Taurolidine

Medical uses

Taurolidine is an antimicrobial agent used in an effort to prevent catheter infections. It however is not approved for this use in the United States as of 2011.

Side effects

No systemic side effects have been identified. The safety of taurolidine has also been confirmed in clinical studies with long-term intravenous administration of high doses (up to 20 g daily). In the body, taurolidine is metabolized rapidly via the metabolites taurultam and methylol taurinamide, which also have a bactericidal action, to taurine, an endogenous aminosulphonic acid, CO2 and H2O. Therefore, no toxic effects are known or expected in the event of accidental injection. Burning sensation while instilling, numbness, erythema, facial flushing, headache, epistaxis, nausea

Toxicology

Taurolidine has a relatively low acute and subacute toxicity. Intravenous injection of 5g taurolidine into humans over 0.5 – 2 hours period produce only burning sensation while instilling, numbness and erythema at the injection sites. For treatment of peritonitis, taurolidine was administered by peritoneal lavage, intraperitoneal instillation or intravenous infusion, or by a combination thereof. The total daily dose ranged widely from 0.5 to 50g. The total cumulative dose ranged from 0.5 to 721g. In those patients who received intravenous taurolidine, the daily intravenous dose was usually 15 to 30 g but several patients received up to 40g/day. Total daily doses of up to 40g and total cumulative doses exceeding 300g were safe and well tolerated.

Pharmacology

Mechanism of action

Following administration of taurolidine, the antimicrobial and antiendotoxin activity of the taurolidine molecule is conferred by the release of three active methylol (hydroxymethyl) groups as taurolidine is rapidly metabolized by hydrolysis via methylol taurultam to methylol taurinamide and taurine. These labile N-methylol derivatives of taurultam and taurinamide react with the bacterial cell-wall resulting in lysis of the bacteria, and by inter- and intramolecular cross-linking of the lipopolysaccharide-protein complex, neutralization of the bacterial endotoxins which is enhanced by enzymatic activation. This mechanism of action is accelerated and maximised when taurolidine is pre-warmed to 37 °C. Microbes are killed and the resulting toxins are inactivated; the destruction time in vitro is 30 minutes.

The chemical mode of action of taurolidine via its reactive methylol groups confers greater potency in vivo than indicated by in vitro minimum inhibitory concentration (MIC) values, and also appears to preclude susceptibility to resistance mechanisms.

Taurolidine binding to lipopolysaccharides (LPS) prevents microbial adherence to host epithelial cells, thereby prevents microbial invasion of uninfected host cells. Although the mechanism underlying its antineoplastic activity has not been fully elucidated, it may be related to this agent's anti-adherence property. Taurolidine has been shown to block Interleukin 1 (IL-1) and tumour necrosis factor (TNF) in human peripheral blood mononuclear cells (PBMC). In addition, taurolidine also promotes apoptosis by inducing various apoptotic factors and suppresses the production of vascular endothelial growth factor (VEGF), a protein that plays an important role in angiogenesis.

Taurolidine is highly active against the common infecting pathogens associated with peritonitis and catheter sepsis, this activity extends across a wide-spectrum of aerobic/anaerobic bacteria and fungi (with no diminution of effect in the presence of biological fluids, e.g. blood, serum, pus).

Chemical properties

The chemical name for taurolidine is 4,4'-Methylene-bis(1,2,4-thiadiazinane)-1,1,1’,1'-tetraoxide.

It is a white to off white odourless crystalline powder. It is practically insoluble in chloroform, slightly soluble in boiling acetone, ethanol, methanol, and ethyl acetate, sparingly soluble in water 8 at 20° and ethyl alcohol, soluble in dilute hydrochloric acid, and dilute sodium hydroxide, and freely soluble in N,N-dimethylformamide (at 60 °C).

History

Taurolidine was first synthesized in the laboratories of Geistlich Pharma AG, Switzerland in 1972. Clinical trials begun in 1975 in patients with severe peritonitis.

Research

Taurolidine demonstrates some anti-tumor properties, with positive results seen in early-stage clinical investigations using the drug to treat gastrointestinal malignancies and tumors of the central nervous system. More recently, it has been found to exert antineoplastic activity. Taurolidine induces cancer cell death through a variety of mechanisms. Even now, all the antineoplastic pathways it employs are not completely elucidated. It has been shown to enhance apoptosis, inhibit angiogenesis, reduce tumor adherence, downregulate pro-inflammatory cytokine release, and stimulate anticancer immune regulation following surgical trauma. Apoptosis is activated through both a mitochondrial cytochrome-c-dependent mechanism and an extrinsic direct pathway. A lot of in vitro and animal data support taurolidine's tumoricidal action. Taurolidine has been used as an antimicrobial agent in the clinical setting since the 1970s and thus far appears nontoxic. The nontoxic nature of taurolidine makes it a favorable option compared with current chemotherapeutic regimens. Few published clinical studies exist evaluating the role of taurolidine as a chemotherapeutic agent. The literature lacks a gold-standard level 1 randomized clinical trial to evaluate taurolidine's potential antineoplastic benefits. However, these trials are currently underway. Such randomized control studies are vital to clarify the role of taurolidine in modern cancer treatment.