creatinol-O-fosfato

Otros Nombres

1-(2-Hydroxyethyl)-1-methylguanidine dihydrogen phosphate1-(2-Hydroxyethyl)-1-methylguanidine dihydrogen phosphate (ester)1-(2-hydroxyethyl)-1-methylguanidine-O-phosphate1-[2-(Phosphonooxy)ethyl]-1-methylguanidine2-(1-Methylguanidino)ethyl dihydrogen phosphate2-(1-Methylguanidino)ethyl dihydrogenphosphat2-(1-Methylguanidino)ethyl phosphate2-[Carbamimidoyl(methyl)amino]ethyl dihydrogen phosphateCOPCreatinol phosphateCreatinolfosfatCreatinolfosfateCreatinolfosfatoCreatinolfosfatumCreatinolo O-fosfatoCreatinolo-phosphateGipronGuanidine, 1-(2-hydroxyethyl)-1-methyl-, dihydrogen phosphateGuanidine, 1-(2-hydroxyethyl)-1-methyl-, dihydrogen phosphate (ester)Guanidine, N-methyl-N-[2-(phosphonooxy)ethyl]-N-(2-hydroxyethyl)-N-methylguanidine dihydrogen phosphateN-Methyl-N-(beta-hydroxyaethyl)guanidine-O-phosphatN-Methyl-N-(beta-hydroxyethyl)guanidine O-phosphateN-Methyl-N-(β-hydroxyethyl)guanidine O-phosphateN-Methyl-N-[2-(phosphonooxy)ethyl]guanidineN-methylguanidinoacetic acid O-phosphateNergizeO-Phosphate of N-methyl-N-(beta-hydroxyethyl)guanidineO-Phosphate of N-methyl-N-hydroxyethylguanidine

Sinopsis

Creatinol-O-Phosphate: A Comprehensive Reference

1. Identity and Chemical Characterization

Names and Nomenclature

Creatinol-O-phosphate (COP) is a synthetic, low-molecular-weight organic compound belonging to the guanidine class. It is a cardioprotective drug and a structural analog of creatine, and should not be confused with phosphocreatine (a phosphorylated creatine molecule). Its full molecular name is N-methyl-N-(beta-hydroxyethyl)guanidine O-phosphate. The compound is also encountered in the scientific literature and on commercial databases under several synonyms, including:

Creatinolfosfate (Italian and Wikidata nomenclature)
Creatinol phosphate
COP (common abbreviation in pharmacological literature)
Aplodan (pharmaceutical trade name under which early clinical studies were conducted)
1-(2-hydroxyethyl)-1-methylguanidine O-phosphate (alternative IUPAC-style name, as found in patent literature)

Its chemical formula is C₄H₁₂N₃O₄P, with a PubChem CID of 23342 and CAS registry number 6903-79-3. Its canonical SMILES notation is CN(CCOP(=O)(O)O)C(=N)N. Creatinol-O-phosphate has a molecular weight of 197.13 and likely exists in a zwitterionic form to some extent.

Key Structural Distinction from Related Compounds

Creatinol-O-phosphate is a guanidine compound or analog which contains a hydroxyl functional group, unlike creatine phosphate, which contains a carboxyl functional group. This structural difference — the phosphate group being esterified to an oxygen atom on the ethanolamine side-chain rather than on the guanidino nitrogen — is the defining chemical feature of COP and distinguishes its pharmacological profile from that of phosphocreatine (PCr) itself.

Physical Form

Creatinol-O-phosphate is a synthetic analogue of creatine presented as a white to almost white crystalline powder.

Pharmaceutical Salts

Creatinol-O-phosphate, in the free form or also as sodium salt, has been proposed for the treatment of cardiovascular diseases, among which are coronary insufficiency and cor pulmonale (right heart failure). A magnesium salt of creatinol-O-phosphate was additionally developed and is characterized, with respect to the free form creatinol-O-phosphate, by its elective action in the treatment and prevention of myocardial infarction.

2. Natural Source and Synthetic Origin

COP does not occur naturally in plants, animals, or microorganisms as a free compound; it has no botanical origin. COP is chemically synthesized via phosphorylation of creatinol or related precursors under controlled conditions, followed by purification steps (crystallization, filtration, drying) to produce the stable phosphate salt for supplement use. The creatinol O-phosphate is preferably formed from a creatinol compound, which contains a creatinol group chemically reacting with a chemical compound selected from a group consisting of POCl₃, ClPO₃OH₂, and P₂O₅.

The parent moiety, creatinol (N-methyl-N-(2-hydroxyethyl)guanidine), is itself a synthetic compound and does not represent a natural metabolite in humans, unlike creatine, which is biosynthesized endogenously from the amino acids glycine, arginine, and methionine and is obtained through dietary meat consumption.

3. Common Preparations and Dosage Forms

In early pharmacological and clinical research conducted from the 1970s through the 1980s, COP was administered primarily via intravenous (i.v.) injection or infusion, as the research focus was on acute cardiac conditions. In clinical studies on patients with acute myocardial infarction, COP was administered as 3.06 g i.v./24 h for a 3-day period. In acute tolerance studies, COP was administered intravenously at three different dosages: 1020 mg (group A), 2040 mg (group B), and 3060 mg (group C).

In the contemporary sports nutrition market, COP is available primarily in oral forms. Powdered blends, capsules, and tablets are the standard forms; powder is convenient for pre-workout mixes, while capsules provide taste masking and controlled dosing for consumers. Both carnitine and creatinol-phosphate are well known for their important metabolic and pharmacological effects which have led to several positive pharmacological and clinical findings. The transition from a pharmaceutical parenteral drug to an orally ingested dietary supplement has been driven commercially rather than by robust clinical evidence for oral bioavailability.

COP exhibits moderate stability in mildly acidic matrices; however, prolonged exposure to very low pH may increase the risk of hydrolysis. Formulators should validate stability in intended pH ranges.

4. Traditional and Historical Use

Creatinol-O-phosphate has no traditional or historical use in ethnobotany, herbal medicine, or any pre-modern healing tradition. It is an entirely synthetic molecule that emerged from mid-twentieth-century Italian pharmaceutical research. The compound was developed and studied predominantly by Italian and Belgian pharmacologists starting in the late 1960s and 1970s, with the pharmaceutical brand name Aplodan associated with its early clinical application in cardiovascular medicine.

The foundational pharmacological characterization was published in 1971 by Marchetti et al. (Arch Int Pharmacodyn Ther., 191(2):337–44), who documented the effects of COP on isolated and in situ heart preparations. A series of comprehensive pharmacological and clinical papers appeared in a dedicated supplement issue of the journal Arzneimittel-Forschung in 1979 (volume 29, supplement 9a), representing the most extensive published body of evidence on COP and covering its toxicology, antiarrhythmic activity, cardiac metabolic effects, and early clinical data. Subsequent work by Godfraind and colleagues in the early 1980s further explored its cardioprotective mechanisms in isolated heart models.

COP's transition into the dietary supplement industry, particularly in North American sports nutrition, occurred in the late 2000s and early 2010s, when it began appearing in pre-workout formulations marketed alongside beta-alanine for purported ergogenic effects on muscular endurance. This use is an extension of mechanisms proposed in the earlier cardiac literature, applied — without dedicated clinical support — to skeletal muscle physiology during intense exercise.

5. Key Constituents and Active Compounds

COP is itself the single active compound; it is not a botanical extract containing multiple constituents. As a pure synthetic chemical entity, its activity is attributed entirely to the intact COP molecule and to the products generated upon its dephosphorylation within cells. The following active and derived species are relevant:

Creatinol-O-phosphate (parent molecule): The intact phosphorylated form. Acts as a cell membrane stabilizer and the initial carrier of a transferable phosphate group.
Free phosphate (Pi) released intracellularly: In theory, on the inside of a cell, creatinol-O-phosphate loses its attached phosphate, which is used to form the high-energy molecule ATP (adenosine triphosphate).
Creatinol (dephosphorylated product): Creatinol-O-phosphate is distributed in all organs, particularly in the liver and kidney, where it is dephosphorylated and eliminated with urine.

6. Established and Proposed Mechanisms of Action

6.1 Promotion of Anaerobic Glycolysis

The most prominently proposed mechanism relevant to skeletal muscle is the prolongation of anaerobic glycolysis under conditions of metabolic acidosis. Once muscle cells are saturated, the primary action of creatinol-O-phosphate is to prolong anaerobic glycolysis in the presence of excess lactic acid. COP overrides the mechanism of excess lactic acid accumulation by acting as an intracellular buffer, preventing a dramatic drop in pH and allowing muscle contractions to continue beyond the point at which the body would normally shut down activity. This proposed mechanism shares conceptual ground with the buffering role attributed to phosphocreatine in exercising muscle. Functions of creatine phosphate metabolism include the buffering of hydrogen ions produced during anaerobic glycolysis; as both ADP and hydrogen ion accumulation are factors that may contribute to development of fatigue during sprint exercise, the size of the skeletal muscle creatine phosphate store may be an important determinant of performance during high-intensity exercise.

6.2 ATP Resynthesis and Phosphate Donation

Creatinol-O-phosphate appears to donate its phosphate group for improved resynthesis of ATP (adenosine 5′-triphosphate), which can provide improved strength, endurance, recovery, and muscle performance. This mechanism, if operative, would parallel the role of phosphocreatine in the creatine kinase system, though COP is not a substrate for creatine kinase and the enzymatic pathway by which its phosphate is liberated in vivo has not been fully elucidated in published human studies.

6.3 Cardioprotective Mechanisms: Positive Inotropy in Anoxia

In normoxia, creatinol-O-phosphate at 100 µmol/L evoked a positive inotropic effect only when glucose was present in the physiological solution; it also evoked a slight negative chronotropic effect that was independent of glucose. When creatinol-O-phosphate was present during hypoxia, the recovery of contraction after reoxygenation was improved in a dose-dependent manner. When present before ischemia, the recovery of contractility after reperfusion was higher than in controls; the presence of creatinol-O-phosphate during reperfusion after ischemia accelerated the recovery of contractility.

6.4 Cell Membrane Stabilization

The decrease in cardiac enzymes observed in clinical COP studies was attributed to the protective action of COP on cell membrane permeability. Experiments indicate COP's ability to stabilize cell membranes, which may be more resistant to attack by reactive oxygen species (ROS).

6.5 Calcium Overload Attenuation

The protective action of COP against serum CPK enhancement is common to other classes of drugs, such as beta-blocking agents, calcium antagonists, and corticosteroids. In the case of COP and calcium antagonists, a common mechanism, which has the effect of reducing myocardial calcium overload, may be assumed on the basis of previous investigations.

6.6 Distinction from Beta-Blockers and Calcium Antagonists

Pharmacological research demonstrated that creatinol-O-phosphate is distinguished from the class of beta-blocking agents and from that of the calcium antagonists. It is different not only from a pharmacological point of view, but also because it has no side effects such as negative inotropic action and atrioventricular block. It has been assessed that creatinol-O-phosphate causes a positive inotropic effect in the anoxic heart.

6.7 Contractile Enhancement Under Catecholamine Excess

The action of creatinol-O-phosphate was studied on the contractility of the heart, in vitro on isolated rat atria and in vivo in anesthetized dogs. Creatinol-O-phosphate was without action on the contractility of isolated rat atria stimulated by isoprenaline at a dose producing the maximum inotropic effect. It increased the contractility evoked by isoprenaline at higher doses and impaired the development of the negative inotropic effect evoked by prolonged treatment with this large dose. In dogs, creatinol-O-phosphate pretreatment increased the positive inotropic effect of large but not low isoprenaline dosages. It is concluded that creatinol-O-phosphate increased the contractile efficiency of the heart submitted to the action of an excess of catecholamines.

7. Scientific Evidence by Area of Use

7.1 Cardiovascular System: Antiarrhythmic Activity

Preclinical (Animal and In Vitro) Evidence

The activity of creatinol-O-phosphate on two in vitro and in vivo experimental arrhythmias was investigated. The substance proved to be active in delaying the onset time of aconitine-induced arrhythmias in guinea-pig atria. COP showed also a definite antagonizing activity against chloroform-induced ventricular fibrillation in mice.

Clinical (Human) Evidence

Double-blind trial — ischemic heart disease with ventricular premature beats (VPBs): In a double-blind investigation, creatinol-O-phosphate was checked versus a reference substance (solvent of COP) in volunteers affected by ischemic heart disease with persistent ventricular premature beats (VPB). COP was able to reduce VPB by 50–100% in 85% of the volunteers treated with this drug. The virtual absence of side-effects of COP led the authors to conclude that COP merits more extensive investigations in view of its clinical employment alone or in association with specific antiarrhythmic agents. (Di Maio F et al., Arzneimittelforschung, 1979;29(9a):1488–1490; PubMed PMID 395959)

Double-blind trial — inadequate coronary circulation: Creatinol-O-phosphate was checked in patients suffering from inadequate coronary circulation (12 patients had a recent myocardial infarction and 13 were suffering from angina pectoris) versus a reference substance in a double-blind study. COP improved rhythm disturbances, chest pains, and symptoms of contractility failure to a statistically significant degree. (PubMed PMID 395958)

Electrophysiological study in humans: Additionally, COP does not alter electrophysiological parameters in humans, indicating its safety for use in patients with pre-existing heart conditions. (Botti G et al., "Preliminary report on electrophysiological effectiveness of creatinol O-phosphate (COP) in human subjects," Arzneimittelforschung, 1979;29(9a):1491–1494)

Evidence Assessment: The antiarrhythmic clinical data for COP are derived from a cluster of small Italian trials published in a single journal supplement in 1979. Findings are positive but the studies are dated, small in sample size, and have not been replicated in modern large-scale randomized controlled trials. The overall clinical evidence for antiarrhythmic use is preliminary and historically limited.

7.2 Cardiovascular System: Myocardial Infarction and Cardioprotection

Myocardial Enzyme Reduction (Clinical)

Two groups of 23 patients each with acute myocardial infarction were treated. The first group (control) received glucose-insulin-K⁺ (GIK) over a 3-day period, and the second received GIK and creatinol-O-phosphate (3.06 g i.v./24 h) for a 3-day period. The six enzymes investigated — GOT, GPT, LDH, HBDH, CK, and MBCK — all decreased between 33 and 49% in the COP group as compared with the control group, reaching a degree of statistical significance of less than 0.01. The decrease in these enzymes was attributed to the protective action of COP on the cell membrane permeability.

In animal models, COP was shown to reduce ischemic lesions induced by isoprenaline. It has been demonstrated that creatinol-O-phosphate causes the number and the surface extension of ischemic lesions, as induced by the subcutaneous injection of isoprenaline in rats, to be reduced. Such an effect has been confirmed in humans, since creatinol-O-phosphate was found to cause the CPK release in the blood to be reduced, also having a reducing action on arrhythmic episodes occurring in patients suffering from myocardial ischemia.

Preclinical isoprenaline-model studies in rats showed a dose-dependent reduction in serum CPK. When rats were pretreated with COP, the CPK enhancement was reduced to an extent related to the doses of COP (250, 500, and 1000 mg/kg i.p.). COP protection was about 16% with the lower dose but increased to 50% with the highest dose according to linear regression (p < 0.01).

Evidence Assessment: The clinical evidence is limited to two small controlled trials (n = 23 per arm in the most detailed enzyme study) from the late 1970s, with intravenous dosing. These studies provided a signal of cardioprotection but have not been validated in adequately powered modern RCTs. Evidence is preliminary.

7.3 Skeletal Muscle Performance and Endurance

Proposed Mechanism

Administration of creatinol-phosphate, even at low doses, may induce a substantial increase in muscular creatine and the consequent formation of creatine phosphate. Its administration has been reported to cause an increase in muscular strength in human subjects, which is also marked in the elderly, as well as the disappearance of asthenia and muscular weakness in convalescent subjects and the restoration of cardiac efficiency in subjects who have suffered an infarct.

A PubMed-indexed clinical trial entry explicitly titled "Creatinol O-phosphate (COP) and muscular performance: a controlled clinical trial" (PubMed PMID 808375) exists, confirming that at least one controlled trial on muscular performance was conducted and published (in Arzneimittelforschung). However, the full text of this study is not freely available, and detailed results (population size, specific performance metrics, and outcome data) could not be independently verified from available sources.

The broader hypothesis is that during sustained intensive exercise, or exercise sustained under conditions of local hypoxia, the accumulation of hydronium ions formed during glycolysis and the accumulation of lactate (anaerobic metabolism) can severely reduce the intracellular pH. The reduced pH can compromise the function of the creatine-phosphorylcreatine system and can affect other functions within cells, such as the function of the contractile proteins in muscle fibers. COP is proposed to counter this acidification.

Limitations of the Evidence Base

Due to limited research, the optimal dosage and long-term effects of creatinol-O-phosphate are not as well established as those of creatine monohydrate. The efficacy of creatinol-O-phosphate for treating heart conditions has shown some promise in early studies. However, its role in improving exercise performance is less clear, with limited evidence. No systematic review or meta-analysis specifically evaluating COP in athletic or exercise performance contexts is available in the published literature.

Evidence Assessment: Human evidence for exercise performance enhancement is very limited. The biological plausibility exists based on its proposed buffering mechanism, but dedicated, independently replicated clinical trials with oral dosing are absent from the accessible published literature. Claims made in sports nutrition marketing for COP substantially outpace the available evidence.

7.4 Cardiac Contractility: Isolated Heart and Hemodynamic Studies

Marchetti and colleagues investigated the effects of COP on hemodynamics and cardiac metabolism in both isolated and in situ heart preparations. Studies examined the recovery of contractility of rat isolated heart after hypoxia or ischemia. In normoxia, COP (100 µmol/L) evoked a positive inotropic effect only when glucose was present, and a slight negative chronotropic effect independent of glucose. When COP was present during hypoxia, recovery of contraction after reoxygenation was improved in a dose-dependent manner. When present before ischemia, recovery of contractility after reperfusion was higher than in controls, and its presence during reperfusion after ischemia accelerated recovery of contractility.

Evidence Assessment: This body of work is from animal/in vitro models only. While the data are internally consistent and mechanistically informative, they cannot be directly extrapolated to humans without confirmatory clinical trials.

8. Body Systems and Health Areas of Association

8.1 Cardiovascular System

This is the body system for which the strongest available (though still preliminary) evidence exists. COP has been studied as: (a) an antiarrhythmic agent in ischemic heart disease; (b) a cardioprotective agent in acute myocardial infarction; (c) a positive inotropic agent under anoxic or hypoxic conditions; and (d) a potential therapeutic in coronary insufficiency. Clinical trials have shown COP to significantly reduce ventricular premature beats in patients with ischemic heart disease without side effects, supporting its potential use in antiarrhythmic therapy.

8.2 Skeletal Muscle and Exercise Physiology

COP is marketed primarily in the sports nutrition sector for its putative ability to prolong anaerobic glycolysis, buffer intracellular acidosis, and extend muscular endurance. COP is a synthetic compound primarily used in sports nutrition for its potential to support muscle endurance and recovery. Its unique structure allows it to maintain cellular integrity under stress, which may enhance physical performance during high-intensity exercise.

8.3 Energy Metabolism

COP is hypothesized to participate in cellular energy metabolism by donating its phosphate group to regenerate ATP from ADP. Creatinol-O-phosphate appears to donate its phosphate group for improved resynthesis of ATP, which can provide improved strength, endurance, recovery, and muscle performance.

8.4 Cell Membrane Integrity

COP has been associated with membrane-stabilizing properties, particularly under conditions of ischemia or oxidative stress. COP may help stabilize cell membranes and improve energy metabolism in heart tissue, potentially leading to improved cardiac function under stress.

9. Dosage Forms and Doses Reported in Studies

All doses below are stated exactly as reported in the referenced sources:

Intravenous (Clinical Studies)

Acute myocardial infarction (enzyme study): 3.06 g intravenously per 24 hours, administered over a 3-day period, alongside GIK (glucose-insulin-K⁺) infusion.
Acute tolerance study in healthy volunteers: COP was administered i.v. at three different dosages: 1020 mg (group A), 2040 mg (group B), and 3060 mg (group C), in comparison with a placebo (group D).

Intraperitoneal (Preclinical Animal Studies)

In rat studies on CPK protection, doses of 250, 500, and 1000 mg/kg body weight i.p. were used.

Oral (Supplement Industry)

No rigorously controlled peer-reviewed clinical study establishing an evidence-based oral dose for humans is available from the accessed literature. Due to limited research, the optimal dosage and long-term effects are not as well established as those of creatine monohydrate.

10. Safety Considerations

10.1 Acute Tolerance in Humans

The most directly relevant human safety data come from a formal acute tolerance study. Acute clinical tolerance to COP was investigated in volunteer human subjects without heart or renal disease and without other serious illness. COP was administered i.v. at 1020 mg, 2040 mg, and 3060 mg versus placebo. Arterial pressure, heart rate, ECG pattern, and a complete blood analysis showed no change at any COP dosage, with the exception of blood phosphate, which increased in the two higher-dose groups. Cumulative urinary excretion of phosphate and creatinine and diuresis increased, whereas other urine parameters did not change. The phosphate and creatinine increases derived from the COP molecule, and the increase in diuresis from a simple osmotic process required to dilute the phosphate in the tubular fluid.

10.2 Absence of Electrophysiological Interference

COP does not alter electrophysiological parameters in humans, indicating its safety for use in patients with pre-existing heart conditions. This is in contrast to classical antiarrhythmic drugs, which can exhibit proarrhythmic effects and hemodynamic depression at therapeutic doses.

10.3 Absence of Negative Inotropy and AV Block

Unlike beta-blocking agents and calcium antagonists used for similar indications, creatinol-O-phosphate does not produce negative inotropic action or atrioventricular block.

10.4 Metabolic Fate and Renal Excretion

Creatinol-O-phosphate is distributed in all organs, particularly in the liver and kidney, where it is dephosphorylated and eliminated with urine. The resulting increase in urinary phosphate and creatinine observed at higher doses in the acute tolerance study was attributed to normal catabolism and osmotic handling of the phosphate load, not to renal toxicity.

10.5 Absence of Established Drug Interaction Data

No peer-reviewed clinical studies characterizing specific drug–drug interactions for COP were identified in the accessed literature. Given its pharmacological distinction from classical antiarrhythmic agents (no sodium channel blockade, no calcium antagonism, no beta-adrenergic blockade), major pharmacodynamic interactions of the types seen with Class I–IV antiarrhythmics are not expected based on mechanism, but this has not been systematically studied in humans with co-administered medications.

10.6 Elevation of Blood Phosphate

A study on healthy volunteers revealed that COP is tolerated well at various dosages. No significant changes were observed in arterial pressure, heart rate, ECG patterns, or blood analysis, aside from an increase in blood phosphate at higher doses. This finding is clinically relevant in individuals with impaired renal phosphate handling.

10.7 Limitations of the Safety Evidence Base

It must be emphasized that the available safety data were generated primarily from short-term intravenous use in clinical populations in the 1970s and 1980s. Safety data specifically for the oral route of administration, the doses typically found in contemporary dietary supplement formulations, and long-term exposure are absent from the peer-reviewed literature. The bioavailability of creatinol-O-phosphate has not been as thoroughly studied as that of creatine monohydrate. Creatinol-O-phosphate is considered relatively stable, but specific data on its absorption and utilization in the body are limited.

11. Current Evidence Summary

Creatinol-O-phosphate occupies an unusual position in the landscape of bioactive compounds: it has a reasonably well-characterized preclinical profile and a cluster of small, positive clinical trials from the late 1970s in cardiovascular disease, but has never been systematically developed through modern large-scale clinical trials. COP has been studied for various conditions, particularly those related to heart health and exercise performance, including cardiac insufficiency, ischemic heart disease, and as a potential supplement for improving muscle strength and endurance during physical activity. The efficacy of COP for treating heart conditions has shown some promise in early studies. Its use in the dietary supplement market is primarily based on an extension of its proposed intracellular buffering and phosphate-donation mechanisms to skeletal muscle physiology — an application that lacks dedicated, peer-reviewed clinical validation.

References

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