Taurolidine

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Taurolidine
Taurolidine.png
Clinical data
ATC code
Identifiers
  • 4,4'-methylenebis(1,2,4-thiadiazinane)-1,1,1',1'-tetraoxide
CAS Number
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard 100.039.090 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C7H16N4O4S2
Molar mass 284.35 g·mol−1
3D model (JSmol)
  • C1CS(=O)(=O)NCN1CN2CCS(=O)(=O)NC2
  • InChI=1S/C7H16N4O4S2/c12-16(13)3-1-10(5-8-16)7-11-2-4-17(14,15)9-6-11/h8-9H,1-7H2
  • Key:AJKIRUJIDFJUKJ-UHFFFAOYSA-N

Taurolidine is an antimicrobial that is used to prevent infections in catheters. [1] Side effects and the induction of bacterial resistance is uncommon. [1] It is also being studied as a treatment for cancer. [2]

Contents

It is derived from the endogenous amino acid derivative taurine. The putative method of action involves the metabolism of taurolidine to taurinamide and ultimately taurine and water, liberating methylol groups that chemically react with the mureins in the bacterial cell wall and with the amino and hydroxyl groups of endotoxins and exotoxins. This reaction denatures the endotoxins and complex polysaccharide and lipopolysaccharide components of the bacterial cell wall and inactivates susceptible exotoxins. [3]

Medical uses

Taurolidine is an antimicrobial agent used as part of a catheter lock solution in an effort to prevent catheter infections. [4]

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 grams 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, carbon dioxide and water. Therefore, no toxic effects are known or expected in the event of accidental injection. Burning sensation while instilling, numbness, erythema, facial flushing, headache, epistaxis, and nausea have been reported. [12]

Toxicology

Taurolidine has a relatively low acute and subacute toxicity. [1] Intravenous injection of 5 grams taurolidine into humans over 0.5–2 hours produce only burning sensation while instilling, numbness, and erythema at the injection sites. [12] 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 50 g. The total cumulative dose ranged from 0.5 to 721 g. In those patients who received intravenous taurolidine, the daily intravenous dose was usually 15 to 30 g but several patients received up to 40 g/day. Total daily doses of up to 40 g and total cumulative doses exceeding 300 g were safe and well tolerated. [12] [13] [14] [15] [16]

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 (99 °F). Microbes are killed and the resulting toxins are inactivated; the destruction time in vitro is 30 minutes. [19]

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. [14]

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. [6] [7] Taurolidine has been shown to block interleukin 1 (IL-1) and tumour necrosis factor (TNF) in human peripheral blood mononuclear cells (PBMC). [20] 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. [21]

Taurolidine is highly active against the common infecting pathogens associated with peritonitis and catheter sepsis, this activity extends across a wide-spectrum of aerobic and anaerobic bacteria and fungi (with no diminution of effect in the presence of biological fluids, e.g. blood, serum, pus). [15] [16] [22]

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. [23] 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. [24] [25] [26] 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. [21] [2]

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References

  1. 1 2 3 4 5 6 Liu Y, Zhang AQ, Cao L, Xia HT, Ma JJ (2013). "Taurolidine lock solutions for the prevention of catheter-related bloodstream infections: a systematic review and meta-analysis of randomized controlled trials". PLOS ONE. 8 (11): e79417. Bibcode:2013PLoSO...879417L. doi: 10.1371/journal.pone.0079417 . PMC   3836857 . PMID   24278133.
  2. 1 2 Neary PM, Hallihan P, Wang JH, Pfirrmann RW, Bouchier-Hayes DJ, Redmond HP (April 2010). "The evolving role of taurolidine in cancer therapy". Annals of Surgical Oncology. 17 (4): 1135–43. doi:10.1245/s10434-009-0867-9. PMID   20039217. S2CID   23807182.
  3. ↑ Waser PG, Sibler E (1986). "Taurolidine: A new concept in antimicrobial chemotherapy". In Harms AF (ed.). Innovative Approaches in Drug Research. Elsevier Science Publishers. pp. 155–169.
  4. ↑ O'Grady NP, Alexander M, Burns LA, Dellinger EP, Garland J, Heard SO, et al. (May 2011). "Guidelines for the prevention of intravascular catheter-related infections". Clinical Infectious Diseases. 52 (9): e162-93. doi:10.1093/cid/cir257. PMC   3106269 . PMID   21460264.
  5. 1 2 Bradshaw JH, Puntis JW (August 2008). "Taurolidine and catheter-related bloodstream infection: a systematic review of the literature". Journal of Pediatric Gastroenterology and Nutrition. 47 (2): 179–86. doi:10.1097/MPG.0b013e318162c428. PMID   18664870. S2CID   19136945.
  6. 1 2 Gorman SP, McCafferty DF, Woolfson AD, Jones DS (April 1987). "Reduced adherence of micro-organisms to human mucosal epithelial cells following treatment with Taurolin, a novel antimicrobial agent". The Journal of Applied Bacteriology. 62 (4): 315–20. doi:10.1111/j.1365-2672.1987.tb04926.x. PMID   3298185.
  7. 1 2 Blenkharn JI (July 1989). "Anti-adherence properties of taurolidine and noxythiolin". Journal of Chemotherapy. 1 (4 Suppl): 233–4. PMID   16312382.
  8. ↑ Liu H, Liu H, Deng J, Chen L, Yuan L, Wu Y (2014). "Preventing catheter-related bacteremia with taurolidine-citrate catheter locks: a systematic review and meta-analysis". Blood Purification. 37 (3): 179–87. doi: 10.1159/000360271 . PMID   24777144.
  9. ↑ Olthof ED, Rentenaar RJ, Rijs AJ, Wanten GJ (August 2013). "Absence of microbial adaptation to taurolidine in patients on home parenteral nutrition who develop catheter related bloodstream infections and use taurolidine locks". Clinical Nutrition. 32 (4): 538–42. doi:10.1016/j.clnu.2012.11.014. PMID   23267744.
  10. 1 2 Torres-Viera C, Thauvin-Eliopoulos C, Souli M, DeGirolami P, Farris MG, Wennersten CB, et al. (June 2000). "Activities of taurolidine in vitro and in experimental enterococcal endocarditis". Antimicrobial Agents and Chemotherapy. 44 (6): 1720–4. doi:10.1128/aac.44.6.1720-1724.2000. PMC   89943 . PMID   10817739.
  11. ↑ Simon A, Bode U, Beutel K (July 2006). "Diagnosis and treatment of catheter-related infections in paediatric oncology: an update". Clinical Microbiology and Infection. 12 (7): 606–20. doi: 10.1111/j.1469-0691.2006.01416.x . PMID   16774556.
  12. 1 2 3 Gong L, Greenberg HE, Perhach JL, Waldman SA, Kraft WK (June 2007). "The pharmacokinetics of taurolidine metabolites in healthy volunteers". Journal of Clinical Pharmacology. 47 (6): 697–703. doi:10.1177/0091270007299929. PMID   17395893. S2CID   31059736.
  13. 1 2 Knight BI, Skellern GG, Browne MK, Pfirrmann RW (November 1981). "Peritoneal absorption of the antibacterial and antiendotoxin taurolin in peritonitis". British Journal of Clinical Pharmacology. 12 (5): 695–9. doi:10.1111/j.1365-2125.1981.tb01292.x. PMC   1401955 . PMID   7332737.
  14. 1 2 3 Stendel R, Scheurer L, Schlatterer K, Stalder U, Pfirrmann RW, Fiss I, et al. (2007). "Pharmacokinetics of taurolidine following repeated intravenous infusions measured by HPLC-ESI-MS/MS of the derivatives taurultame and taurinamide in glioblastoma patients". Clinical Pharmacokinetics. 46 (6): 513–24. doi:10.2165/00003088-200746060-00005. PMID   17518510. S2CID   33321671.
  15. 1 2 Browne MK, MacKenzie M, Doyle PJ (May 1978). "C controlled trial of taurolin in established bacterial peritonitis". Surgery, Gynecology & Obstetrics. 146 (5): 721–4. PMID   347606.
  16. 1 2 Browne MK (1981). "The treatment of peritonitis by an antiseptic - taurolin". Pharmatherapeutica. 2 (8): 517–22. PMID   7255507.
  17. 1 2 Knight BI, Skellern GG, Browne MK, Pfirrmann RW (September 1981). "The characterisation and quantitation by high-performance liquid chromatography of the metabolites of taurolin". British Journal of Clinical Pharmacology. 12 (3): 439–40. doi:10.1111/j.1365-2125.1981.tb01245.x. PMC   1401804 . PMID   7295478.
  18. ↑ Browne MK, Leslie GB, Pfirrmann RW (December 1976). "Taurolin, a new chemotherapeutic agent". The Journal of Applied Bacteriology. 41 (3): 363–8. doi:10.1111/j.1365-2672.1976.tb00647.x. PMID   828157.
  19. ↑ Braumann C, Pfirrman RW, et al. (2013). "Taurolidine, an Effective Multimodal Antimicrobial Drug Versus Traditional Antiseptics and Antibiotics". In Willy C (ed.). Antiseptics in Surgery - Update 2013. Lindqvist Book Publishing. pp. 119–125.
  20. ↑ Bedrosian I, Sofia RD, Wolff SM, Dinarello CA (November 1991). "Taurolidine, an analogue of the amino acid taurine, suppresses interleukin 1 and tumor necrosis factor synthesis in human peripheral blood mononuclear cells". Cytokine. 3 (6): 568–75. doi:10.1016/1043-4666(91)90483-t. PMID   1790304.
  21. 1 2 Jacobi CA, Menenakos C, Braumann C (October 2005). "Taurolidine--a new drug with anti-tumor and anti-angiogenic effects". Anti-Cancer Drugs. 16 (9): 917–21. doi:10.1097/01.cad.0000176502.40810.b0. PMID   16162968. S2CID   33876185.
  22. 1 2 Nösner K, Focht J (1994). "In-vitro Wirksamkeit von Taurolidin und 9 Antibiotika gegen klinische Isolate aus chirurgischem Einsendegut sowie gegen Pilze". Chirurgische Gastroenterologie. 10 (Suppl 2): 10.
  23. ↑ Stendel R, Picht T, Schilling A, Heidenreich J, Loddenkemper C, Jänisch W, Brock M (2004-04-01). "Treatment of glioblastoma with intravenous taurolidine. First clinical experience". Anticancer Research. 24 (2C): 1143–7. PMID   15154639.
  24. ↑ Calabresi P, Goulette FA, Darnowski JW (September 2001). "Taurolidine: cytotoxic and mechanistic evaluation of a novel antineoplastic agent". Cancer Research. 61 (18): 6816–21. PMID   11559556.
  25. ↑ Clarke NW, Wang JH, et al. (2005). "Taurolidine inhibits colorectal adenocarcinoma metastases in vivo and in vitro by inducing apoptosis". Ir J Med Sci. 174 (Supplement 3): 1.
  26. ↑ Stendel R, Scheurer L, Stoltenburg-Didinger G, Brock M, Möhler H (2003-06-01). "Enhancement of Fas-ligand-mediated programmed cell death by taurolidine". Anticancer Research. 23 (3B): 2309–14. PMID   12894508.
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