transporter. In another related aspect, the symptoms of cardiovascular complications are selected from the group comprising elevated systolic and diastolic blood pressure, elevated mean arterial pressure, elevated heart rate and elevated levels of cardiac markers. . In another related aspect, the cardiac marker is selected from the group comprising aspartate aminotransferase, lactate dehydrogenase and creatine kinase. In another related aspect, the effective dose of the composition is 50-400 mg/kg body weight. In another aspect, the mammal is a human. In another related aspect, the composition is formulated with a pharmaceutically/nutraceutical acceptable bioavailability enhancer, antioxidant, excipient, adjuvant, diluent or carrier, It is administered in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewable tablets, drops or edibles.
Specific illustrative examples clearly stating the most preferred embodiments are included herein below.

Example 1 Composition Details The present invention provides 30-60% w/w garlic extract, 10-30% w/w beet extract, 5-15% w/w for inhibition of PGT. w Nigella sativa extract and 10-30% w/w Terminalaria arjuna extract are disclosed. The aforementioned extracts have been reported to induce cardioprotective and antihypertensive effects independently. Some of the medicinal properties of the above extracts are specified herein below:

Garlic is a well-known plant used in the traditional system of Ayurveda. Garlic has been reported to induce a number of therapeutic effects on different disorders, including cardiovascular disease, regulation of blood pressure, and reduction of blood sugar and cholesterol levels. Garlic is also reported to be effective against bacterial, viral, fungal and parasitic infections and to boost the immune system. This plant also has antitumor properties (Ayaz and Alpsoy, Garlic (Allium sativum) and traditional medicine, Turkiye Parazitol Derg. 2007;31(2):145-9). Garlic contains numerous active molecules such as allicin, saponins, phenols and amino acids that are responsible for its biological activity. Allicin scavenges free radicals and inhibits NADPH oxidase. Allicin increases the production of _H2S , which leads to hyperpolarization of vascular smooth muscle cells, which causes vasodilation. Saponins, phenols, and s-allylcysteine directly quench reactive oxygen species and induce antioxidant effects. The plant also produces arginine, a precursor that produces nitric oxide. The plant extracts used in the present invention are standardized to contain 0.3% or more s-allyl cysteine using an in-house process.

Beet (beet root) is a common vegetable that is used extensively with the regular diet. Beets have excellent therapeutic properties, including hepatoprotective, antidiabetic, hypocholesterolemic and hypolipidemic, antibacterial and antioxidant properties. The plant increases an enzyme called xatin oxidoreductase (XOR) in red blood cells that converts nitrate to nitrite and then to nitric oxide. Nitric oxide relaxes the walls of blood vessels and has an effect on blood pressure. The extracts used in the present invention were standardized to contain no less than 2% nitrate using an in-house process.

Nigella sativa is well known for its numerous therapeutic properties in the Ayurvedic, Siddha and Unani systems of medicine. This plant contains thymoquinone, thymohydroquinone, dithymoquinone, p-cymene, carvacrol, 4-terpineol, t-anethole, the sesquiterpenes longifolene, α-pinene, thymol, α-hederin and hederagenin, which are responsible for the beneficial effects of this plant. (Ahmad et al., A review on therapeutic potential of Nigella sativa: A miracle herb, Asian Pac J Trop Biomed. 2013; 3(5): 337- 352). This plant is a known antioxidant, cardiodepressant and calcium channel blocker, thus affecting blood pressure and heart function. The extract used in the present invention comprises 0.1%-5% w/w thymoquinone, about 0.01%-10% w/w thymohydroquinone, about 20%-95% w/w fatty acids, Standardized to contain approximately 0.001% to 3% w/w α-hederin or hederagenin.

Terminalia Arjuna or Arjuna is a well known medicinal plant used in ancient Ayurvedic medicine. The bark of Terminalia arjuna has been reported to contain numerous bioactive compounds that can be harvested for use in the treatment of numerous diseases. Arjunoglucosides, compounds obtained from the bark of Terminalia arjuna, are well documented for their cardioprotective activity. In addition to its cardioprotective properties, Terminalia arjuna and its bark extract have anticancer activity, hepatoprotective activity, antiviral activity, antioxidant activity, antiasthma activity, contraceptive activity, antidiabetic activity, wound healing activity, A wide range of activities have been reported, including antiplatelet and anticoagulant, antibacterial and antifungal activities (Saxena et al., Cytotoxic agents from Terminalia arjuna, Planta Med. 2007;73(14): 1486-90). It also prevents narrowing of blood vessels by reducing atherosclerotic lesions and plaque deposition in blood vessels. This extract was standardized to contain 3% w/w arjunoglucosides.

Table 1 discloses details of the formulations and their doses.

Example 2 Inhibition of Prostaglandin Transporter The formulation was evaluated for its effect of inhibiting the prostaglandin transporter (PGT). A renal cell line, MDCK, was seeded in 6 well plates at 30% confluence. After 3 days, the cells were treated with 10 μM bradykinin (available from Sigma-Aldrich to increase endogenous PGE2 synthesis) in the presence of vehicle (DMSO) at 37° C. for varying periods of time. The formulations were simultaneously added in graded concentrations to the cell culture, which was further incubated for 24 hours. Medium was collected for determination of extracellular concentrations of PGE2. Cells were washed twice with phosphate-buffered saline and lysed with 250 μl of phosphate-buffered saline containing 0.1 M HCl and 0.1% Triton X-100 for 15 minutes at room temperature. and scraped off the plate. The cell suspension was pipetted up and down several times to ensure complete lysis. Cell lysates were harvested and centrifuged at 10,000 g for 10 minutes at 4°C. The supernatant was collected. Intracellular PGE2 was measured in the supernatant. (Yuling et al., Development of a High-Affinity Inhibitor of the Prostaglandin Transporter. The journal of pharmacology and experimental therapeutics, 2011; 339(2); 633-641). Both intracellular and extracellular PGE2 were measured using a commercially available PGE2 ELISA kit from R&D Systems according to the user manual. Experiments were performed in triplicate. Values are expressed as mean±s.e.m.

In cultured MDCK cells, this formulation blocks PGE2 uptake. PGE2 triggers a wide variety of signals, including inflammation, vasodilation and angiogenesis (Weeks JR (1972) Prostaglandins. Annu Rev Pharmacol 12:317-336; Clyman RI, Mauray F, Roman C, and Rudolph AM (1978) PGE2 is a more potent vasodilator of the lamb ductus arteriosus than is either PGI2 or 6 keto PGF1alpha. Prostaglandins 16:259-264; Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, and DuBois RN ( 1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705-716). The extent of PG signaling is highly dependent on its concentration at cell surface receptors, which in turn is determined by the relative rates of PG synthesis and metabolism and transport by prostaglandin transporters. Cell culture medium was harvested for extracellular PGE2 measurements (Fig. 1) and cells were lysed for intracellular PGE2 measurements. Decreased levels of extracellular PGE2 in formulation-treated cells (FIG. 2) indicate that prostaglandin transporters were blocked and intracellularly formed PGE2 was unable to exit the cells into the medium. .

Thus, the formulations act as effective inhibitors of PGT, blocking transmembrane transport of prostaglandins.
The therapeutic effects of blocking/inhibiting PGT are manifold. PGTs play an important role in reducing inflammation and play a role in ovulation, mucus secretion in the GI tract, vasodilation and angiogenesis. Inhibition of PGT plays a role in hypertension by increasing PG in circulation, thereby exhibiting vasodilatory effects (Yuling et al., Development of a High-Affinity Inhibitor of the Prostaglandin Transporter. journal of pharmacology and experimental therapeutics, 2011; 339(2); 633-641).
The therapeutic effect of formulations by PGT inhibition was exemplarily assessed by their antihypertensive and cardioprotective effects.

Example 3 Method of Antihypertensive Action of the Formulation Normotensive Wistar rats were used in this experiment. These rats were dosed with DOCA (deoxycorticosterone acetate), a synthetic mineralocorticoid derivative, in the drinking water at 25 mg/kg s.c. twice weekly for a period of 30 days. c. and 1% w/v NaCl to induce spontaneous hypertension (model: DOCA salt-induced hypertensive rats). These rats were divided into the following groups containing 6 rats each:

以下のパラメータを推定し、本製剤の抗高血圧作用を評価した。
・ ＰＧＴの発現量
・ 一酸化窒素の推定
・ 血圧
・ 心拍
・ 平均動脈圧
・ 尿の量

The following parameters were estimated to evaluate the antihypertensive effect of this preparation.
・ Expression level of PGT ・ Estimation of nitric oxide ・ Blood pressure ・ Heart rate ・ Mean arterial pressure ・ Amount of urine

PGT Expression A member of the solute carrier organic anion transporter family, 2A1, is also known as a prostaglandin transporter (PGT). Prostaglandin transporters are members of the 12-transmembrane organic anion-transporting polypeptide superfamily of transporters. The encoded protein is involved in mediating prostaglandin uptake and clearance in numerous tissues. The efficacy of this formulation was estimated in rat plasma by ELISA.
The results showed that increased salt uptake increased plasma PGT expression, which was dose-dependently inhibited by this formulation (Figure 3).
Nitric Oxide Levels Nitric oxide levels were significantly lower in the salt-induced group. This formulation showed a dose-dependent increase in the expression of total nitric oxide in plasma (Fig. 4).

Urinary Output Diuretics work on the kidneys by increasing the amount of salt and water excreted through the urine. Too much salt can cause excess fluid to build up in your blood vessels, raising your blood pressure. Diuretics lower blood pressure by flushing salt out of the body and taking this unwanted excess fluid with it. The diuretic effect of this formulation was tested by measuring urine output. The results are presented in tabular form in Table 3.

At 200 mg/kg, the formulation effectively increased urine output, indicating that the formulation acts as an effective diuretic.
Blood Pressure, Heart Rate and Mean Arterial Pressure Blood pressure, heart rate and mean arterial pressure were estimated using standard protocols. Increased salt intake, increased systolic and diastolic blood pressure, heart rate and mean arterial pressure levels. By effectively inhibiting PGT, the formulation dose-dependently lowered blood pressure (Figures 5A and 5B), heart rate (Figure 6) and mean arterial pressure (Figure 7), and the formulation was highly It has been shown to be an effective antihypertensive composition.

Example 4 Cardioprotective Effects of Formulations Formulations containing plant extracts are highly effective in inhibiting PGT, thereby causing antihypertensive effects. The formulation was effective in lowering heart rate, systolic and diastolic blood pressure. Since elevated heart rate is associated with the development of cardiovascular complications, the reduction in heart rate due to inhibition of PGT by this formulation can confer cardioprotection. Therefore, the cardioprotective effect of this formulation on isoproterenol-induced cardiotoxicity was tested in rats.

Isoproterenol [1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol hydrochloride] (ISO), a synthetic catecholamine and β-adrenergic agonist, causes severe oxidative stress in the myocardium, causing myocardial resulting in infarct-like necrosis. Isoproterenol is also known to generate free radicals and stimulate lipid peroxidation. The following cardiac markers were evaluated:
a) aspartate aminotransferase (AST).
b) lactate dehydrogenase (LDH).
c) Creatine Kinase-MB (CK-MB).

AST occurs in all human tissues and is abundant in liver, kidney, heart and musculoskeletal tissues. Its levels are elevated in myocardial infarction, muscular dystrophy and liver disease. Elevated AST levels in the present invention indicate damage to the heart due to increased cardiotoxicity by isoproterenol. The formulation effectively reduced AST levels (Figure 8), thereby indicating that the formulation alleviates cardiotoxicity developed by increased salt uptake. Similarly, LDH and CK-MB levels (FIG. 9) also returned to normal in rats administered the formulation, indicating that the formulation is cardioprotective.
These results indicated that this formulation is an excellent PGT inhibitor. The formulation also conferred the relevant therapeutic benefit of PGT inhibition by being antihypertensive by reversing the elevation of heart rate, blood pressure and mean arterial pressure to near normal levels. The formulation also provides cardioprotection by reducing elevated cardiac markers to near normal levels.

Other modifications and variations to the invention will be apparent to those skilled in the art from the above disclosure and teachings. Thus, while only certain embodiments of the invention have been specifically described herein, it will be apparent that many modifications may be made without departing from the spirit and scope of the invention. be. The scope of the invention should be interpreted only in relation to the appended claims.

Claims (19)

30-60% w/w Garlic (Allium sativum) extract, 10-30% w/w Beet (Beta vulgaris) extract, 5-15% for use as prostaglandin transporter inhibitors A composition comprising w/w Nigella sativa extract and 10-30% w/w Terminalia arjuna extract. 2. The composition of claim 1, wherein the garlic extract is standardized to contain 0.3% or more S-allylcysteine. 2. The composition of claim 1, wherein the beet extract is standardized to contain 2% or more nitrates. The Nigella sativa extract contains 0.1%-5% w/w thymoquinone, about 0.01%-10% w/w thymohydroquinone, about 20%-95% w/w fatty acid, about 0 A composition according to claim 1, standardized to contain 0.001% to 3% w/w α-hederin or hederagenin. 2. The composition of claim 1, wherein the Terminalaria arjuna extract is standardized to contain 3% w/w arjunoglucosides. 2. The composition of Claim 1, wherein the prostaglandin is selected from the group comprising prostaglandin E2, prostacyclin, prostaglandin D2 and prostaglandin F2[alpha]. 30-60% w/w garlic extract, 10-30% w/w beet extract, 5-15% w/w nigella for use in the therapeutic management of hypertension and related conditions in a mammal • A composition comprising sativa extract and 10-30% w/w Terminalaria arjuna extract. 8. The composition of claim 7, wherein said management of hypertension is effected by inhibiting/blocking prostaglandin transporters. 8. The composition of claim 7, wherein the symptoms of hypertension are selected from the group comprising elevated systolic and diastolic blood pressure, elevated mean arterial pressure, elevated heart rate and reduced nitric oxide levels. The composition according to claim 7, wherein the effective dose of said composition is 50-400 mg/kg body weight. 8. The composition of claim 7, wherein said mammal is human. Tablets, capsules, syrups, gummies, powders formulated with pharmaceutically/nutraceutical acceptable bioavailability enhancers, antioxidants, excipients, adjuvants, diluents or carriers 8. The composition according to claim 7, administered in the form of , suspensions, emulsions, chewable tablets, drops or edibles. 30-60% w/w garlic extract, 10-30% w/w beet extract, 5-15% for use in the therapeutic management of cardiovascular complications and related conditions in mammals A composition comprising w/w Nigella sativa extract and 10-30% w/w Terminalaria arjuna. 14. The composition of claim 13, wherein said management of cardiovascular complications is effected by inhibiting/blocking prostaglandin transporters. 14. The symptom of cardiovascular complications according to claim 13, wherein the symptoms of cardiovascular complications are selected from the group comprising elevated systolic and diastolic blood pressure, elevated mean arterial pressure, elevated heart rate and elevated levels of cardiac markers. Composition. 16. The composition of claim 15, wherein said cardiac marker is selected from the group comprising aspartate aminotransferase, lactate dehydrogenase and creatine kinase. 14. The composition according to claim 13, wherein the effective dose of said composition is 50-400 mg/kg body weight. 14. The composition of claim 13, wherein said mammal is human. Tablets, capsules, syrups, gummies, powders formulated with pharmaceutically/nutraceutical acceptable bioavailability enhancers, antioxidants, excipients, adjuvants, diluents or carriers 14. The composition according to claim 13, administered in the form of , suspensions, emulsions, chewable tablets, drops or edibles.

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