Basic Introduction

Procaine hydrochloride is a pharmaceutical medication belonging to the aminoester group of local anesthetics. German chemist Alfred Einhorn first synthesized the drug as a safer anesthetic alternative to cocaine due to its side effect profile, patenting Procaine hydrochloride under the trade name “Novocain,” and even today, Procaine hydrochloride is often labeled generically as “novocaine” in some parts of the world. Historically, Procaine hydrochloride has been used for local, regional, and neuraxial anesthesia via local infiltration, peripheral nerve blockade, and intrathecal injection. Since its development, however, newer local anesthetics such as lidocaine, bupivacaine, and mepivacaine have largely supplanted the use of Procaine hydrochloride in everyday practice.

Between 1946 and 1956, Ana Aslan described a significant number of Procaine hydrochloride beneficial actions exerted on cellular functions and metabolism, following long-term treatment in low doses, highlighting its “rejuvenating” effects, and developed Gerovital H3 (GH3)—an original Procaine hydrochloride-based pharmaceutical formulation. Due to these findings, Procaine hydrochloride which was known only for its anesthetic properties became one of the most disputed medical developments of the sixties and seventies in the field of “anti-aging” therapy. Procaine hydrochloride is part of the history of medicine and gerontoprophylaxis, an old-timer of clinical practice, but still a molecule with great potential which continues to reveal new biological and pharmacological effects within novel experimental approaches. [1]

Synthesis of procaine hydrochloride

(1) Esterification reaction: 180kg of p-nitrobenzoic acid, 126kg of 2-diethylaminoethanol, 630kg of xylene, 4.5kg of formic acid was put into the esterification kettle, refluxed at a temperature of 140 °C ~ 145 °C for 11h, and then the water and formic acid were removed through the water separator, the solid was precipitated by cooling, filtered, the filtrate was put into the separating distillation kettle for 2h, xylene was removed, the residual liquid and the filtered solid were put into the acid control kettle, and 508kg of 8% dilute hydrochloric acid was added to stir the reaction for 1h, filtered, and 2.5kg of p-nitrobenzoic acid was removed to obtain the filtrate, that is, 790kg of nitrocaine hydrochloride solution;(2) Reduction reaction: 790kg of nitrocaine hydrochloride solution in step (1) is put into the reduction kettle, Add 20% sodium hydroxide solution to adjust the pH to 4~4.2, then add 144kg of iron powder to react at a temperature of 100 °C~105 °C for 2h, filter to remove iron filings, wash the iron filings, mix the washing liquid and filtrate solution and put it into the sedimentation kettle, then add dilute hydrochloric acid to adjust the pH to 5, then add saturated sodium sulfate solution to adjust the pH to 7.8~8, precipitate for 2h, filter to remove iron sulfide sludge, obtain 960kg of filtrate, and add soda ash 108kg and 1395kg xylene to mix, put it into the separator kettle and stand for 2h, remove the aqueous alkaline water, extract the organic phase and add insurance powder 3.5kg and 383kg of 10% dilute hydrochloric acid were mixed, put into a separator kettle and stratified, the aqueous procaine hydrochloride solution was extracted, the organic phase was removed, the pH of procaine hydrochloride solution was adjusted to 4.2 with dilute sulfuric acid, and 594kg of procaine hydrochloride solution with pH 4.2 was obtained, and the content of procaine was 41% after testing, and the yield of procaine was 97% calculated by the p-nitrobenzoic acid involved in the reaction;(3) Crystallization: 594kg of procaine hydrochloride solution in step (2) is filtered into a microperforator, the filtrate and filtrate are put into the concentrator to concentrate, 235kg of water is removed, the concentrate is put into the crystallization kettle while it is hot and 105kg of absolute ethanol is added to mix, it is cooled to 10 °C below the crystallization for 7h, it is put into the centrifuge for centrifugal separation for 1h, the mother liquor is removed, and the separated solid is dried for 6h to obtain 265kg of procaine hydrochloride finished product. The purity was 99.7%, and the yield was 91.5% based on the p-nitrobenzoic acid involved in the reaction.[2]

Procaine hydrochloride Pharmacokinetics and Metabolism

Procaine hydrochloride is a drug with limited distribution and tissue uptake and a short duration of action: during a continuous intravenous infusion of 2% Procaine hydrochloride, the steady-state plasma level is achieved within 20 to 30 minutes. Following the termination of the administration, drug concentration decreases rapidly, with a distribution half-life (t1/2 alpha) of 2.49 ± 0.36 minutes and an elimination half-life (t1/2 beta) of 7.69 ± 0.99 minutes. It exerts its effect by blocking the transmission of nerve impulses through the inhibition of sodium ion flux across neuronal membranes. At systemic level, Procaine hydrochloride is hydrolyzed to diethyl-amino-ethanol (DEAE) and para-aminobenzoic acid (PABA), as primary metabolites, by the enzyme pseudocholinesterase. In different organs, Procaine hydrochloride is hydrolyzed under the microsomal carboxylesterases. DEAE displays local anesthetic activity.

Procaine hydrochloride hydrolysis represents an important feature that could support some of its effects on cellular functions and metabolism, as the primary and secondary metabolites could have additional pharmacologic actions or participate as precursors in the synthesis of essential biomolecules. Kietzmann and Kaemmerer (1989) tested the influence of orally-administrated Procaine hydrochloride hydrochloride on intermediary metabolism in rats and pointed out the fact that the ratio of acetyl coenzyme A to coenzyme A clearly was enhanced in the liver and, to a minor extent, in the cerebellum. Also, Procaine hydrochloride hydrochloride, GH3, as well as DEAE increased, in a dose- and time-dependent mode, the hepatic incorporation rate of amino acids in protein, while PABA yielded no effect.

A very attractive hypothesis, which needs more studies and scientific evidence, is the second stage of Procaine hydrochloride metabolism (remarkable from the pharmacodynamics viewpoint): the possible generation of ethanolamine from DEAE. Ethanolamine is a possible precursor in the biosynthesis of membrane phospholipids (phosphatidylethanolamine and phosphatidylcholine), which can be converted into the neurotransmitter acetylcholine (Ach)

Procaine hydrochloride Effects on Lifespan

The studies researching Procaine hydrochloride's influence on lifespan are scarce. An experimental study conducted by Aslan et al. (1965) on 1840 rats pointed out 18-21% longer lifespan in treated animals than that of controls injected with saline solution. Another investigation on lifespan was conducted on 3680 animals from 5 successive generations. The outcome supported that GH3 administered since early ages induced a lifespan extension both in the treated animals, as well as in the first generation of not-treated offspring. In Drosophila melanogaster grown on nutritive medium enriched with GH3 was also found out a 22.7% lifespan extension, compared with controls. Unfortunately, there are no recent studies regarding the effects of Procaine hydrochloride and/or GH3 on lifespan.[3]

Summarizing its cellular actions, Procaine hydrochloride is able to bind to membrane constituents and interact with a series of ion channels exerting its anesthetic action and also has a significant influence on oxidative stress response, on the modulation of critical metabolic pathways, as well as on epigenetic regulation.The antioxidant action of Procaine hydrochloride is supported by in vitro and in vivo experimental studies regarding the inhibition of ROS generation and lipid peroxidation, in enzymatic and nonenzymatic systems, associated with a modulating effect on antioxidant enzymes. Several studies confirm its involvement in mitigating cellular and systemic oxidative stress, acting on the main targets of aging and age-related diseases

References

[1] Moynahan E. J. Treatment of acute sprains by procaine infiltration (Leriche’s method) British Medical Journal. 1939;1(4082):671–672.

[2] ANHUI CHENGSHI PHARMACEUTICAL - CN118221536, 2024, A

[3] Winter L. Intravenous procaine infusions in the postoperative period. Annals of Surgery. 1950;132(1):143–146.