INTRODUCTION:

Pumpkin (Cucurbita sp.) is a fruit vegetable, native to the Western Hemisphere and easily cultivated in Tropical Asia countries such as Indonesia, Malaysia, and Philippines (Tindall, 1983). There are many varieties of pumpkin such as Cucurbita maxima, Cucurbita pepo, Cucurbita moschata, Cucurbita ficifolia, and Cucurbita turbaniformis in which Cucurbita moschata exhibits the widest variation in Indonesia, (Gemrot, et al., 2006)¹. Although the pumpkin itself has various benefits, the pumpkin seeds have been the focus of interest in the last few years in the field of diet and disease research due to the emerging various active components. Research on pumpkin increases progressively during the last decade, especially focusing on its health benefits.

Pubmed recorded more than 200 papers within 2007-2018 of pumpkin and its seeds covering on the field of chemistry, biology, pharmacology, and health. Among those of the researches, pumpkin seeds become the focus of interest due to its complexity of the chemical ingredient as well as the health benefits². Pumpkin seeds are highly nutritional and rich nutraceutical components such as unsaturated fatty acids especially palmitic acid, stearic acid, oleic acid and linoleic acid (Stevenson, et al., 2007). Those essential fatty acids are belonging to the w-6 and w-3 family which exert amazing nutritional functions and play important role in many metabolic pathways (Miura, 2013). Phytoestrogen supplementation with pumpkin seeds extract has been reported to increase uterine weight, mammary gland, bone density, and prevent hyperlipidemia, the indication of estrogen-like activities in ovariectomized female Sprague dawley rats (Gossell-Williams, et al., 2008). Pumpkin seeds oil contains rich vitamin E such as a-tocopherol and g-tocopherol that exhibited positive health effects (Rabrenovic, et al., 2014)³. The researchers have so far focused particularly on the three major components of fatty acids, phytoestrogens, and tocopherol in pumpkin seeds oil because they gained attention due to the several health benefits such as antioxidant, anti-inflammation, antidiabetic, anticancer, anti-cardiovascular, antihyperlipidemia, and estrogenic-like effect. Thus, in this review, we explained more detail about the three major bioactive compounds of pumpkin seeds such as fatty acids, phytoestrogens. The pumpkin fruit (left) and its seeds (right) commonly cultivated in Indonesia known as Cucurbita moschata. and tocopherols as well as to highlight the immense potential effects in the form of roasted, oil and/or extract of pumpkin seeds as the excellent nutraceuticals in the future⁴.

Lphysicochemical compositions of pumpkin seeds:

The different species of pumpkin seeds exerts the different components and biological activities (Caili, et al., 2006). Many researchers studied the bioactive compositions of pumpkin seeds oil that grown in the different areas of the world⁵. Due to the differences among the species and/or varieties of Cucurbita spp., the yield of fatty acids, sterols or phytoestrogens and tocopherols was quite similar to those of each other and belong to the three major components of pumpkin seeds that have been focused by many studies. However, the minor components of pumpkin seeds such as protein, mineral, terpenic alcohol, and fiber also could not be ignored, because they have played role in the synergistic positive effects of pumpkin seeds (Fu, et al., 2006). Some technologies are applied to isolate the higher yield of oil from crude pumpkin seeds. Although several studies reported that crude pumpkin seeds extract itself exhibited the broad-spectrum pharmacological effects through in vitro, in vivo and human trial⁶. Cucurbita pepo L. is the most popular pumpkin species to be a focus of interest of researches in the world. Recent studies have shown that Cucurbita pepo species is rich in polyunsaturated fatty acids such as palmitic acid, stearic acid, oleic acid and linoleic acid, vitamin E like α-tocopherols, γ-tocopherols and carotenoid, phytoestrogens and phytosterols such as daidzein, genistein, secoisolariciresinol, and the trace components. Among those of total percentage of ingredients in pumpkin seeds, unsaturated fatty acids showed the hugest components ranging up to 80%. This value is relatively higher than those reported for peanut seeds oil and soybean seeds oil (Cerny, et al., 1971; Sanders, 1980)⁷

Pumpkin seeds are also known as “pepitas,” a Mexican Spanish term.

Unlike the hard white seeds from a carving pumpkin, most pumpkin seeds bought at the supermarket don’t have a shell.

These shell-free seeds are green, flat, and oval.

1 ounce (oz), or 28 grams (g), of shell-free pumpkin seeds has roughly 160 calories, which are mainly from fat and protein.

In addition, a 1-oz (28-g) serving contains the following nutrients

· Carbs: 3 g

· Protein: 8.6 g

· Fat: 14 g

· Fiber: 1.7 g

· Manganese: 56% of the Daily Value (DV)

· Copper: 42% of the DV

· Magnesium: 40% of the DV

· Phosphorus: 28% of the DV

· Zinc: 20% of the DV

· Iron: 14% of the DV

In addition to the nutrients listed above, pumpkin seeds also contain some antioxidants and small amounts of potassium, riboflavin, and folate.⁸

The prevalence of urinary disorders such as nocturia and associated symptoms gradually increases with age, and has a great influence on the quality of life. Elderly people with nocturia are at great risk for bone fracture and mortality. Thus, prevention and treatment of urinary disorders are expected to improve this problem. Overactive bladder (OAB), a common urinary disorder, is well known and defined by the International Continence Society (ICS) as a syndrome with urgency, with or without urge incontinence, usually with frequency and nocturia. OAB symptoms are commonly observed in patients with dysfunction of the lower urinary tract. Recently, the Overactive Bladder Symptom Score (OABSS) was developed and validated by Homma et al. as a useful assessment tool specifically for evaluating OAB symptoms. OABSS scores are based on answers to self-assessed questions.⁹

Pumpkin is an edible fruit found in the American and European continents and is grown in Asia and Africa. The extract of the seed is a rich source of vitamins, linoleic acid, oleic acid, and microelements. Especially, the oil extracted from Cucurbita pepo has been useful for the treatment of urinary disorders. In previous reports, the effect of the pumpkin seed oil from C. pepo has been investigated in clinical trials involving over 2000 men suffering from benign prostate hypertrophy (BPH). The oil significantly improved their urinary dysfunction¹⁰. In an animal study, Gossell-Williams et al. demonstrated that oil from the pumpkin seed of C. pepo inhibited testosterone-induced hyperplasia of the prostate of rats. Rats treated with 0.3 mg/100 g body weight of testosterone showed an increase of prostate size ratio, but administration of 2.0 or 4.0 mg/100 g body weight of pumpkin seed oil from C. pepo inhibited the prostate size ratio in rats treated with testosterone. These previous studies have clarified the effect of pumpkin seed oil extracted from C. pepo, but there has been no clinical investigation on urinary disorder treatment using any other kind of pumpkin seed oil.¹¹

In Japan, especially in Hokkaido, Cucurbita maxima is the main pumpkin species grown for food. Thus, numerous pumpkin seeds are available here. Ojiako et al. have analyzed the composition of seeds of C. maxima as having various fatty acids, proteins, carbohydrates, and minerals. Recently, we have developed a product extracted from the pumpkin seed oil of C. maxima, and we herein evaluated the effect of the product on urinary disorders in volunteers suffering from OAB symptom.¹²

General health benefits derived from pumpkin seeds:

In general, pumpkin seeds are an extraordinarily rich source of nutraceutical, pharmaceutical, and cosmeceutical properties that exhibit many pharmacological effects and health benefits. In recent years, in vitro, in vivo, and pre-clinical studies have proven that pumpkin seeds oil has a wide spectrum of amazing biological activities . Moreover, the presence of high percentage of unsaturated fatty acids, sterols and tocopherol make it an excellent product which could prevent against some diseases (Patel, 2013)¹¹. The widespread usage of pumpkin seed gains positive acceptance not only as edible oil but also nutraceutical. Not only the therapeutic uses of pumpkin seeds were explored, the safeties of pumpkin seeds against some organs were also tested using several methods. For example, Schiebel-Schlosser and Friederich (1998) found that there were no side effects of Benign Prostatic Hyperplasia (BPH) patients under the treatment of capsules containing 500 mg of a pumpkin seed extract¹². Those research findings have accumulated in the recent years that endorse the wide range of therapeutic values of pumpkin seeds. More clinical trials are required to optimally utilize the nutritional potential of pumpkin seeds¹³.

Antidiabetic effect of flax and pumpkin seed mixture powder:

Reactive oxygen species play a crucial role in the pathogenesis of diabetes and its complications. This study aims to examine the effects of flax and pumpkin powder seed mixture on alloxan induced diabetes in Wistar rats¹⁴. Animals were allocated into three groups of six rats each: a control group (CD), diabetic group (DD) and diabetic rats fed with flax and pumpkin seed mixture (DMS) group. The diabetic rats (DD) presented a significant increase in glycemia, plasma and liver lipid parameters such as total lipid, total cholesterol and triglycerides compared to the control group (CD). In addition, plasma and liver malonaldialdehyde levels (MDA, an index of lipid peroxidation) significantly increased compared to (CD). Antioxidant enzymes activities such as catalase, superoxide dismutase, and reduced glutathione (GSH) levels significantly decreased in the plasma and liver of diabetic rats compared to controls¹⁵. Diet supplemented with flax and pumpkin seed mixture in the DMS group ameliorated antioxidant enzymes activities and level of GSH in diabetic rats and significantly decreased MDA levels. The present study revealed a significant increase in the activities of aspartate aminotransferase and alanine aminotransferase on diabetic status, indicating considerable hepatocellular injury. The administration of flax and pumpkin seed mixture attenuated the increased levels of the plasma enzymes produced by the induction of diabetes and caused a subsequent recovery towards normalization comparable to the control group animals. Our results thus suggest that flax and pumpkin seed mixture supplemented to diet may be helpful in preventing diabetic complications in adult rats¹⁶.

Estrogenic-like effects:

As we know that estrogen hormones play a key role in the menstrual cycle, reproduction, modulation of bone density, and cholesterol transport in the body (Rosano, et al., 2007). Phytoestrogen is a polyphenol compound from plant that exerts mammalian estrogenic-like effect due to the binding ability with estrogen receptor¹⁷. The oil of pumpkin seeds has proved to contain high percentage of phytoestrogens and sterols such as secoisolariciresinol and lariciresinol (Patel, et al., 2012). Sicilia, et al. (2003) reported that pumpkin seeds contain secoisolariciresinol approximately 21 mg/100 g of dry weight and Philips, et al. (2005) found 265 mg of phytoestrogens/100 g of seeds. Supplementation of pumpkin seeds to rats showed anti-atherogenic and hepato-protective effect in hypercholesterolemic rats (Mazur and Adlercreutz, 1998; Makni, et al., 2008)¹⁸. Further study revealed that pumpkin seeds exhibited estrogenic-like effects such as regulating lipid metabolism, bone remodeling, mammary gland and uterus epithelial cells development. Phytoestrogen components were the key role in inhibiting cardiovascular outcomes and balancing the plasma lipids level such as total cholesterol, low-density lipoprotein (LDL), highdensity lipoprotein (HDL), and triglyceride (GossellWilliams, et al., 2008; Jones, et al., 2000; Zeb and Ahmad, 2017). In conclusion, phytoestrogens and tocopherols presented in pumpkin seeds contribute to their estrogenic-like effects¹⁹.

Anticancer activities:

The previous studies reported that phytoestrogen compounds in pumpkin seeds also exerted an anticancer effect. Some reports showed that pumpkin seeds are a good candidate for cancer prevention and/or cancer treatment. As described in the previous sentences, phytoestrogen compounds are related to estrogen hormones. Thus, several studies explored the association of the effect on estrogen hormone-dependent malignancies, mainly breast cancer. Richter, et al., (2013) conducted research about the anticancer effect of pumpkin seeds extract using human breast cancer cells (MCF7), human chorionic carcinoma cell lines (Jeg3 and BeWo), the results showed a cytotoxic effect on those cancer cells and elevated the estradiol production in a concentration-dependent manner²⁰. Interestingly, this phenomenon looks to be a contradiction because usually estrogenic-like effect promotes cell proliferation. One of the explanations for this phenomenon is that pumpkin seeds exert a biphasic effect, estrogenic and antiestrogenic activities through different pathways. This phenomenon also found in several phytoestrogen compounds such as genistein and daidzein (Guo, et al., 2004). Another in vitro result was reported by Medjakovic, et al. (2016), they found that hydroalcoholic pumpkin seed extract inhibited not only cancer cells proliferation but also hyperplastic cells, while weaker effects on non-hyperplastic cells. They concluded that the anticancer effect of pumpkin seeds was not mediated through sex steroid hormone receptors. The previous research also claimed that phytoestrogen like isoflavones are considered to exert estrogenic-like effects but possess nonhormonal properties that also may contribute to their effects (Messina and Loprinzi, 2001)²¹.

Cytotoxic effect of pumpkin seeds ethanolic and aqueous extracts in prostate cancer in vitro was conducted by Rathinavelu, et al. (2013) and confirmed that the cytotoxic effects of both extracts of pumpkin seeds was mediated through oxidative stress, mitochondrial depolarization and apoptosis mechanisms. Jiang, et al. (2012) reported that there was an inhibition of prostate cancer in vitro and in vivo experiments in the group treated by pumpkin seeds as a dietary supplement. The animal study using Sprague dawley rats showed that the oil from pumpkin seeds inhibited testosterone-induced hyperplasia that would be useful in the management of benign prostatic hyperplasia (Gossell-William, et al., 2006). The clinical trial of benign prostate cancer (BPH) patients has proved that after 3-months treatment with pumpkin seed oil, the symptoms were reduced especially in the early stage of cancer (Friederich, et al., 2000; Hong, et al., 2009). In the same study of human trial, a whole extract of Stryrian oil pumpkin seeds was correlated to reduce benign prostate hyperplasia-related symptoms (Fruhwirth and Hermetter, 2007). Many reports also claimed that the components such as cucurbitacins and moschatin were found in pumpkin seeds and in charge for anticancer activities. Cucurbitacins have been isolated from several species of pumpkin seeds and have been reported to induce apoptosis through JAK/STAT, PARP, MAPK pathways (Rios, et al., 2012). Moreover, Xia, et al. (2003) reported that moschatin from the mature seeds of pumpkin (Curcurbita moschata) inhibited the growth of targeted melanoma cells M21. In general, the molecular mechanism of anticancer effect of pumpkin seeds should be clarified further based on particular concentrations and several types of cancer cells.²²

Antioxidant and free radical scavenging properties:

Pumpkin seeds oil has been proven to contain high antioxidant vitamins like tocopherol and carotenoid by several studies along with sufficient oxidative stability (Xanthopoulou, et al., 2009; Seif, 2014; Hernández-Santos, et al., 2016). In vivo experiment was conducted by Bardaa, et al., (2016) using the cutaneous wound healing rats and revealed that oil from pumpkin seeds extracted by cold pressure was better in macroscopic, morphometric and histological data of rat skin than the untreated group. The potent antioxidant effect and protective activity against genotoxic chemicals of pumpkin seeds has performed by Elfiky, et al., (2012)²³. Those findings have been consistently and strongly demonstrated that pumpkin seeds oil was accepted as antioxidant and free radical scavenger. Fahim, et al. (1995) observed that treatment with pumpkin seeds oil decreased free radicals and was helpful for arthritis. In addition, Yasir, et al. (2016) reported that extract of pumpkin seeds exhibited antioxidant and genoprotective effects. Overall, the high amount of tocopherol present in the pumpkin seeds might be considered as playing a protective role against toxic substances and free radicals²⁵

Nutraceutical potential and future prospective:

In the recent years, pumpkin seeds have a large range of application as a food or herbal medicine. Those waste streams are valuable and can be utilized for food products and/or nutraceutical products. They can be consumed as a snack, salads or breakfast cereal in the roasted form (salted or not). In addition, they could be used in baking as the excellent ingredients of bread or cakes. Moreover, their oil is excellent and could gain acceptance as edible oil and additive component in food, pharmaceutical and cosmetic industries. Pumpkin seeds oil is useful for frying, cooking, baking and salad dressing. Supplement from pumpkin seeds could be developed in the form of a soft capsule. In cosmetic industries, they usually use for skin care products such as antiaging, free-radical scavenging, skin protection and hair care products such as hair growth stimulants and emollients. The consumption of pumpkin seeds in the oil form or roasted pumpkin seeds is proved to exhibit several positive health effects²⁶

Pumpkin seed oil and its effects in various physiological processes:

Several studies have demonstrated that pumpkin seeds and daily rich diet of zinc can decrease the undesirable side effect of lead contaminants and improve the sexual health status. Pumpkin seeds improve sexual stimulation and intromission and ejaculatory latency. On the other hand, pumpkin plant extract caused a significant reduction in sperm count with primary and secondary abnormalities by producing further zinc and protein²⁷. Therefore, pumpkin seed oil but not the plant extract has been used in preclinical studies to explore its role in both the prevention and treatment of infertility in male animal models. Along similar lines, studies by Aghaei et al have demonstrated that pumpkin seed extract could recover the side effects of cyclophosphamide (CP) mediated changes in histology of epididymis and sperm parameters through preventing oxidative stress. The sperm characteristics in CP-treated rats were significantly decreased and biochemical analysis revealed that the administration of pumpkin seed extract significantly enhanced the total antioxidant capacity (TAC)²⁸. In addition, pumpkin seed extract remarkably improved the histopathological parameters such as vacuolization, disorganization and separation of epididymal epithelium in CP-treated rats. These finding indicate that the pumpkin seed extract could be used to prevent CP-induced reproductive toxicity. Similarly, Mohammadi et al have shown that administration of ginger and pumpkin seed extract simultaneously increased the number of germ cells in seminiferous tubes and had positive effects on the recovery of spermatogenesis in adult rats after cyclophosphamide (CP) treatment. Studies by Bourre et al have further brought the importance of oleic acid, a monounsaturated fatty acid also present in pumpkin in reducing the susceptibility of the testis and epididymis to lipid Peroxidation²⁹.

Multiple studies have demonstrated that an antioxidative property of pumpkin seed extract could improve the fertility and help in preventing arteriosclerosis, high blood pressure and heart diseases as well as in stimulating the metabolism of accumulated fats. Studies by Bharti et al have provided pharmacological evidence of tocopherol fraction of raw seeds of Cucurbita pepo L. as possessing an anti-hyperglycemic property mediated via the interactions of its various components with multiple signaling targets that play crucial roles in diabetes mellitus (DM)³⁰. In addition, El-Mosallamy et al have demonstrated the effect of pumpkin seed extract on blood pressure induced by nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME). In this study, rats treated with 50 mg/kg/day L-NAME with or without calcium channel blocker, amlodipine and pumpkin seed oil and their effects on the pathological alterations in the heart and aorta induced by L-NAME were evaluated. Authors demonstrated that both pumpkin seed oil and amlodipine treatments protected the rats from L-NAME induced defects in the heart and aorta through the mechanism that could involve the generation of NO suggesting that pumpkin seed oil exhibits an antihypertensive and cardioprotective effects³¹.

The effects of pumpkin seed oil have also been investigated in influencing the growth of hairs. Interestingly, studies by cho et al have evaluated the effects of pumpkin seed oil on hair growth in men with androgenetic alopecia. After 24 weeks of treatment, self–rated improvement score and self-rated satisfaction scores in the pumpkin seed oil-treated group were higher compared to the placebo group (p = 0.013, 0.003). The pumpkin seed oil-treated group had more hairs after treatment than at baseline, compared to the placebo group (p< 0.001). The mean hairs count increased by 40% in pumpkin seed oil-treated men at 24 weeks compared to 10% in placebo-treated men (p< 0.001)³². In another study, Cucurbita maxima (CM) seed oil has been shown to exhibit antiamnesic activity as indicated by a significant reduction in the latency time in the Morris water maze test and decreased social interaction during trial 2 in the social recognition test. Moreover, CM seed oil treatment have been shown to significantly decrease acetylcholinesterase (AChE) activity and malondialdehyde levels and increase glutathione levels in brain regions. As CM seed oil significantly decreased the expression of proinflammatory cytokine, tumor necrosis factor alpha (TNF-α) in the hippocampus, its effects on the behavior and biochemical parameters was comparable with the rats treated with piracetam. These findings indicate that CM seed oil may exert antiamnesic activity via its ability to inhibit AChE and inflammation as well as its antioxidant activity in the brain.³³

An isocaloric switch from a diet rich in saturated fat to a diet rich in unsaturated fat can attenuate non-alcoholic fatty liver disease (NAFLD) and atherosclerosis development. Given that phytochemical-rich virgin pumpkin seed oil exerts additional anti-inflammatory effects resulting in more pronounced health effects, authors investigated the potential long-term health effects of isocaloric substitution of dietary fat (i.e. partial replacement of saturated by unsaturated fats), as well as putative additional effects of phytochemicals present in unrefined (virgin) oil on the development of NAFLD and associated atherosclerosis³⁴. In a study, Morrison et al used pumpkin seed oil because of its high levels in unsaturated fatty acids and a rich source of phytochemicals. To that end, mice were fed with a western-type diet containing cocoa butter (15% w/w) and cholesterol (1% w/w) for 20 weeks to induce risk factors and disease endpoints. In separate groups, cocoa butter was replaced by refined or virgin pumpkin seed oil. These studies demonstrated that both oils improved dyslipidaemia, with decreased VLDL-cholesterol and triglyceride levels compared to western-type diet, and additional cholesterol-lowering effects were associated with virgin over refined pumpkin seed oil. While refined oil did not affect the plasma inflammatory markers, virgin oil reduced the circulating levels of serum amyloid A and soluble vascular adhesion molecule-1. The development of NAFLD and atherosclerosis was modestly reduced in refined-oil fed mice and virgin-oil strongly decreased liver steatosis, inflammation, atherosclerotic lesion area and disease severity.³⁵

In a clinical trial, effects of the pumpkin seed oil from Cucurbita pepo (CP oil) were evaluated in over 2000 men suffering from benign prostate hypertrophy (BPH). Authors demonstrated that an oral administration of 500–1000mg/day of CP oil for 12 weeks decreased the International Prostate Symptom Scores by 41.4% and more than 96% of the patients had no undesired side effects indicating that CP oil significantly improved the urinary dysfunction in patients³⁶. Studies by Gossell-Williams et al have demonstrated that CP oil inhibited testosterone-induced hyperplasia of the prostate in rats. In this study, rats treated with 0.3 mg/100 g body weight of testosterone showed an increase in prostate size ratio which was inhibited by the administration of 2.0 or 4.0 mg/100 g body weight of CP oil. Along similar lines, Nishimura et al have evaluated the effect of another pumpkin seed oil extract of Cucurbita maxima (CM oil). In these studies, authors demonstrated that CM oil was safe, well tolerated and was effective in preventing urinary disorders such as Overactive bladder (OAB) and benign prostate hypertrophy (BPH). These effects were attributed to the sitosterols content of the CM oil indicating its potential in the prevention or treatment of urinary disorders including OAB³⁷.

Phytochemicals (phytosterols) have been used as an alternative or integrative therapy for the relief of lower urinary tract symptoms caused due to a prostatic disease. This problem seems to be growing quickly all over the world, including the Republic of Korea. In this regard, studies by Hong et al determined the effects of pumpkin seed oil and saw palmetto oil in Korean men with symptomatic benign prostatic hyperplasia³⁸. These studies demonstrated that patients treated with pumpkin seed oil, saw palmetto oil, or a combination of pumpkin seed oil and saw palmetto oil for over 12 months have improved in BPH symptoms compared to the patients on placebo. While the therapeutic efficacy of a combination of these two oils did not improve, no side effects were reported. These studies suggest that pumpkin seed oil and saw palmetto oil are clinically safe and may be effective as complementary and alternative medicines for the treatment of BPH³⁹.

CONCLUSION:

The general conclusion of this literature study is that pumpkin seeds have emerging bioactive compositions that promote health and human life. All of these findings bring us to the new idea in developing and innovating nutraceuticals, pharmaceuticals, and cosmeceuticals products from pumpkin seeds for the large range application. Studies confirmed that the pumpkin seeds Have nutritional and therapeutic properties as well as these are also Served as delicious food in many regions of the globe. The pumpkin Seeds are cultivated in tropical and subtropical areas. There are Three main types are cultivated such as Cucurbita pepo, Cucurbita Maxima and Cucurbita moschata. The nutrient composition Analysis of pumpkin seeds showed that these are very nutritious and provide many essential nutrients for health. However, the Pumpkin seeds have been used for medicinal purpose and these Possess also nutritional and therapeutic importance. The pumpkin Seeds play a significant role in providing of micronutrients and Also used in treatment and management of diabetes, inflammation, Hyperlipidaemia, hypertension, cancer management and protect Heart etc.

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Received on 02.02.2023 Modified on 27.02.2023

Res. J. Pharmacology and Pharmacodynamics.2023;15(2):59-65.

DOI: 10.52711/2321-5836.2023.00012