C10H12N4O5
58-63-9
Inosine is an endogenous purine nucleoside that occupies a central position in cellular metabolism and molecular biology. As a key intermediate in the degradation of adenosine and the biosynthesis of uric acid, it is fundamental to purine homeostasis. This monograph provides a comprehensive, evidence-based analysis of Inosine (DrugBank ID: DB04335), synthesizing its biochemical roles, complex pharmacological profile, extensive history of clinical investigation, and current regulatory standing.
The report addresses the significant dichotomy between the public perception of Inosine and its scientifically validated effects. It definitively concludes that widespread commercial claims of Inosine as an athletic performance enhancer are unsubstantiated and refuted by controlled clinical trials. The primary focus of modern therapeutic investigation has instead been on its potential as a neuroprotective agent. This research was driven by the "urate hypothesis," which posited that by serving as a precursor to the natural antioxidant uric acid, Inosine could slow the progression of neurodegenerative diseases. This rationale led to major, multi-year clinical trial programs in Parkinson's disease (the SURE-PD and SURE-PD3 trials) and multiple sclerosis. Despite successfully elevating urate levels, these pivotal trials ultimately failed to demonstrate a disease-modifying effect, providing a significant case study in the challenges of translating epidemiological observations and surrogate biomarker modulation into clinical efficacy.
In contrast to the failed urate-dependent strategy, promising preclinical evidence suggests an alternative, urate-independent mechanism of action involving the promotion of axonal rewiring and neuronal sprouting. This has shown potential benefits in animal models of stroke and spinal cord injury, representing a nascent but potentially more viable future therapeutic avenue.
Pharmacologically, Inosine is characterized by its excellent stability and long plasma half-life (~15 hours) compared to its precursor adenosine (<10 seconds), making it suitable for oral administration. Its primary safety concern is a direct consequence of its metabolism: the elevation of uric acid can lead to hyperuricemia and an increased risk of urolithiasis (kidney stones), a side effect frequently observed in clinical trials.
Finally, this report provides a critical clarification, distinguishing Inosine from the synthetic, multi-component drug Inosine Pranobex. The latter is an approved antiviral and immunomodulatory agent with a distinct composition, mechanism of action, and set of clinical indications, and the frequent conflation of the two entities has led to significant confusion in scientific and commercial literature. This monograph serves as a definitive reference for researchers, clinicians, and regulatory professionals, contextualizing Inosine's past failures, present status, and potential future in medicine.
Establishing the precise chemical and physical identity of a molecule is the foundation of its pharmacological and toxicological assessment. This section provides a definitive reference for Inosine, consolidating its nomenclature, structural details, and key physicochemical characteristics that govern its behavior in biological and pharmaceutical contexts.
Inosine is identified by a variety of systematic names, common synonyms, and unique registry codes across numerous chemical and biomedical databases. Its primary CAS (Chemical Abstracts Service) Registry Number is 58-63-9.[1] The systematic IUPAC (International Union of Pure and Applied Chemistry) name for the molecule is 9--1H-purin-6-one.[2]
It is widely known by several synonyms, including Hypoxanthine 9-β-D-ribofuranoside, Hypoxanthosine, Ribonosine, and (−)-Inosine.[4] The comprehensive list of identifiers, detailed in Table 1.1, ensures unambiguous cross-referencing between pharmacological, chemical, and clinical literature.
Of particular note are the Anatomical Therapeutic Chemical (ATC) Classification System codes assigned to Inosine: D06BB05 (Antivirals for topical use), G01AX02 (Other anti-infectives and antiseptics for gynecological use), and S01XA10 (Other ophthalmologicals).[1] These classifications are initially perplexing, as the primary clinical investigations of pure Inosine have focused on neuroprotection, and it is not recognized as an antiviral agent. This ambiguity arises from the conflation of Inosine with a distinct synthetic drug, Inosine Pranobex, which is an approved immunomodulatory antiviral. This critical distinction is a recurring theme and will be fully elucidated in Section 7 of this report.
Table 1.1: Key Identifiers for Inosine
Identifier Type | Identifier Code | Source(s) |
---|---|---|
CAS Number | 58-63-9 | 1 |
DrugBank ID | DB04335 | 1 |
PubChem CID | 6021 | 3 |
UNII | 5A614L51CT | 2 |
ChEBI ID | CHEBI:17596 | 2 |
ChEMBL ID | CHEMBL1556 | 2 |
KEGG ID | C00294, D00054 | 2 |
HMDB ID | HMDB0000195 | 2 |
ATC Codes | D06BB05, G01AX02, S01XA10 | 1 |
Inosine is a small molecule classified as a purine nucleoside.[1] Its structure consists of two main components: a purine base, hypoxanthine (specifically, its 6-oxo tautomer), linked to a pentose sugar, D-ribose, in its furanose form (ribofuranose). The linkage is a β-N9-glycosidic bond, connecting the N9 nitrogen atom of the hypoxanthine ring to the C1 carbon atom of the ribose sugar.[1]
The empirical chemical formula for Inosine is C10H12N4O5.[1] Its average molecular weight is most accurately cited as 268.2261 g/mol, though it is commonly rounded to 268.23 g/mol in many sources.[1] The monoisotopic mass is 268.080769514 Da.[1] For computational modeling and structural database searching, its standardized identifiers are crucial:
The physical and chemical properties of Inosine dictate its stability, solubility, and ultimately its pharmacokinetic behavior. It typically presents as a white, odorless, crystalline powder or solid.[2] It is noted to be hygroscopic, meaning it can absorb moisture from the air.[7]
The melting point is reported with slight variation across sources but consistently with decomposition, in the range of 218 °C to 226 °C.[2]
Inosine's solubility is a key determinant of its biological fate. It is highly soluble in water, with reported values of 15.8 g/L (or 15,800 mg/L) at 20 °C.[2] Another source lists its water solubility as 2.1 g/100 mL at 20 °C.[7] This high hydrophilicity is quantitatively confirmed by its octanol-water partition coefficient (LogP), which is -2.1.[2] A negative LogP value indicates a strong preference for the aqueous phase over a lipid phase. This property explains why Inosine is readily dissolved and transported in the aqueous environment of the bloodstream. However, it also implies that Inosine cannot easily pass through the lipid bilayer of cell membranes via passive diffusion and therefore requires specialized protein transporters to enter cells and cross biological barriers like the blood-brain barrier.
Before its investigation as an exogenous therapeutic agent, Inosine's primary identity is that of a fundamental endogenous molecule with critical roles in cellular metabolism and molecular biology. Understanding these native functions provides the essential context for interpreting its pharmacological effects and the rationale behind its clinical development.
Inosine occupies a central crossroads in purine metabolism, acting as a key intermediate in both the degradation and salvage of purine nucleotides.[1] Its position in these pathways is the source of its dual identity as both a metabolic product and a precursor to other vital molecules.
There are three primary endogenous pathways for Inosine production [9]:
Once formed, Inosine itself is subject to further metabolism. The same enzyme, PNP, also catalyzes the reverse reaction, the phosphorolysis of Inosine to yield hypoxanthine and ribose-1-phosphate.[3] This hypoxanthine can either be re-utilized in salvage pathways or enter the final degradation cascade. In this cascade, the enzyme xanthine oxidase sequentially oxidizes hypoxanthine to xanthine and then to uric acid.[9] In humans and higher primates, uric acid is the final, non-degradable end-product of purine metabolism and is excreted primarily in the urine.[1]
This metabolic conversion of Inosine to uric acid is of paramount pharmacological importance. Uric acid is one of the most abundant and potent endogenous antioxidants in human plasma.[3] The entire rationale for investigating Inosine in neurodegenerative diseases like Parkinson's disease and multiple sclerosis was based on using exogenous Inosine as a prodrug to intentionally elevate systemic levels of this protective antioxidant.[3] Thus, Inosine's role as a therapeutic candidate is inextricably linked to its function as a direct metabolic precursor to uric acid.
Beyond its role in small-molecule metabolism, Inosine is a critical component of macromolecules involved in the flow of genetic information.
It is commonly found in the anticodon loop of certain transfer RNA (tRNA) molecules.[1] The anticodon is the three-nucleotide sequence that base-pairs with a complementary codon on a messenger RNA (mRNA) molecule during protein synthesis. Inosine's unique chemical structure allows it to form non-canonical base pairs with adenine (A), cytosine (C), and uracil (U).[3] This flexibility at the third position of the codon-anticodon interaction is known as the "wobble" hypothesis. The presence of Inosine in the wobble position of a tRNA anticodon enables a single tRNA species to recognize and bind to multiple different codons that code for the same amino acid, thereby increasing the efficiency and fidelity of genetic code translation.[3]
Inosine also arises in RNA through a post-transcriptional modification process known as Adenosine-to-Inosine (A-to-I) RNA editing.[12] A family of enzymes called adenosine deaminases acting on RNA (ADARs) can bind to double-stranded RNA structures and deaminate specific adenosine residues, converting them to Inosine.[3] Since the cellular translation machinery interprets Inosine as guanosine (G), this editing event can effectively change the sequence of an mRNA transcript, leading to the production of a protein with an altered amino acid sequence from what was originally encoded in the DNA. This process can profoundly impact protein function, as famously demonstrated in the editing of glutamate receptor subunits in the central nervous system, which alters their ion channel properties.[12] A-to-I editing can also destabilize double-stranded RNA structures by converting canonical A-U base pairs into mismatched I-U pairs.[3]
In addition to its synthesis within human cells, recent research has identified the gut microbiome as a significant source of systemic Inosine.[9] Several species of beneficial bacteria, including
Bifidobacterium pseudolongum and Akkermansia muciniphila, have been shown to produce and secrete Inosine.[11] This microbially-derived Inosine can be absorbed by the host and enter the systemic circulation, where it can modulate host immune and inflammatory functions.[9]
This discovery adds a substantial layer of complexity to Inosine pharmacology. It suggests that the gut microbiome acts as a variable, endogenous "organ" that contributes to an individual's baseline Inosine levels. Consequently, inter-individual differences in gut flora composition could lead to variability in both basal Inosine concentrations and the physiological response to exogenous Inosine supplementation. This link between diet, gut health, purine metabolism, and host immunity represents a modern and evolving area of Inosine research, suggesting that therapeutic strategies targeting the microbiome, such as the use of specific probiotics, could indirectly modulate Inosine-related signaling pathways.[10]
The pharmacological profile of Inosine is multifaceted, characterized by a range of proposed mechanisms of action that extend beyond its role as a simple metabolite. Its effects are mediated through both receptor-dependent and receptor-independent pathways, influencing the immune, nervous, and cardiovascular systems. A central theme in its pharmacology is the distinction between effects attributable to Inosine itself and those mediated by its primary metabolite, uric acid.
The mechanisms by which Inosine exerts its biological effects are diverse and, in some cases, not fully elucidated. They can be broadly categorized into interactions with cell surface receptors, modulation of intracellular signaling cascades, and direct effects on cellular processes.
While often considered an "inert" nucleoside compared to its precursor adenosine, Inosine can engage with and signal through the adenosine receptor family, which includes the A1, A2A, A2B, and A3 G-protein coupled receptors.[9] The adenosine A2A receptor (A2AR) appears to be a particularly important target. Inosine-mediated activation of the A2AR has been shown to stimulate downstream signaling events, including the production of cyclic AMP (cAMP) and the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2).[15]
Interestingly, Inosine may function as a biased agonist at the A2AR. One study demonstrated that while adenosine produces cAMP-biased signaling, Inosine produces ERK1/2-biased signaling, highlighting a pharmacological distinction between the two agonists.[15] This receptor-mediated activity is implicated in several of Inosine's observed effects in disease models, including the inhibition of Th1 and Th2 cell differentiation in a model of IPEX syndrome and the activation of protective signaling axes in models of ulcerative colitis and Alzheimer's disease.[9]
Inosine exhibits significant immunomodulatory and anti-inflammatory properties. A primary mechanism is the inhibition of pro-inflammatory cytokine production. In cell culture studies using immunostimulated macrophages and spleen cells, Inosine has been found to suppress the production of tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-12 (IL-12), and interferon-gamma (IFN-γ).[1] This effect, which may occur via a post-transcriptional mechanism, has been confirmed in animal models of endotoxemia, where Inosine administration reduced both pro-inflammatory cytokine levels and mortality.[1] These actions are thought to account for many of its observed anti-inflammatory and anti-ischemic effects.[1]
The role of Inosine in cancer immunology is more complex and context-dependent. Within the glucose-restricted tumor microenvironment, Inosine may serve as an alternative carbon source for effector T-cells, thereby enhancing their function and supporting immune checkpoint blockade therapies.[9] This suggests a dual role where Inosine can be anti-inflammatory in some contexts but can support pro-inflammatory anti-tumor responses in others.
A distinct and compelling area of Inosine's pharmacology lies in its neurorestorative capabilities, which appear to be independent of its metabolism to uric acid. Preclinical studies have consistently shown that Inosine has potent axon-promoting effects. In animal models of unilateral corticospinal tract transection, ischemic stroke, and spinal cord injury, administration of Inosine stimulates neurons in undamaged regions of the brain and spinal cord to sprout new axonal projections, rewire neural circuits, and form "detour" pathways around the site of injury.[1] This anatomical reorganization is paralleled by significant improvements in motor function and behavioral outcomes.[14]
The precise molecular mechanism for this effect remains under investigation, but several possibilities have been proposed [1]:
This mechanism, involving direct action on neuronal growth signaling, is fundamentally different from the indirect, antioxidant-based mechanism proposed in the Parkinson's and multiple sclerosis trials.
Inosine has been reported to exert several cardioprotective effects, though the mechanisms are not fully defined. It is described as a potent coronary vasodilator and is reported to have a positive inotropic (contractility-enhancing) effect on heart muscle.[1] Exogenous Inosine may favorably affect cardiac bioenergetics by contributing to the high-energy phosphate pool of myocardial cells.[1] Furthermore, it has been reported to shift myocardial metabolism, enhancing the uptake and utilization of carbohydrates relative to free fatty acids, a potentially beneficial adaptation during ischemic conditions.[1]
Pharmacodynamics describes the measurable biochemical and physiological effects of a drug on the body. For Inosine, the most well-characterized pharmacodynamic effect is the elevation of its primary metabolite, uric acid.
The administration of oral Inosine leads to a reliable, dose-dependent increase in the concentration of uric acid (urate) in both serum and cerebrospinal fluid (CSF).[19] This was the primary pharmacodynamic endpoint and therapeutic goal of the large-scale clinical trials in Parkinson's disease and multiple sclerosis.[3] In the Phase II SURE-PD trial, Inosine titration successfully raised serum urate by 2.3 to 3.0 mg/dL into the target therapeutic ranges of 6.1-7.0 mg/dL and 7.1-8.0 mg/dL.[19] This elevation of urate, a potent natural antioxidant and peroxynitrite scavenger, was hypothesized to confer neuroprotection by mitigating oxidative stress.[3]
Inosine can influence cellular energy metabolism. As an intermediate in purine nucleotide reactions required for muscle movements, it is linked to the availability of high-energy phosphates like ATP.[3] By entering the pentose phosphate pathway, it can contribute to the generation of NADH and ATP, potentially enhancing cellular energy resources.[11] This proposed effect on bioenergetics formed the (since-disproven) basis for its use as a performance-enhancing supplement.
Pharmacokinetics describes the journey of a drug through the body, encompassing its absorption, distribution, metabolism, and excretion (ADME). Inosine's pharmacokinetic profile is a key factor in its viability as a therapeutic agent.
When administered orally, Inosine is absorbed from the small intestine.[1] Due to its hydrophilic nature, its transport across cell membranes is not passive but is mediated by specific equilibrative and concentrative nucleoside transporters.[9] Once absorbed, it is transported via the systemic circulation and distributed to various tissues throughout the body.[1] Importantly, Inosine is capable of permeating the blood-brain barrier, allowing systemic administration to affect the central nervous system.[11] This was clinically confirmed in the SURE-PD trial, which demonstrated that oral Inosine administration increased urate levels not only in the serum but also in the CSF.[19]
Inosine undergoes extensive metabolism, primarily in the liver, though metabolic processes also occur in other tissues.[1] As detailed in Section 2.1, it can be directed into two main pathways:
The most critical pharmacokinetic property of Inosine is its stability and long half-life, especially when compared to its precursor, adenosine. While adenosine is extremely labile, with a plasma half-life of less than 10 seconds, Inosine is a stable metabolite with a much longer half-life of approximately 15 hours.[15]
This dramatic difference in stability is what makes Inosine a viable candidate for oral, chronic therapy. The short half-life of adenosine restricts its use to acute, intravenous administration for transient effects (e.g., treating supraventricular tachycardia). In contrast, the 15-hour half-life of Inosine allows for convenient oral dosing schedules (e.g., once or twice daily) to achieve sustained plasma concentrations and prolonged systemic effects. This pharmacokinetic advantage is the fundamental prerequisite for its investigation in chronic conditions like neurodegenerative diseases. The final end-product of its catabolism, uric acid, is eliminated from the body through renal excretion into the urine.[1]
The clinical history of Inosine is marked by a stark contrast between its commercial promotion for unproven benefits and its rigorous, formal investigation for complex diseases. This section provides a critical analysis of the human clinical data, evaluating the evidence for its various proposed applications, from its disproven role as an ergogenic aid to its extensively studied but ultimately unsuccessful use in neurodegenerative disorders.
For decades, Inosine has been a common ingredient in fitness and bodybuilding supplements, marketed with claims that it enhances energy production, oxygen delivery, and overall athletic performance.[3] This narrative, however, is a prominent example of a disconnect between commercial marketing and scientific reality. The available body of clinical evidence not only fails to support these claims but directly refutes them.[1]
Multiple double-blind, placebo-controlled studies have been conducted in trained athletes to test the ergogenic potential of Inosine supplementation. A study involving highly trained endurance runners who consumed 6 g of Inosine per day found no improvements in maximal treadmill run time, 3-mile run time, or maximal oxygen consumption (VO2 max).[28] Another trial in competitive male cyclists using a daily dose of 5 g for five days similarly found no significant differences in peak power, fatigue index, or total work completed during either anaerobic or aerobic cycling tests when compared to placebo.[28]
More concerningly, some of these studies have suggested that Inosine may have an ergolytic, or performance-impairing, effect. In the study on cyclists, time to fatigue during a supramaximal sprint was significantly shorter in the Inosine trial compared to the placebo trial.[29] The study on runners also noted that time to exhaustion was better during the placebo phase.[28] Based on this consistent lack of benefit and potential for harm, the scientific consensus is that Inosine is not an effective ergogenic aid and its use for enhancing athletic performance is not supported by evidence.[28]
The most significant and well-funded clinical development program for Inosine has been in the field of neurology. These investigations were founded on a strong and logical biological rationale: the neuroprotective properties of its metabolite, uric acid.
The investigation of Inosine for Parkinson's disease (PD) represents a major effort in translational medicine, moving from epidemiological observation to a pivotal Phase III clinical trial.
The rationale for investigating Inosine in multiple sclerosis (MS) was similar to that for PD, focusing on the antioxidant and peroxynitrite-scavenging properties of uric acid to protect against axon degeneration.[3] However, the clinical trial evidence in MS is smaller, more heterogeneous, and ultimately inconclusive.
An early, small (n=16) randomized, double-blind trial in patients with relapsing-remitting MS (RRMS) reported promising results. Over one year, Inosine treatment to raise serum urate levels was associated with a significant decrease in the number of new, active gadolinium-enhanced lesions on MRI and an improvement in disability scores on the Expanded Disability Status Scale (EDSS).[23]
However, these encouraging findings were not replicated in subsequent studies. Two larger clinical trials that evaluated Inosine as an add-on therapy to interferon-beta in patients with RRMS failed to show any additional benefit. A 12-month trial with 36 patients and a longer 2-year trial found no significant effect of combined Inosine and interferon-beta treatment on disability progression or other clinical and MRI outcomes compared to interferon-beta with placebo.[23] A significant safety concern emerged from these studies: a high incidence of kidney stone formation, affecting up to 25% of participants in one trial, which was a direct consequence of the induced hyperuricemia.[3]
While the urate hypothesis has failed in human trials for chronic neurodegenerative diseases, a separate line of preclinical research suggests a different and potentially more promising role for Inosine in acute neurological injury. This research focuses on a urate-independent mechanism of action involving the promotion of neuronal plasticity and axonal growth.[18]
Numerous studies in rodent models of ischemic stroke and spinal cord injury have demonstrated that direct administration of Inosine into the central nervous system or systemically can induce profound anatomical and functional recovery.[1] Inosine treatment stimulates neurons in the intact hemisphere contralateral to a cortical infarct to sprout new axonal connections to denervated areas of the midbrain and spinal cord.[1] Similarly, after a spinal cord transection, Inosine enhances the formation of compensatory "detour circuits" by promoting sprouting of corticospinal tract axons to connect with propriospinal interneurons, bypassing the injury site.[17] This axonal rewiring is consistently associated with significant improvements in skilled motor function of the impaired limbs.[14] Despite this compelling preclinical evidence and the patenting of its use for stroke by Alseres Pharmaceuticals, this neurorestorative potential has not yet been advanced into major human clinical trials.[3]
Inosine is being explored in several other clinical contexts, often as part of combination therapies.
Separate from its investigational therapeutic uses in patients, Inosine has an established role as a component in medical solutions used for laboratory procedures. It is an ingredient in red blood cell (RBC) rejuvenation solutions, such as Rejuvesol.[1] These solutions are used
in vitro to restore levels of ATP and 2,3-diphosphoglycerate in units of stored blood, thereby improving the function and viability of the red blood cells prior to transfusion.[1] This is a well-defined, non-therapeutic application.
Table 4.1: Summary of Major Clinical Trials Investigating Inosine
Trial Name/Identifier | Indication | Phase | N | Treatment Arms | Primary Endpoint(s) | Key Outcomes | Source(s) |
---|---|---|---|---|---|---|---|
SURE-PD (NCT00833690) | Parkinson's Disease | II | 75 | Inosine (mild urate elevation), Inosine (moderate urate elevation), Placebo | Safety, tolerability, elevation of serum and CSF urate | Inosine was safe, well-tolerated, and effective in raising urate to target levels. Supported progression to Phase III. | 19 |
SURE-PD3 (NCT02642393) | Parkinson's Disease | III | 298 | Inosine (titrated to 7.1-8.0 mg/dL urate), Placebo | Rate of change in MDS-UPDRS score over 2 years | No significant difference in rate of clinical progression vs. placebo. Trial stopped early for futility. Does not support Inosine use for PD. | 30 |
Markowitz et al., 2009 | Multiple Sclerosis | II | 16 | Inosine, Placebo (crossover) | Relapse rate, EDSS, MRI lesions | Inosine treatment correlated with decreased MRI lesions and improved EDSS. High rate of kidney stones (25%). | 23 |
ASIIMS Trial | Multiple Sclerosis | N/A | 159 | Inosine + Interferon-β, Placebo + Interferon-β | Disability progression | No additional benefit of Inosine over interferon-β alone on clinical or MRI metrics. | 23 |
Muñoz et al., 2015 | Multiple Sclerosis | N/A | 36 | Inosine + Interferon-β, Placebo + Interferon-β | Clinical and radiological activity | No significant difference in efficacy parameters between groups. Inosine was associated with hyperuricemia and renal colic. | 23 |
A thorough understanding of a compound's safety profile is paramount to its clinical evaluation and use. For Inosine, the primary safety concerns are directly linked to its intended mechanism of action and primary metabolic pathway—the production of uric acid.
Clinical trials have generally found Inosine to be well-tolerated, with most serious adverse events occurring at rates comparable to placebo. However, specific adverse effects related to its metabolism are consistently reported.[19]
The most predictable and consistent biochemical effect of Inosine administration is an increase in serum and urinary uric acid levels, known as hyperuricemia.[41] This is not an off-target effect but a direct consequence of its catabolism. Chronically elevated uric acid levels can lead to the deposition of urate crystals in joints and soft tissues, causing gout, a form of inflammatory arthritis characterized by severe pain and swelling.[41] While no participants in the SURE-PD trial developed gout, individuals with a pre-existing history of the condition are at significantly increased risk, and Inosine supplementation could worsen their condition.[20]
The most clinically significant and frequently reported adverse event associated with Inosine treatment is urolithiasis, the formation of kidney stones.[41] When urinary concentrations of uric acid become too high, it can precipitate out of solution and form solid crystals or stones in the urinary tract. This risk was observed across multiple clinical trials. In the SURE-PD trial, three participants receiving Inosine developed symptomatic urolithiasis.[19] The risk appeared to be even higher in the MS trials, where one study reported kidney stone formation in 4 out of 16 patients (25%).[3] This high incidence underscores that the therapeutic window for urate elevation is narrow, as the dose required to achieve a potential therapeutic effect directly increases the risk of this significant adverse event.
Other less common side effects reported with Inosine or its derivative, Inosine Pranobex, include mild gastrointestinal discomfort (nausea, stomach cramps, diarrhea) and, rarely, skin reactions or mood changes.[41]
Based on its known metabolic effects and safety profile, Inosine is contraindicated or should be used with extreme caution in several populations:
Inosine's metabolic pathway and effects on uric acid levels create the potential for clinically significant drug-drug interactions. The majority of interaction data comes from studies on Inosine Pranobex, but the principles often apply to Inosine itself.
Table 5.1: Clinically Significant Drug Interactions with Inosine
Interacting Drug/Class | Nature of Interaction | Potential Clinical Outcome | Source(s) |
---|---|---|---|
Antigout Drugs (e.g., Allopurinol, Febuxostat, Probenecid) | Pharmacodynamic | Inosine increases uric acid production, directly opposing the mechanism of antigout medications that either inhibit production (xanthine oxidase inhibitors like allopurinol) or increase excretion (uricosurics like probenecid). This can lead to a reduction in the efficacy of the antigout drug. | 41 |
Uricosuric Diuretics (e.g., Thiazides) | Pharmacokinetic/Pharmacodynamic | Some diuretics can alter the renal handling of uric acid. Thiazide diuretics, for example, can increase serum urate levels, potentially having an additive effect with Inosine and increasing the risk of hyperuricemia and its complications. | 45 |
Zidovudine (AZT) | Pharmacokinetic | Concomitant use with Inosine Pranobex has been shown to increase the plasma bioavailability and intracellular phosphorylation of AZT, leading to higher levels of the active AZT nucleotide. This potentiates the effect of AZT. | 45 |
Immunosuppressants | Pharmacodynamic | Due to the immunomodulatory properties of Inosine and particularly Inosine Pranobex, concomitant use with immunosuppressive agents is cautioned against, as there may be opposing effects or unpredictable pharmacokinetic influences. | 45 |
Drugs Affecting Renal Excretion | Pharmacokinetic | A large number of drugs may compete for or alter renal excretion pathways. Drugs that decrease Inosine's excretion rate (e.g., acetylsalicylic acid, acyclovir) could lead to higher serum levels of Inosine and its metabolites. Conversely, drugs that increase its excretion (e.g., acetazolamide) could lower its serum level and reduce its effect. | 50 |
Inosine occupies a unique and complex position in the regulatory and commercial landscape. It exists simultaneously in three distinct categories: as a regulated food additive, as a largely unregulated over-the-counter dietary supplement, and as a formally investigated but unapproved new drug. This fragmented identity creates a confusing environment for consumers, clinicians, and researchers.
Inosine is widely available for purchase directly by consumers as an over-the-counter (OTC) dietary or nutritional supplement.[1] It is marketed primarily to the fitness and athletic communities, often with claims of performance enhancement that, as detailed in Section 4.1, are not supported by scientific evidence.[1] In the United States, dietary supplements are regulated under the Dietary Supplement Health and Education Act of 1994 (DSHEA), which does not require manufacturers to provide the Food and Drug Administration (FDA) with evidence of efficacy or safety prior to marketing.[51]
In stark contrast to its status as a supplement, Inosine has also been the subject of rigorous, large-scale clinical trials conducted under an Investigational New Drug (IND) application with the FDA.[52] The SURE-PD3 trial, for example, was a multi-year, multicenter Phase III study subject to the same stringent regulatory oversight as any other potential prescription drug.[34] This dual status means that while a researcher must navigate a complex regulatory framework to study Inosine's effects in a controlled setting, any individual can purchase and consume it with minimal oversight.
As a standalone therapeutic agent, Inosine is not an approved drug by either the U.S. FDA or the European Medicines Agency (EMA) for any clinical indication.[53]
In the U.S., a salt form of Inosine, Disodium Inosinate (CAS 4691-65-0), is regulated by the FDA as a food additive. It is listed as Generally Recognized as Safe (GRAS) for its use as a flavor enhancer, as specified in the Code of Federal Regulations, 21 CFR 172.535.[54] This classification applies only to its use in food and is distinct from its status as a dietary supplement or investigational drug.
In Europe, the EMA's oversight primarily concerns Inosine Pranobex, not pure Inosine. Inosine Pranobex is nationally authorized in numerous EU member states, and its safety data is subject to periodic review (Periodic Safety Update Report Single Assessments, or PSUSAs) by the EMA's Pharmacovigilance Risk Assessment Committee (PRAC).[55] This further highlights the critical regulatory and clinical distinction between the two entities.
Despite the definitive scientific evidence refuting its ergogenic effects, Inosine remains an ingredient in some fitness supplements.[3] It is typically marketed with claims related to energy metabolism, endurance, and recovery.[58] Anecdotal consumer reviews are varied and do not constitute scientific evidence of efficacy.[27] The persistence of Inosine in this market underscores the gap between scientific consensus and commercial practice in the dietary supplement industry, where marketing claims can continue long after they have been scientifically disproven.
One of the most significant sources of confusion in the scientific and medical literature surrounding Inosine is its conflation with Inosine Pranobex. The similarity in name has led to the misattribution of pharmacological properties, regulatory approvals, and clinical indications. It is critical to understand that these are two fundamentally different chemical and clinical entities.
Inosine is a single, naturally occurring purine nucleoside with the chemical formula C10H12N4O5.[1]
Inosine Pranobex (also known by the names Isoprinosine, Methisoprinol, and Inosine Acedoben Dimepranol) is a synthetic, multi-component drug.[59] It is a precisely formulated combination of Inosine and dimepranol acedoben. Dimepranol acedoben is itself a salt formed from p-acetamidobenzoic acid (PAcBA) and N,N-dimethylamino-2-propanol (DIP).[59] The final drug product, Inosine Pranobex, consists of Inosine and the PAcBA-DIP salt complex in a fixed 1:3 molar ratio.[59] Its molecular formula is
C52H78N10O17, and its molecular weight is 1115.2 g/mol, reflecting its complex composition.[65]
The pharmacological profiles and clinical uses of the two substances are distinct.
Because of this distinct mechanism, Inosine Pranobex is approved and marketed in over 70 countries worldwide for the treatment of various viral infections and diseases associated with immune deficiency.[68] Its approved and investigated indications include mucocutaneous herpes simplex virus (HSV) infections, human papillomavirus (HPV) infections (genital warts), subacute sclerosing panencephalitis (SSPE), and other viral respiratory infections.[59]
The immunomodulatory and antiviral effects of Inosine Pranobex are attributed to the synergistic action of the entire 1:3 complex, not just the Inosine component. While some hypotheses suggest the Inosine moiety may contribute to the antiviral action, the clinical efficacy is a property of the complete drug product. Therefore, it is pharmacologically incorrect to attribute the approved antiviral indications or the immunomodulatory mechanism of Inosine Pranobex to pure Inosine. The ATC codes for antiviral (D06BB05) and anti-infective (G01AX02) use, which are sometimes associated with the base Inosine molecule in databases, properly belong to the drug Inosine Pranobex.
This comprehensive analysis of Inosine reveals a molecule with a complex and dichotomous history. It is a fundamental building block of life, a widely marketed but scientifically discredited athletic supplement, and the subject of a major, yet ultimately failed, therapeutic strategy for neurodegenerative disease. Synthesizing the available evidence allows for clear conclusions and highlights potential paths for future research.
Despite the definitive failures in major clinical areas, several questions remain, pointing to potential new avenues of investigation.
Published at: September 3, 2025
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