Pomegranate (Punica granatum) and Caffeine: A Review of Their Combined Effects on Skin Health and Aging

Pomegranate (Punica granatum)

• Biological name: PunicaGranatum [17]
• Family: Lythraceae (previously named Punicaceae) [18]
• Geographical source:It originates from Iran and the northwestern Himalayas and has been cultivated in Mediterranean regions of Asia, Africa, and Europe for centuries.
• Chemical constituents: [19]

PunicaGranatum is along-lived, deciduous, evergreen shrub that can grow 6–10 meters tall. It features thorny branches and evergreen leaves that are 1–10 cm long, typically arranged in clusters of 5–6 on the branches. Its red flowers, which are 3 cm wide, have pointed sepals and many stamens, with two to seven flowers found at the ends of the branches. The fruit is hexagonal, measuring 6–12 cm wide and weighing about 200 grams, topped with a thick tubular calyx. It has a hard, leathery, red rind. The edible part of the fruit is a berry called sarcotesta, containing around 600 arils (seed casings) beneath a thick skin. When ripe, the fruit turns red, and the arils are grouped together, separated by thin membranes and white in color.

Pomegranate species:

• Punica granatum

Punica Granatum varities:

• Parfianka                           
• Desertnyi
• GissarskiiRozovyi
• Pink Satin
• Purple Heart
• Red Silk.

Taxanomical Classification: [2]

• Kingdom: Plantea
• Division: Magnoliophyte
• Class: Magnoliopsida
• Subclass: Rosidae
• Order: Myrtales

• Family: Punicaceae

• Genus: Punica
• Species: Punica Granatum

Dermatiological Effets of Punica Granatum: [4]

Since ancient times, Punica Granatum has been utilized for addressing skin inflammation across the Middle East, India,and Iran. In Ayurvedic medicines, various parts of Punica Granatum are restore skin balance. Research has illustrated the dermatological benefits of different Punica Granatum fractions through various in vivo and in vitro studies. Punica Granatum exihibits a range of effects, making it effective for treating both diseased skin  such as in case eczema due to its anti-inflammatory properties, psoriasis, striae, and bacterial or fungal infection and healthy skin, by helping prevent UV-induced photoaging and skin cancer, combat chrono-aging, and enhance the appearance of wrinkels

The pomegranate shows properties as below:

1. Antioxidant properties:

The antioxidant activity of pomegranate is attributed to its polyphenol hydroxyl groups, which effectively neutralize free radicals. Similarly, the catechol hydroxyl groups found in complex and   condensed tannins are capable of chelating iron and other transition metals.

Pomegranate is also abundant in anthocyanins, which are known for their strong antioxidant capabilities. Research by Gill et al. indicated that phenolic compounds contribute to 28% of pomegranate's overall antioxidant activity, highlighting the significance of anthocyanins in this capacity.

Numerous studies have investigated the antioxidant properties of pomegranate, predominantly using the DPPH assay. Generally, various parts of the pomegranate exhibit notable anti-radical and antimicrobial properties, suggesting that this plant could be regarded as a safe herbal source of preservatives and antioxidants. Consequently, P. granatum may serve as a beneficial additive in the pharmaceutical and food industries. [5]

1. Anti-Inflammatory Activity:

Ellagic acid (EA) exhibits anti-inflammatory properties in chronic conditions. It also inhibits inflammatory responses in keratinocytes by modulating crucial signaling pathways related to inflammation, such as mitogen-activated protein kinases and signal transducers and activators of transcription (STAT). In experiments conducted on mice with DfE-induced atopic dermatitis, EA showed improvement in skin symptoms by diminishing inflammatory responses. Thus, EA has the potential to serve as an alternative treatment for atopic dermatitis by blocking inflammatory signaling pathways. Due to the risks associated with NSAIDs for pain and inflammation relief, there is a growing interest in medicinal plants as alternative therapies. Research by Ben Saad et al. demonstrated that ellagic acid, gallic acid, and punicalagin A&B could effectively reduce the production of NO, PGE-2, and IL-6 induced by LPS. These compounds, key constituents of pomegranate, are likely to play a significant role in their anti-inflammatory effects.  [5]

1. Antimicrobial activity:

Tannins may exert their antimicrobial effects through three primary mechanisms: by inhibiting enzymatic functions, precipitating membrane proteins, and reducing metal ions.   Herpes disease continually necessitates new and effective treatment options. Consequently, Houston et al. investigated the effects of pomegranate fruit and zinc metal ions on herpes simplex virus. In their study, they assessed how these compounds affected herpes simplex virus type 1 and acyclovir-resistant strains in Vero host cells using the MTS method and a commercial kit. Zinc sulfate, zinc citrate, zinc stearate, and zinc gluconate demonstrated an increase in antiviral activity comparable to pomegranate rind extract (PRE) against HSV-1, with enhancements up to four times. Punicalagin exhibited eight times the antiviral activity compared to an equal amount of PRE; however, it showed significantly lower viricidal activity than PRE, which was similar to that of acyclovir. Similarly, PRE showed effectiveness against acyclovir-resistant HSV, whereas acyclovir itself was ineffective. The combined antiviral effects of PRE and Zn (II) suggest potential for a new topical treatment for HSV infections, such as cold sores. Pomegranate, recognized as an herbal drug with notable antimicrobial activity, has had its antiviral effects highlighted by Houston DM et al., who found that the activity of pomegranate rind extract was significantly enhanced by zinc (II) ions, achieving up to a 7-log reduction against the herpes simplex virus. HSV1 and HSV2 lesions can provoke significant local inflammation, resulting in erythema, swelling, and pain, especially in advanced stages of the infection. Moreover, Sadeghian et al. assessed pomegranate peel extract as an antibacterial agent against Gram-positive bacteria like Staphylococcus aureus, Gram-negative bacteria such as Pseudomonas aeruginosa, and pathogenic yeasts including Candida albicans. They compared the antibacterial activity of both aqueous and methanolic extracts with antibiotics using three different methods: agar dilution, cylinder plate, and antibiogram. Their findings showed that the extracts had notable bactericidal effects against Staphylococcus aureus and P. aeruginosa. Furthermore, the methanolic extract demonstrated strong antifungal activity against C. albicans. The antimicrobial effects on Staphylococcus aureus, P. aeruginosa, and C. albicans were comparable to those of cloxacillin, gentamicin, and clotrimazole, respectively. Overall, the methanolic extract of pomegranate fruit peel was more effective than the aqueous extract against all tested bacteria, suggesting that P. granatum extracts could be a valuable source for developing new antibacterial drugs. Duman et al. investigated the antimicrobial properties of the arils from six cultivars of P. granatum L. from Turkey using agar diffusion and minimum inhibitory concentration (MIC) methods against seven bacterial strains: Bacillus megaterium, Pseudomonas aeruginosa, Staphylococcus aureus, Corynebacterium xerosis, Escherichia coli, Enterococcus faecalis, and Micrococcus, as well as three fungi (Kluvyeromyces marxianus, Rhodotorula rubra, and Candida albicans).  Pomegranate aril extract demonstrated antimicrobial activity against all microorganisms, producing inhibition zones ranging from 13 to 26 mm. The MIC values for the active extracts varied between 30 and 90 µg/ml, further supporting the antimicrobial potential of species within the P. granatum genus. [5]

2. Anti-acne activity:

Acne vulgaris is a common skin condition characterized by excessive sebum production, hyperkeratosis, and the presence of Cutibacterium acnes, Staphylococcus aureus, as well as inflammation. Lee et al. found that pomegranate extract significantly reduced swelling caused by C. acnes in the ears of Wistar rats. Their findings demonstrated that pomegranate extract not only inhibited bacterial growth but also affected lipase activity. The four identified hydrolysable tannins include punicalagin, punicalin, strictinin A, and granatin B. Among these, punicalagin and punicalin exhibited stronger antibacterial properties and effects on testosterone-induced proliferation of HaCaT cells compared to the others. Punicalagin, strictinin A, and granatin B were shown to inhibit lipase activity. Granatin B specifically reduced the expression of cyclooxygenase-2 and the production of prostaglandin E2 in RAW 246.7 cells exposed to P. acnes. In conclusion, the hydrolysable tannins from pomegranate demonstrate significant anti-acne, anti-lipase, anti-keratinocyte proliferation, and anti-inflammatory effects. Thus, pomegranate extract (PG-E) holds substantial promise for use as a topical anti-acne treatment, with punicalagin emerging as the most effective compound and a key quality control marker. [5]

1. Anti-aging activity:

Ultraviolet (UV) radiation can lead to several skin issues, such as sunburn, inflammation, increased skin cell production, weakened immune response, premature aging, and skin cancer. Research by Park et al. using the GC-MS method has demonstrated that polyphenols from pomegranate can help mitigate the harmful effects of UV radiation on the skin. To assess how pomegranate can protect against UVB-induced skin aging, they measured procollagen type I and MMP-1 levels. The key compounds identified were catechin, quercetin, kaempferol, and equol. Exposure to sunlight affects the expression of procollagen type I and MMP-1 in fibroblasts, and findings indicate that pomegranate catechins, a significant polyphenol component, play a crucial role in shielding the skin from UVB damage. Numerous in vivo and in vitro studies have shown that polyphenols exhibit antioxidant, anti-inflammatory, and anti-cancer properties. Pomegranate fruit extract, particularly standardized for punicalagins, has been found to effectively prevent fibroblast apoptosis following UV exposure, likely by inhibiting the pro-inflammatory transcription factor NF-kappa B, downregulating the pro-apoptotic caspase-3, and promoting the G0/G1 phase associated with DNA repair. This research highlights the protective benefits of pomegranate extract against apoptosis induced by UVA and UVB and suggests its potential use in topical formulations. Pomegranate fruit extract is recognized for its strong antioxidant and anti-inflammatory properties. Recent studies have shown that treatment with pomegranate extract protects human epidermal keratinocytes from UVB-triggered activation of MAPK and NF-kappa B pathways. The pathways regulated by Signal Transducers and Activators of Transcription 3 (STAT3), Protein Kinase B/AKT, and MAP Kinases (MAPKs) influence cellular processes, including proliferation and apoptosis. Pomegranate extract also shields the skin from UVA-induced activation of STAT3, AKT, and extracellular signal-regulated kinase (ERK1/2). Our findings demonstrate that pomegranate extract is an effective protector against UVA damage and warrants further investigation as a potential photoprotective agent. [5]

2.  Skin whitening activity:

A topical microemulsion featuring P. granatum extract effectively manages erythema and skin redness while also regulating melanin levels in individuals. Rich in polyphenolic compounds, P. granatum demonstrates significant antioxidant properties that combat free radicals. It is thought that ellagic acid serves as a skin brightener by binding to copper in the enzyme tyrosinase. This study indicates that the P. granatum extract microemulsion may be beneficial in topical applications for addressing skin spots and redness.

Currently, there are several potent ingredients and skin-lightening products that can inhibit tyrosinase activity in the melanogenesis process. However, common tyrosinase inhibitors such as hydroquinone, kojic acid, and arbutin can sometimes lead to skin irritation or acute dermatitis, raising safety concerns about these agents. As a result, the demand for safe, natural skin lightening alternatives has surged. Pomegranate fruit extract contains elements that suppress melanogenesis, suggesting its potential use in lightening creams within cosmetic products. Specifically, punicalagin, a polyphenolic compound found in pomegranate extract, has been identified as an inhibitor of melanin production.

Recent research demonstrates that a 1:1 mixture of Larix sibirica and P. granatum extracts resulted in a twofold reduction in melanin levels within cells, compared to using either extract alone. [5]

2. Anti-stretch marks:

Stretch marks, which are dermal lesions resulting from various factors, have yet to be fully understood. While they generally do not lead to significant medical problems, they remain a cosmetic issue for those affected. A study by Bogdan C. and colleagues found that a cream formulation containing PSO extract and C. lechleri might be effective in preventing or improving the appearance of stretch marks. [5]

3. Wound healing activity:

Numerous studies have demonstrated that P. granatum enhances the wound healing process. Nayak et al. evaluated the wound healing effects of P. granatum fruit peel, finding a 95% reduction in wound area in animals treated with the extract, compared to an 84?crease in the control group.

The rate of skin epithelialization was quicker in the group treated with pomegranate extract, which also showed significantly higher hydroxyproline levels than the control. Therefore, P. granatum noticeably improved wound healing in rats.

Additionally, Murthy KN et al. found that pomegranate extract contained a high concentration of phenolic compounds (44%). They developed a 10% water-soluble gel to study its effects on wound healing, skin contraction, collagen, and hydroxyproline levels in a rat model.

Rats treated with the 2.5% gel exhibited a mean improvement of 55.8% and 40.8% when compared to the positive and negative control groups, respectively. The 5.0% gel group showed even better results, with improvements of 59.5% and 44.5% relative to the negative and positive controls, respectively. Hydroxyproline levels were notably higher in the group treated with the 5% gel. Histological assessments supported the effectiveness of gels containing the extracts in promoting wound healing. The hydroxyproline content in the 5% gel doubled, corroborating the histopathological findings regarding healing. The wound healing durations for the 5.0% gel, 5.2% gel, and control were recorded at 10, 12, and 16 to 18 days, respectively. Chromatographic analysis identified catechin and gallic acid as the primary active components responsible for the healing effects. In another study, the efficacy of methanolic extracts of P. granatum at concentrations of 10% and 15% w/w was examined in a cut wound model in rats. Results were comparable to those of nitrofurazone ointment, with wound contraction rates of 97.8% and 98.4% for the 10% and 15% ointments, respectively, showing significant improvement (P < 0>

4.  Anti-cancer activity:

The anticancer effects of pomegranates are attributed to their polyphenol content, which has shown anticarcinogenic activity both in laboratory and animal studies. Pomegranate extract has been found to induce apoptosis and reduce proliferation in cancer cells, notably causing significant apoptosis in myeloid and lymphoid leukemia cell lines while also halting the cell cycle. Studies indicated that pomegranate extracts inhibited the growth of breast, colon, lung, and prostate cancer cells in vitro. Furthermore, preclinical animal trials demonstrated a reduction in the growth of skin, colon, lung, and prostate tumors with pomegranate extract. In an early Phase II clinical trial, prostate cancer patients who consumed pomegranate juice experienced a notably extended doubling time of prostate-specific antigen levels. Laboratory studies have shown that pomegranate seed oil can inhibit the growth of various tumor cells and reduce skin cancer development in mice and in mouse mammary organ culture models. The effects of pomegranate juice may be enhanced by the other phytochemicals it contains. Additionally, extracts from pomegranate peel have been observed to inhibit cell growth across several cancer cell lines. Previous evaluations of pomegranate's phytochemicals have indicated their anti-carcinogenic properties. Research conducted by Tang et al. demonstrated that punicalagin inhibits the ?-catenin signaling pathway, contributing to its chemopreventive and chemotherapeutic potential against human cervical cancer. [20]

 Medicinal Uses: [6]

• Used as facial scrub and exfoliates while also containing sun?blocking agents that offer protection from the sun's harmful UV rays.
• Restore heart health.
• Lower blood pressure.

CAFFEINE (1,3,7- trimethlxanthine)

Caffeine is an alkaloid present in coffee, tea, and certain soft drinks. While the effects of caffeine on the human body are well-known, its mechanism of action in cosmetics remains largely unexplained. As coffee and caffeine are becoming more prevalent in various cosmetic products, it raises the question of whether they can genuinely enhance skin appearance and hair health. Understanding caffeine's capacity to penetrate the skin barrier is crucial for exploring how it affects skin and hair.[7]

• Biological name: Coffee bean or coffee seed
• Family: Rubiaceae
• Geographical source: The plant originates from Ethiopia and various regions of Eastern Africa, and it is commonly grown in Indonesia, Sri Lanka, and Brazil.
• Chemical constituents: Beans contain oil, wax, caffeine, aromatic oil, tannic acid, caffetannic acid, gum, sugar, protin.
• Structure: [8]

        
           
       
Caffeine

Taxonomical Classification:

• Class: Methylxanthine
• Family: Rubiaceae
• Species: Coffee Arabica

Bioactive component:

1. Chlorogenic acid:

Chlorogenic acid, a polyphenol found in coffee, is recognized for its biological activity and ability to slow carbohydrate absorption. This compound, which exists in the coffee plant, is derived from trans-cinnamic and quinic acids, both of which are beneficial nutritional phenols. Often referred to as 5-O-caffeoylquinic acid, its concentration in a 200 ml (7-oz) cup of coffee typically ranges from 70 to 350 mg, along with approximately 35 to 175 mg of caffeic acid. Chlorogenic acid plays a significant role in regulating glucose and lipid metabolism, aiding in the management of various disorders such as diabetes, cardiovascular diseases, obesity, cancer, and hepatic steatosis. Additionally, it offers numerous potential health benefits, including anti-diabetic, anti-carcinogenic, anti-inflammatory, and anti-obesity effects, and may serve as a non-pharmacological and non-invasive option for the treatment and prevention of certain chronic diseases. [8]

• Structure of  Chlorogenic acid:[9]

       
           
       
Coffee lipids(Cafestol and Kahweol ):

The average bean of Coffea arabica contains cafestol and its structural analog kahweol, with concentrations varying from 0.1 to 7 mg/ml in coffee. These two coffee-specific diterpenes exhibit anticarcinogenic properties and have protective effects against aflatoxin B1 (AFB1) in human cells, while also increasing serum cholesterol levels when boiled coffee is consumed. Diterpenes cafestol and kahweol (C+K) can produce various biochemical effects that help reduce the genotoxicity of several carcinogens, including DMBA, AFB1, benzo[a]pyrene (B[a]P), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Coffee consumption constitutes the primary source of human exposure to C+K and is relevant for health, especially for those consuming moderate amounts (up to 5 cups a day). Additionally, these compounds are present in liver, kidney, lung, and intestinal tissues. Generally, natural diterpenes from coffee, specifically cafestol and kahweol, promote apoptosis by regulating the expression of specific proteins in human malignant pleural mesothelioma. They can be found in boiled coffee and contribute to increased plasma cholesterol levels in humans. [8]          

• Structure of Cafestol and Kahweol [10]

       
           
       
Dermatiological effect of Caffeine:

1. Sun protection:

Caffeine is linked to protective effects against UV damage, which has significance for cancer prevention and age-related skin harm. A study found that applying caffeine topically in a solution significantly decreased wrinkle formation caused by UVB exposure in the skin of mice, with a reduction in wrinkle area of over 35% compared to a control group. Moreover, caffeine has been shown to prevent the formation of thymine dimers induced by UVB and promote UVB-triggered cell death in both tumors and UV-damaged skin cells, giving it a dual role as a sunscreen and a pro-apoptotic substance.

 Its ability to enhance apoptosis occurs through both p53-dependent and p53-independent pathways. Research indicates that caffeine can inhibit UVB-induced cancer development by blocking the “ataxia telangiectasia and rad3-related” (ATR) kinase, which is involved in the DNA damage response. Translating these findings to clinical applications, a 2019 study revealed that caffeine could effectively enhance sunscreens, increasing the sun protection factor (SPF) in both laboratory and real-world settings without causing skin irritation or damage to the skin barrier, yielding a 25% increase in UVB protection. However, no research has specifically investigated caffeine's effectiveness against UV-A radiation. [11]

2. Anti-acne activity:

Four primary factors are recognized to contribute to acne development: overactivity of sebaceous glands leading to excess sebum production (seborrhea), increased proliferation of follicular skin cells, colonization by Propionibacterium acnes, and subsequent inflammation that involves the release of inflammatory mediators and an immune response. Given that chlorogenic acid (CGA) has shown anti-inflammatory and antimicrobial properties, a study by Luo et al. aimed to investigate the effects of CGA on the mechanisms underlying acne. They utilized the ears of ICR mice infected with live P. acnes to model skin inflammation. The results indicated that CGA treatment reduced ear swelling, redness, and erythema, as well as significantly lowered the expression of inflammatory cytokines. Additionally, the analysis suggested that CGA markedly decreased lipogenesis, with significant reductions in triglycerides, cholesterol, and free fatty acids following treatment. These findings imply that CGA may serve as a potential anti-acne treatment by addressing both sebum production and inflammation. [14]

3)  Anti-aging activity:

The skin, being the body's largest organ, is vulnerable to aging due to factors from the harsh external environment. Skin aging results from diminished cellular function, gradual loss of homeostatic regulation, and alterations in skin tissue structure. These processes are closely associated with visible signs of aging, such as wrinkle formation, uneven skin tone, and slower wound healing. Recently, alternative cell-based assays have emerged as a way to examine the cosmetic potential of substances, minimizing the need for painful animal testing. Human skin cells, particularly fibroblasts, are utilized to assess the properties of natural extracts related to antioxidants, inflammation reduction, wound repair, collagen production, and cell growth, as these cells play a crucial role in extracellular matrix synthesis. Understanding the biological processes involved in dermal cell aging is essential to grasp skin aging mechanisms. Numerous biological changes, like reduced protein synthesis in the extracellular matrix and heightened degradation rates, are known to occur as skin ages.

 As part of ongoing efforts to find ways to combat and mitigate skin aging, this study focused on using fibroblast cultures to explore skin anti-aging mechanisms, specifically studying cell proliferation, antioxidant effects (by enhancing SOD activity and inhibiting nitric oxide), and blocking collagenase activity through in vitro tests. [13]

4)  Wound healing:

The beneficial effects of topical CGA on wound healing were assessed using carbopol hydrogels containing 10% extract from both green and roasted coffee press cake (a residue left after oil extraction) in a mouse model. Both extracts significantly decreased the size of the wound during the inflammatory phase, but green coffee extract exhibited the most notable reduction, achieving results comparable to the positive control. This supports the observation that green coffee extract has the highest concentration of phenolic compounds. [14]

5)  Anti- cellulite:

Cellulite is a multifaceted issue linked to the microcirculatory and lymphatic systems, the extracellular matrix, and excess subcutaneous fat in adipose tissue. Caffeine has lipolytic effects by inhibiting phosphodiesterase in adipocytes, the enzyme that breaks down cAMP. This increase in cAMP boosts lipase activity, leading to the breakdown of triglycerides. Additionally, caffeine enhances blood microcirculation, which can improve the appearance of cellulite. A formulation for cellulite treatment was created using caffeine extracted from chitosan and integrated into nanostructured lipid carriers (NLCs). The addition of chitosan did not affect the size of the nanoparticles, and the formulation demonstrated good chemical stability for up to 180 days across various temperatures and humidity levels. Evaluation of the caffeine permeation from chitosan extracts through pig ear skin revealed better penetration of the nanoparticles. However, it's important to mention that due to caffeine's hydrophilic characteristics, only about 30% of caffeine from the extracted chitosan could be incorporated into these lipid nanoparticles. [14]

6) Anti-carcinogenic activity:

Increasing evidence suggests that caffeine may help protect against melanoma and non-melanoma skin cancers. While coffee contains various potentially anti-cancer compounds, caffeine is one of the most thoroughly studied components regarding its chemopreventive properties. It plays a role in inhibiting cell proliferation and carcinogenesis by controlling cell growth, development, and programmed cell death (apoptosis). Research has demonstrated that caffeine possesses sunscreen-like effects, reduces the formation of sunburn lesions in the skin, and mitigates UV-induced cancer development by preventing thymine dimer formation. Additionally, caffeine enhances the removal of damaged precancerous cells and promotes apoptosis within tumors. It influences the cell cycle and boosts UV-induced apoptosis through both p53-dependent and p53-independent pathways. Recent studies have shown that caffeine inhibits the growth of both melanoma and non-melanoma cell lines. [15]

7)   Neutraceutical activity:

In addition to their topical applications, coffee by-products may also be utilized in nutraceuticals. A study conducted by Fukagwa et al. on human volunteers with dry skin demonstrated that consuming coffee phenolic extracts enhanced skin barrier function, microcirculation, and hydration. These findings suggest that coffee by-products containing comparable phenolic compounds could be beneficial for research into nutraceuticals aimed at dermatological issues related to dryness and epithelial dysfunction. [14]

8)  Skin cancer:

An increasing body of research suggests that caffeine may offer protection against melanoma and non-melanoma skin cancers. While coffee contains various potential anticancer components, caffeine is one of the most extensively studied for its chemopreventive properties. It demonstrates antiproliferative and anti-carcinogenic effects by influencing cell growth, development, and apoptosis. Studies have indicated that caffeine acts as a sunscreen, minimizes sunburn lesions on the epidermis, and inhibits ultraviolet (UV)-induced carcinogenesis by reducing thymine dimer formation. Additionally, caffeine promotes the elimination of damaged precancerous cells through apoptosis in tumors. It also modulates the cell cycle and enhances UV-induced apoptosis via both p53-dependent and p53-independent pathways. Recent studies have shown that caffeine can inhibit the proliferation of melanoma and non-melanoma cell lines. [15]

Medicinal uses:[16]

• Used to treat a wide variety of clinical diseases, including Parkinson's, atopic dermatitis. 
• Used to treat minimal brain dysfunction in children and apnea in newborns .
• Used to treat migraine headaches. 

Marketed products and their uses:

Table 3: Marketed products of Caffeine