Nuvastatic (Standardized Orthosiphon stamineus Extract): A Comprehensive Review of its Botanical Origin, Pharmacology, Clinical Evidence, and Therapeutic Potential

I. Nuvastatic: An Overview of a Botanical Therapeutic Agent

A. Introduction to Nuvastatic and its Therapeutic Context

Nuvastatic is a botanical therapeutic agent, formulated as an effervescent powder drink, derived from natural product sources.[1] Its development by NatureCeuticals is the culmination of over a decade of preclinical and clinical research focused on botanical drugs for a variety of conditions, including cancer, diabetic retinopathy, and infectious diseases such as COVID-19.[1] The primary clinical application for Nuvastatic, as supported by current research and market positioning, is in the domain of supportive oncology care. It is particularly investigated for its capacity to alleviate cancer-related fatigue (CRF), a common and debilitating symptom complex experienced by individuals undergoing cancer treatment.[1] Beyond oncology, Nuvastatic is also being explored for its potential efficacy in managing non-proliferative diabetic retinopathy.[3]

The development of Nuvastatic occurs within a broader healthcare landscape that is increasingly recognizing the potential of scientifically validated complementary and alternative medicines. There is a growing impetus to integrate such therapies, especially in supportive care for chronic and severe illnesses like cancer. Botanical drugs, such as Nuvastatic, are of particular interest due to their potential to offer novel mechanisms of action and possibly more favorable safety profiles compared to some conventional synthetic pharmaceuticals, thereby addressing unmet patient needs. The journey of Nuvastatic from a traditional herbal remedy to a candidate undergoing rigorous clinical trials exemplifies a significant trend: the systematic scientific validation of traditional medicinal knowledge. This process aims to elevate traditional remedies to the status of evidence-based botanical drugs, meeting contemporary pharmaceutical standards.[1] Nuvastatic is also characterized as a "polymolecular botanical drug".[3] This designation is significant as it implies that its therapeutic effects are likely derived from the complex interplay of multiple phytochemical constituents within the

Orthosiphon stamineus extract, rather than a single active compound. This multi-component nature distinguishes it from conventional single-molecule synthetic drugs and suggests potential for synergistic effects and action on multiple biological targets.

B. Origin from Orthosiphon stamineus and Traditional Use

Nuvastatic is derived from a standardized extract of Orthosiphon stamineus (OS) leaves, a plant also known by its botanical synonym Orthosiphon aristatus and common names such as "cat's whiskers" or "misai kucing".[1] This medicinal herb has a well-documented history of traditional use, especially in Malaysia and Southeast Asia, where it has been employed for a wide range of health issues including kidney disorders, diabetes, rheumatism, edema, hypertension, and certain tumors.[5]

The Committee on Herbal Medicinal Products (HMPC) of the European Medicines Agency has acknowledged the traditional applications of Orthosiphon leaves, classifying them as a traditional herbal medicinal product. Traditional uses recognized include increasing urine output and flushing the urinary tract, particularly for minor urinary complaints and renal gravel.[9] This long-standing traditional use provides an ethnobotanical basis for its modern scientific investigation. However, it is essential that such traditional claims are substantiated through rigorous scientific research to establish specific efficacy and safety for defined medical indications, a process that is currently underway for Nuvastatic. The current registration of Nuvastatic as a "traditional medicine" with the Malaysian National Pharmaceutical Regulatory Agency (NPRA) [1] reflects its current evidence base and market positioning, primarily in supportive care, rather than as a prescription treatment for specific diseases like cancer based on approvals from agencies like the US FDA or EMA. This distinction is important for understanding its current therapeutic role.

II. Composition, Formulation, and Standardization

A. Active Ingredient: The Proprietary Orthosiphon stamineus Extract (C5OSEW5050ESA)

The central active pharmaceutical ingredient in Nuvastatic is a proprietary, standardized water-soluble extract derived from the leaves of Orthosiphon stamineus. This specific extract is identified by the code name C5OSEW5050ESA [2], sometimes referred to as C5EOSEW5050ESA.[3] It is obtained from a selected cultivar or unique genotype of

Orthosiphon stamineus (syn. Orthosiphon aristatus) [5], a strategy aimed at ensuring a consistent phytochemical profile and potentially higher concentrations of desired bioactive compounds. This extract is commercially known as Lanctos 75TM.[5] The use of such a proprietary, standardized extract is fundamental for developing botanical drugs, as standardization ensures batch-to-batch consistency in chemical fingerprint and concentration of key compounds, which is crucial for reliable clinical trial results and predictable therapeutic effects.

B. Key Phytochemicals and Standardization

The C5OSEW5050ESA extract is meticulously standardized to ensure consistent levels of several key phytochemicals, reflecting its complex, polymolecular nature. This standardization is a critical quality control measure, distinguishing it from unstandardized herbal supplements and aiming to ensure consistency in biological activity and clinical outcomes.

• Rosmarinic Acid: This is the primary marker compound, with the extract standardized to contain 6% rosmarinic acid by weight.[1] Rosmarinic acid, an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid, is a well-characterized phenolic compound recognized for its significant anti-inflammatory and antioxidant activities.[2] Its prominence as a standardized component highlights its perceived contribution to Nuvastatic's therapeutic effects.
• Other Standardized Phytochemicals:
• Eupatorin: 0.6% w/w.[5]
• Sinensetin: 0.2% w/w.[5]
• 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (TMF): 0.05-0.1% w/w.[5]
• Other Bioactive Compounds: While not explicitly part of the primary standardization panel for C5OSEW5050ESA in all provided documents, O. stamineus extracts are known to contain other bioactive compounds such as betulinic acid, oleanolic acid, and ursolic acid.[5] Comprehensive phytochemical analyses of O. stamineus have identified numerous compounds, including various flavonoids, diterpenes, phenols, and volatile oils, many of which possess potential biological activity.[7]

The presence of multiple standardized active marker compounds supports the hypothesis that Nuvastatic's therapeutic benefits likely arise from the synergistic or additive interactions of these various phytochemicals—an "entourage effect." This concept is central to understanding the pharmacology of many botanical medicines, where the whole extract may be more effective or possess a different range of activities than any single isolated constituent.[5]

C. Pharmaceutical Formulation

Nuvastatic is formulated as an effervescent powder drink, designed for oral administration after dissolution in water.[1] Clinical trials have utilized dosages of the C5OSEW5050ESA extract, such as 1000 mg per serving administered three times daily for studies on cancer-related fatigue.[2] A Nuvastatic® formulation containing 300 mg of the extract is also mentioned for ongoing Phase III studies in chemotherapy-induced fatigue, suggesting dose optimization efforts.[3]

The choice of an effervescent powder formulation is likely a patient-centric decision. For a product intended for supportive oncology care, particularly for managing cancer-related fatigue, factors such as palatability, ease of swallowing, and overall convenience are crucial for patient adherence, especially for individuals who may experience treatment-related side effects like nausea or mucositis.[1]

D. Manufacturer

Nuvastatic is developed and manufactured by NatureCeuticals Sdn. Bhd., a company specializing in the research and development of botanical drug products.[1]

III. Pharmacological Profile: Mechanisms of Action

The therapeutic potential of Nuvastatic, and its core extract C5OSEW5050ESA OS, is underpinned by a range of pharmacological activities, primarily anti-angiogenic, immunomodulatory, and antioxidant effects. These actions are attributed to the complex mixture of phytochemicals present in the standardized Orthosiphon stamineus extract. The multi-targeted, pleiotropic mechanism of action is a characteristic feature of many botanical medicines and may offer advantages in treating complex conditions.

A. Anti-Angiogenic Activity

The C5OSEW5050ESA OS extract demonstrates significant anti-angiogenic properties, which are critical in oncology as angiogenesis fuels tumor growth and metastasis.[5]

• Modulation of Key Angiogenic Growth Factors: In vitro studies using Human Umbilical Vein Endothelial Cells (HUVECs) have shown that the extract inhibits several pro-angiogenic growth factors:
• It significantly decreases Vascular Endothelial Growth Factor (VEGF) content in a dose-dependent manner.[5]
• It causes a significant, dose-dependent decrease in Epidermal Growth Factor (EGF) expression.[5]
• It significantly reduces Fibroblast Growth Factor (FGF) levels, particularly basic-FGF, at concentrations of 50 and 100 µg/mL.[5]
• Transforming Growth Factor-α (TGF-α) levels are reduced by the extract at 50 and 100 µg/mL.[5]
• Nerve Growth Factor β (NGF-β) expression is downregulated in a dose-dependent manner.[5]
• Impact on Endothelial Cell Functions: The extract directly interferes with endothelial cell behaviors essential for angiogenesis:
• It inhibits endothelial cell proliferation and migration by 92.6%.[4]
• It disrupts the tube assembly process, necessary for new blood vessel formation, by 98.26%.[4]
• Supporting Evidence from Ex vivo and In vivo Models:
• In the ex vivo rat aortic ring assay, the extract dose-dependently reduced microvessel outgrowth, with an IC50 of 18.2 ± 2 µg/mL.[5]
• In the in vivo Chick Chorioallantoic Membrane (CAM) assay, neovascularization was inhibited by 82.7%.[5]
• In the in vivo Matrigel plug assay in mice, the extract inhibited neovascularization by 91.4 ± 3%.[5]

B. Immunomodulatory Effects

The C5OSEW5050ESA OS extract also exhibits notable immunomodulatory properties by influencing various cytokines crucial for immune responses and inflammation.[5] These effects are likely interconnected with its anti-angiogenic actions; for instance, interferons, which are upregulated by the extract, are known to possess anti-angiogenic properties.

• Influence on Cytokine Profiles:
• Upregulation of Interferons (IFNs): The extract significantly upregulates IFN-α, IFN-β, and IFN-γ in HUVECs. These interferons play roles in anti-tumor immunity and can inhibit angiogenesis.[5]
• Upregulation of GM-CSF (Granulocyte-macrophage colony-stimulating factor): The extract significantly induces GM-CSF expression at 100 µg/mL in HUVECs. GM-CSF can stimulate hematopoietic progenitor cells and enhance myeloid cell function.[5]
• Inhibition of Specific Interleukins and TNF-β:
• The extract causes a significant, dose-dependent reduction of Interleukin-2 (IL-2) levels.[5]
• It exhibits a dose-dependent reduction of Interleukin-7 (IL-7) levels.[5]
• The extract also inhibits Tumor Necrosis Factor-β (TNF-β, or Lymphotoxin-alpha).[5]

C. Antioxidant Properties and Other Potential Mechanisms

Rosmarinic acid, the major standardized component of the C5OSEW5050ESA extract (6% w/w), is a well-established antioxidant and anti-inflammatory compound.[2] This activity is likely a key contributor to Nuvastatic's overall pharmacological effects, especially where oxidative stress and inflammation are pathological drivers.

• Reduction of Oxidative Stress Markers: Clinical data from the Phase II trial on cancer-related fatigue (CRF) showed that Nuvastatic administration led to a significant lowering of urinary F2-isoprostane concentrations, which are reliable biomarkers of systemic oxidative stress and lipid peroxidation.[2] While rosmarinic acid is a key modulator, the polymolecular nature of the extract suggests that other constituents (e.g., eupatorin, sinensetin, TMF) also contribute to the overall pharmacological profile, including its antioxidant effects.
• Broader Mechanisms of O. stamineus Extracts: Research on various O. stamineus extracts (not always specific to C5OSEW5050ESA) has indicated a wide range of biological activities:
• Enzyme inhibition relevant to diabetes, such as α-amylase and α-glucosidase.[15]
• Modulation of lipid metabolism, promotion of insulin secretion, and amelioration of insulin resistance.[6]
• Hepatoprotective effects, potentially beneficial for non-alcoholic fatty liver disease (NAFLD), by targeting pathways involving JNK, mTOR, NFKB1, PPAR, and AKT1.[6]
• Anti-inflammatory actions beyond rosmarinic acid, including inhibition of NO production and pro-inflammatory cytokines.[15]

Although Nuvastatic's current clinical development is focused on cancer-related conditions and diabetic retinopathy, the preclinical potential of O. stamineus extracts in modulating lipid metabolism, improving insulin sensitivity, and exerting hepatoprotective effects suggests a broader range of therapeutic applications in metabolic disorders that could be explored in the future.[6]

IV. Clinical Investigations and Therapeutic Efficacy

Nuvastatic has been the subject of several clinical investigations, with the most advanced research focusing on its role in managing cancer-related fatigue. Earlier stage explorations have also been undertaken for diabetic retinopathy, and preclinical studies suggest a potential adjunctive role in pancreatic cancer. The clinical development pathway shows a clear prioritization, with CRF being the most advanced indication.

A. Management of Cancer-Related Fatigue (CRF)

Cancer-Related Fatigue (CRF) is a highly prevalent, persistent, and debilitating symptom complex that significantly impairs the quality of life for many cancer patients. Nuvastatic has shown promise in this area.

• Phase II Multicenter Randomized Controlled Trial (NCT04546607): This pivotal trial provided initial evidence for Nuvastatic's efficacy in CRF.2
• Study Design and Population: The study was a multicenter, randomized, double-blind, placebo-controlled trial involving 110 patients with stage II-IV solid malignant tumors undergoing chemotherapy.
• Intervention: Patients received either oral Nuvastatic™ 1000 mg (C5OSEW5050ESA extract; N=56) or placebo (N=54), administered three times daily for 9 weeks.
• Primary Endpoints: Changes in fatigue levels were assessed using the Brief Fatigue Inventory (BFI) and the Visual Analog Scale for Fatigue (VAS-F) at baseline and at weeks 3, 6, and 9.
• Secondary Endpoints: These included the vitality subscale of the SF-36 quality of life questionnaire, urinary F2-isoprostane concentrations (oxidative stress biomarker), ECOG performance status, adverse events, and biochemical/hematologic parameters.
• Efficacy Outcomes: The Nuvastatic™ group demonstrated a statistically significant overall decrease in fatigue scores compared to placebo. Specific findings included:
• Significant reduction in BFI-fatigue scores (F (1.4, 147) = 16.554, p < 0.001, partial η2 = 0.333).[2]
• Significant reduction in VAS-F fatigue scores (F (2, 210) = 9.534, p < 0.001, partial η2 = 0.083).[2]
• Improvement in quality of life (SF-36 scores) (F (1.2, 127.48) = 34.07, p < 0.001, partial η2 = 0.243).[2]
• Significantly lower urinary F2-IsoP concentrations (mean difference (95% CI) = 55.57 (24.84, 86.30)), t (55) = 3.624, p < 0.001).[2]

The correlation between improved patient-reported fatigue scores and quality of life with a measurable reduction in an objective biomarker of oxidative stress (F2-isoprostane) provides important biochemical support for Nuvastatic's mechanism of action in alleviating CRF. This suggests a tangible physiological impact underlies the symptomatic relief.

• Conclusion: The trial concluded that Nuvastatic™ is a potentially effective adjuvant for CRF management in solid tumor patients, meriting further investigation in larger trials.[2]

The following table summarizes key efficacy outcomes from the Phase II Nuvastatic trial (NCT04546607) in Cancer-Related Fatigue, based on available data [2]:

Outcome Measure	Time Point	Nuvastatic™ (N=56) (Mean ± SD or as stated)	Placebo (N=54) (Mean ± SD or as stated)	P-value (Between Groups/Interaction)
BFI Score	Baseline	48.07 ± 11.44	49.94 ± 11.18	0.387
	Week 3	42.50 ± 8.26	45.09 ± 5.85	0.060
	Week 6	35.57 ± 7.24	44.83 ± 3.13	< 0.001
	Week 9	28.50 ± 8.98	43.79 ± 2.94	< 0.001
Overall BFI (Time*Group)				< 0.001 (from F-statistic)
VAS-F Score	Baseline	107.0 ± 4.50	106.09 ± 4.68	0.303
	Week 3	88.87 ± 7.46	94.64 ± 5.15	< 0.001
	Week 6	86.89 ± 9.66	92.62 ± 6.49	< 0.001
	Week 9	83.76 ± 9.77	94.96 ± 6.46	< 0.001
Overall VAS-F (Time*Group)				< 0.001 (from F-statistic)
SF-36 Score (Vitality related)	Baseline	197.80 ± 1.55	177.24 ± 1.03	< 0.001
	Week 3	234.63 ± 2.42	197.80 ± 3.06	< 0.001
	Week 6	260.30 ± 2.84	200.42 ± 5.67	< 0.001
	Week 9	266.72 ± 4.17	195.91 ± 4.71	< 0.001
Overall SF-36 (Time*Group)				< 0.001 (from F-statistic)
Urinary F2-Isoprostane Conc.	Week 9	\multicolumn{2}{c	}{Mean Difference (95% CI) = 55.57 (24.84, 86.30) vs Placebo}	< 0.001 (from t-statistic)

Note: SF-36 scores as presented in [2] likely represent a composite or specific subscale related to vitality/QoL rather than just the vitality subscale. P-values for BFI, VAS-F, and SF-36 at individual time points are for between-group comparisons at that specific week.

• Ongoing Phase III Clinical Trials for CRF: Nuvastatic is currently advancing into Phase III development for CRF. One trial (CTRI/2024/11/076299) is evaluating Nuvastatic® 300 mg in reducing chemotherapy-induced fatigue in patients with metastatic triple-negative breast cancer.3 Another Phase III study is assessing Nuvastatic® 300mg for cancer-induced fatigue in newly diagnosed, chemotherapy-naïve patients with nonresectable metastatic colorectal cancer.3 The dose reduction from 1000 mg (Phase II) to 300 mg (Phase III) for CRF suggests an ongoing process of dose refinement, possibly to optimize the balance of efficacy and tolerability or to improve patient convenience.

The initial product description for Nuvastatic also noted that patients undergoing chemotherapy reported "reduced pain and a significantly enhanced quality of life".1 This hints that Nuvastatic's benefits might extend beyond fatigue to broader symptom management in supportive oncology, potentially due to its anti-inflammatory and immunomodulatory properties.

B. Potential in Diabetic Retinopathy

Nuvastatic™ (C5OSEW5050ESA) has been investigated in a Phase Ib/IIa randomized, double-masked, placebo-controlled clinical study. This trial aimed to assess the clinical efficacy and safety of orally administered Nuvastatic™ over 12 months in patients with non-proliferative diabetic retinopathy (NPDR) without center-involved macular edema.[3] Specific results from this trial are not detailed in the provided information, but its initiation signifies an exploratory avenue for Nuvastatic in ophthalmology. Diabetic retinopathy is a common and serious microvascular complication of diabetes, and its pathogenesis involves chronic inflammation and oxidative stress, mechanisms potentially addressable by

O. stamineus extracts.[2]

C. Adjunctive Role in Pancreatic Cancer

• Preclinical Rationale: Nuvastatic™ (extract C5EOSEW5050ESA) has been explored preclinically for its potential to enhance the efficacy of gemcitabine, a standard chemotherapy for pancreatic cancer, which is often limited by drug resistance.[3] Studies have investigated its ability to sensitize gemcitabine-resistant pancreatic cancer cells by examining effects on multidrug-resistant genes, epithelial-mesenchymal transition, cell senescence, cell death, and Notch signaling.[3]
• In vivo Xenograft Model Results: In a pancreatic cancer xenograft model in mice, C5EOSEW5050ESA, alone and combined with gemcitabine, showed no signs of systemic toxicity.[3] While 200 mg/kg of C5EOSEW5050ESA with gemcitabine showed no additive antitumor effects, a higher dose of 400 mg/kg C5EOSEW5050ESA combined with gemcitabine demonstrated a significantly greater reduction in tumor growth, Ki-67 expression, and tumor necrosis compared to either agent alone.[3] This dose-dependent synergistic effect in preclinical models suggests a potential adjunctive role for Nuvastatic in pancreatic cancer treatment, possibly by sensitizing cancer cells to chemotherapy or by modulating the tumor microenvironment.

V. Safety, Tolerability, and Contraindications

A. Adverse Event Profile from Nuvastatic Clinical Trials

The primary source of clinical safety data for Nuvastatic comes from the Phase II trial (NCT04546607) in patients with solid tumors undergoing chemotherapy for cancer-related fatigue. In this study, where Nuvastatic™ was administered at 1000 mg (C5OSEW5050ESA extract) three times daily for 9 weeks, the product appeared to be generally well-tolerated. The adverse events reported specifically for the Nuvastatic™ group were [2]:

• Vomiting: 0.9% of patients
• Fever: 5.4% of patients
• Headache: 2.7% of patients

These reported incidences are relatively low. However, the provided information does not offer a comprehensive comparison of all adverse event rates between the Nuvastatic and placebo groups, nor does it detail the severity of these events beyond their occurrence. For a botanical product intended for supportive care, particularly in cancer patients who may already be experiencing multiple symptoms and side effects from their primary treatments, a favorable tolerability profile is essential. The preliminary data is encouraging, but more extensive safety information from the ongoing, larger Phase III trials will be critical for a thorough risk-benefit assessment.

B. Toxicological Assessment of C5OSEW5050ESA Extract (Preclinical)

Preclinical toxicological assessments of the C5EOSEW5050ESA extract, particularly in the context of pancreatic cancer xenograft models, have indicated a good safety profile. In these studies, even when administered in combination with gemcitabine, no signs of systemic toxicity or damage to vital organs were observed in the treated animals compared to untreated controls.[3] This preclinical safety data supports the progression to clinical trials in humans.

C. General Safety Considerations for Orthosiphon stamineus and Rosmarinic Acid

• Orthosiphon stamineus (Cat's Whiskers):
• Traditional Use and Regulatory Classification: O. stamineus has a long history of traditional use, particularly as a diuretic and for urinary tract conditions.[5] The European HMPC classifies Orthosiphon leaves as a traditional herbal medicinal product, implying a certain level of accepted safety based on long-standing use.[9]
• Contraindications and Precautions: Standard precautions for herbal diuretics apply. Flushing therapy with O. stamineus should not be performed in the presence of edema due to impaired heart or kidney function. Adequate fluid intake is necessary during treatment. Medical advice should be sought if symptoms like fever, urinary retention, or blood in urine occur.[9]
• Specific Populations: Due to a lack of adequate data, the use in children and adolescents under 18 years, and during pregnancy and lactation, is generally not recommended without medical supervision.[9]
• Adverse Effects: Generally, O. stamineus is considered to have a good safety profile with "none known" undesirable effects commonly reported in traditional use monographs, though hypersensitivity is a general contraindication for any substance.[10]
• Rosmarinic Acid:
• Rosmarinic acid, a major component of Nuvastatic, is also generally considered safe. Pharmacokinetic studies in humans and animals, as well as clinical investigations for various conditions, have reported no serious adverse effects associated with herbal remedies rich in rosmarinic acid.[17] Its widespread presence in culinary herbs (like rosemary, sage, basil, thyme) also contributes to a general assumption of safety when consumed in typical dietary amounts.

The established traditional use and generally favorable safety profile of O. stamineus and its key constituent, rosmarinic acid, provide a supportive background for Nuvastatic's development. However, it is important to note that concentrated extracts used in pharmacological doses, as in Nuvastatic, require specific safety assessments through rigorous clinical trials, as the concentration and exposure to active compounds are significantly higher than in traditional preparations like teas. The ongoing Phase III trials for Nuvastatic will be crucial in establishing a comprehensive long-term safety database for the specific C5OSEW5050ESA extract at therapeutic doses.

VI. Regulatory Status and Market Positioning

A. Current Regulatory Approvals and Designations

As of the information available, Nuvastatic is registered as a "traditional medicine" with the National Pharmaceutical Regulatory Agency (NPRA) in Malaysia.[1] This registration allows it to be marketed in Malaysia under this classification. The process for NPRA registration for traditional medicines involves evaluation of safety, quality, and claimed efficacy, often based on traditional use and supporting data, with typical processing times for traditional medicines and supplements being 116–136 working days.[19]

There is no information within the provided documents to suggest that Nuvastatic or its active extract C5OSEW5050ESA has received marketing authorization as a prescription pharmaceutical drug for specific medical indications (such as cancer-related fatigue or diabetic retinopathy) from stringent regulatory authorities like the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[21] The regulatory pathway for botanical drugs can be complex, often differing from that of conventional synthetic drugs, and the evidence required for approval for specific medical claims is substantial.

B. Market Positioning and Target Patient Populations

Nuvastatic is primarily promoted and positioned as a supportive oncology nutrition product.[1] Its main target indication, based on clinical trial activity, is the management of cancer-related fatigue (CRF) in patients with solid tumors undergoing chemotherapy.[1] The product aims to alleviate fatigue and improve the quality of life for these patients. The initial product description also mentions that patients reported reduced pain, suggesting a broader role in supportive care.[1]

The investigation into non-proliferative diabetic retinopathy indicates a secondary area of interest, targeting patients with this diabetes complication.[3] Preclinical research also points towards a potential adjunctive role in pancreatic cancer treatment, aiming to sensitize resistant tumors to chemotherapy.[3]

The current regulatory status as a traditional medicine in Malaysia and its positioning as a supportive nutrition product reflect its current evidence base and the ongoing nature of its clinical development for more specific, high-level medical claims. Its availability as an effervescent powder drink also suggests a focus on patient convenience and compliance, particularly relevant for the target oncology patient population. The development of Nuvastatic within the supportive care niche, especially for CRF, addresses a significant unmet need, as fatigue is a pervasive and often undertreated symptom in cancer patients.

VII. Related Products from NatureCeuticals

NatureCeuticals, the developer of Nuvastatic, offers a portfolio of other products also derived from Orthosiphon stamineus or other natural sources, leveraging the company's focus on botanical and complementary medicine. These products target different health concerns and are available in various formulations. This broader product line based on O. stamineus suggests a platform approach by NatureCeuticals, capitalizing on the diverse traditional uses and scientifically investigated properties of this medicinal herb.

A. Canssu-5

Canssu-5 is an effervescent powder drink formulation that contains 250 mg of a standardized leaf extract from Orthosiphon stamineus. Similar to Nuvastatic, this extract is standardized to contain 6% rosmarinic acid. Canssu-5 is specifically designed to aid in managing symptoms related to gout and rheumatoid arthritis, leveraging the anti-inflammatory and immunomodulatory properties of the extract.[1]

B. NatureCeuticals Blood Cleanser

This product is a capsule formulation containing 308mg of Orthosiphon stamineus leaf extract per capsule. It is designed to promote blood cleansing. NatureCeuticals Blood Cleanser is listed as a complementary medicine with the Australian Therapeutic Goods Administration (TGA) and is recommended for conditions such as acute and chronic gout, cholesterol reduction, and vasodilation. Each bottle contains 60 capsules.[1] The TGA listing as a complementary medicine implies it meets certain standards for quality and safety but does not necessarily mean it is approved for treating specific diseases with the same level of evidence required for registered prescription medicines.

C. Other Formulations

NatureCeuticals also markets other products incorporating Orthosiphon stamineus or other botanical extracts:

• Canssufive Drink: A functional food beverage made from a whole plant extract of Orthosiphon stamineus (150 mg per serving). It is promoted as an antioxidant-rich, flavonoid-abundant fruity beverage, infused with pineapple extract, contributing to a wholesome lifestyle.[1]
• Roxelle Isotonic Sports Drink Powder: An isotonic effervescent powder beverage containing 500mg of Hibiscus sabdariffa extract (standardized to a minimum of 1% anthocyanins). It is fortified with isotonic salts and dextrose, designed for athletes and active individuals to replenish electrolytes and provide energy.[1]
• URIS Cranberry plus Java Tea Extract: A sparkling herbal beverage formulated to support bladder health. It combines 150 mg of cranberry extract with 150 mg of Cat Whiskers herb (Orthosiphon stamineus) plant extract. This formulation is rich in proanthocyanidins, rosmarinic acid, and sinensetin and is designed to assist in managing urinary tract and bladder infections.[1]

VIII. Conclusion

Nuvastatic, a standardized polymolecular botanical drug derived from Orthosiphon stamineus (C5OSEW5050ESA extract, standardized to 6% rosmarinic acid and other phytochemicals), represents a scientifically investigated natural therapeutic agent primarily targeting supportive oncology care. Its development bridges traditional herbal medicine with modern clinical research methodologies.

The pharmacological profile of Nuvastatic is characterized by pleiotropic mechanisms, including significant anti-angiogenic activity (through inhibition of VEGF, EGF, FGF, and disruption of endothelial cell functions) and immunomodulatory effects (including upregulation of interferons and GM-CSF, and modulation of specific interleukins and TNF-β). Furthermore, its antioxidant properties, evidenced by the reduction of oxidative stress markers like F2-isoprostane, are noteworthy.[2] These multifaceted actions are likely due to the synergistic interplay of its numerous phytochemical constituents, with rosmarinic acid being a key, but not sole, contributor.

Clinically, Nuvastatic has demonstrated promising efficacy in a Phase II randomized controlled trial for the management of cancer-related fatigue in patients with solid tumors undergoing chemotherapy. Significant improvements in fatigue scores (BFI and VAS-F), enhanced quality of life (SF-36), and a reduction in oxidative stress were observed, with a generally favorable safety profile characterized by infrequent and mild adverse events such as vomiting, fever, and headache.[2] These positive findings have led to the initiation of Phase III trials, albeit with a potentially optimized lower dosage (300 mg) for CRF in specific cancer populations (metastatic triple-negative breast cancer and metastatic colorectal cancer).[3] Exploratory clinical research has also been conducted in non-proliferative diabetic retinopathy (Phase Ib/IIa) [3], and preclinical studies suggest a potential adjunctive role in sensitizing resistant pancreatic cancer to chemotherapy.[3]

Currently, Nuvastatic is registered as a traditional medicine with the Malaysian NPRA and is marketed as a supportive oncology nutrition product.[1] It does not hold marketing authorization as a prescription pharmaceutical for specific medical indications from stringent regulatory agencies like the FDA or EMA based on the available information. Its current market position reflects its developmental stage and the existing evidence base.

In summary, Nuvastatic (C5OSEW5050ESA) shows considerable potential as an adjuvant therapy, particularly for alleviating cancer-related fatigue, a significant unmet need in oncology. Its multi-targeted mechanism of action and preliminary clinical safety and efficacy data are encouraging. However, the successful completion and positive outcomes of ongoing and future Phase III trials will be crucial to definitively establish its therapeutic value, confirm its long-term safety profile, and potentially support broader regulatory approvals for specific medical indications. Further research may also elucidate the full spectrum of its activity and the individual contributions of its complex phytochemical matrix. The development of Nuvastatic underscores the valuable therapeutic opportunities that can arise from the rigorous scientific investigation of traditional botanical medicines.

Works cited

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