Taurolidine Synthesis Essay

1. Introduction

Amino acids (AA) are an important class of cell signaling molecules, involved in the regulation of gene expression and the protein phosphorylation cascade. They are also precursors of hormone synthesis and low-molecular nitrogenous substances [1]. Taurine (2-aminoethanesulfonic acid) is a β-AA and is the most abundant amino acid in mammals, being widely distributed in the CNS occupying the second place after glutamate in relation of its concentration, which differs depending on the regions of brain activity and animal species studied [2] and presenting different functions, which have been studied for their potential in neurology as a trophic factor in brain development, in regulating calcium transport, in the integrity of the eardrum, as osmoregulator, neurotransmitter, neuromodulator and for its neuroprotective action [3].

Taurine was first isolated from ox bile for over 150 years, it was considered a sulfur metabolism end product with no biological activity [4]. Recently, several researchers have reported the physiological function of taurine in the liver, kidney, heart, pancreas, retina and brain and the fact that its depletion is associated a several disease conditions such as diabetes [5,6,7], Parkinson’s [8], Alzheimer’s [9,10], cardiovascular diseases [11,12,13], and neuronal damages in the retina [14].

Even though taurine is the most abundant free AA in mammals, man and cats lack the ability to synthesize taurine in sufficient quantities [15]. The biosynthesis takes place in the liver and starts from methionine, through cysteine, leading to cysteine-sulfonic acid which is converted to hypotaurine and taurine (Scheme 1). It was also demonstrated that taurine biosynthesis in the hippocampus and cerebellum ocurrs through the conversion of the amino acid cysteine by the sulfinic acid decarboxylase enzyme (CAD/CSAD and taurine-synthase), [16,17].

Scheme 1. Biosynthesis of taurine.

Scheme 1. Biosynthesis of taurine.

Despite the fact taurine is used in the market in energetic drinks (mistakenly known by the population as a stimulant agent), the neuroinhibitory effect of taurine in the central nervous system (CNS) was acknowledged in reports as early as the decade of the 19?60s. Over the following decade, several studies were carried out in order to gain a deeper insight into this function, and the mechanism behind it [18].

Taurine acts in these areas by binding in specific Tau receptors (TauR) promoting neuronal hyperpolarization via opening of chloride channels [19,20], and producing depressor activity by specific action via GABA A, GABA B and/or the glycine receptor [21].

The action of taurine in GABAA receptors counteracts the seizures produced by picrotoxin, a GABAA antagonist, increasing the latency of such seizures both acutely and chronically [22]. Besides the GABAA agonistic activity, taurine also increases GABA levels, enhancing the production of the two isoforms of the glutamic acid decarboxylase (GAD 65 and 67), involved in the GABA synthesis [23].

Taurine is involved in the modulation of the excitotoxicity produced by glutamate, through the regulation of calcium homeostasis. This effect is related to a neuroprotective action. It is known that glutamate has affinity for N-methyl-D-aspartate (NMDA) receptors, through which the calcium influx occurs. This event activates a cyclic guanosine monophosphate (cGMP)-mediated pathway, culminating in the activation of the protein kinase C (PKC), responsible for the reduction of the magnesium block of NMDA channels, increasing the calcium influx and excitotoxicity [24].

In a stress situation, the neurotoxicity trigger is activated by an excess of glutamate delivery and taurine is quickly evocated for delivery in this situation [25]. Evidence of the taurine neuroprotective effects from β-amyloid action and glutamate receptor agonists involves the neutralization of the NMDA receptors, reduction of the glutamate delivery and the NO superproduction via GABA A activation. In fact, this strongly suggests the taurine prevention in Alzheimer´s disease and other neurological disorders [26]. Similar results were observed in the neuroprotection by taurine against the excess of ammonia and cerebral edema [27,28].

Because taurine has a sulfonic acid instead a carboxylic acid group it presents unique physical properties in comparison to other neuroactive AAs that make it difficult to cross the blood-brain barrier (BBB). In addition, it’s a monobasic acid, with very low solubility in water (10.48 g/100 mL at 25 °C); the pKa value is 1.5 (more acidic than glycine, aspartic acid, β-alanine and GABA). The pKb value is 8.82 (less basic than glycine, β-alanine and GABA). The low passive diffusion of taurine occurs because of its cyclic conformational form with intra-molecular hydrogen bonding [15].

The concentrations of taurine in the CNS are dependent on feeding and a complex transport across TauT specific complex systems at the blood brain barrier (BBB) and it may be involved in the maintenance of taurine levels in the brain in order to protect it against CNS damage [29].

It was reported that the TauT at the BBB was reduced in spontaneously hypertensive rats in comparison with normotensive rats [30]. Also, in other disease conditions or oxidative stress processes, CNS transport of taurine at the BBB fails [29]. Taurine levels were increased in the brain interstitial fluid in ischemia [31] and in the acute phase of Parkinson’s [32]. However, in a chronic situation of the same disease (Parkinson’s), taurine levels are low [8]. In the acute phase of the diseases, taurine is available to protect CNS, but if the BBB taurine transport also fails and because taurine cannot cross the BBB by itself, there is not a sufficient concentration for neuroprotection and then the disease evolves to the chronic phase.

In addition to the physicochemical properties of taurine that promote low passive diffusion through the membranes, and low gastro-intestinal absorption, it is very interesting to plan new lipophilic taurine derivatives that can cross the BBB in disease conditions and or/increase binding receptors.

2. Anticonvulsant Taurine Analogues

In 1983, Lindén and co-workers [33] synthesized 2-phthalimidosulfonamide derivatives of taurine (Figure 1) and tested their anticonvulsant activity. The structure-activity relationship study showed that the two-carbon chain of the taurine molecule is essential for a better activity of these derivatives. Furthermore, it was also noted that substitutions in the terminal sulphonamide moiety increased the lipophilicity of the molecules, thus facilitating the drugs’ access into the brain. However, it was observed that the activity decreased with voluminous groups attached to the sulphonamide moiety.

Figure 1. General structure of phthalimidoetanosulfonamide derivatives.

Figure 1. General structure of phthalimidoetanosulfonamide derivatives.

The anticonvulsant activity in the maximum electroshock seizure (MES) model and in the subcutaneous pentetetrazole seizure threshold (PST) model were effective with unsubstituted amide, methylamide, dimethylamide, ethylamide and isopropylamide derivatives and the efficacy was almost equal. N-Propylamide and N-butylamide were also active, but less potent, No effect were observed in acetamide, pyrrolinedide, piperidide, cyclohexylamide, benzylamide, methylbenzylamide and pyridylamide derivatives. The N-isopropyl derivative (named taltrimide) is now commercially but it is not approved for therapeutic use as the anticonvulsive effects of taltrimide observed in animal experiments were not confirmed in clinical trials. In contrast, the seizures increased statistically significantly during taltrimide treatment, suggesting a proconvulsant effect of taltrimide in humans and the reason for this remains obscure [34].

Isoherranen and co-workers [35] synthesized novel valproyltaurinamide derivatives (Figure 2), that could act not only as mutual prodrugs of valproic acid (VPA) and taurine, but also as a hybrid one. The purpose of this work was to obtain better a valproic acid, an antiepileptic drug useful against a variety of types of epileptic seizures and compounds devoid of teratogenic effects. Three compounds showed good profile (VTD > I-VTD and DM-VTD) in preventing tonic extension, clonus and wild running.

In the pharmacokinetics assay, a good correlation with the brain metabolite N-alkyl-VTD and its anticonvulsant activity was observed, but no correlation was found with log P value and teratogenic potency. Neural tube defects were observed in the order VTA > DM-VTD > I-VTD > VTD. The compound M-VTD had a very low teratogenic potential (1% of the live born fetuses, not significant, P > 0.05).

Figure 2. Valproyltaurine derivatives.

Figure 2. Valproyltaurine derivatives.

Based on the results with valproyltaurinamide derivatives and the knowledge of that anilide groups, with small substituents on the N-phenyl ring, are known to produce potent anticonvulsants, in 2007 Akgul and co-workers, repeated the Lindén et al. research [33] and obtained 15 new 2-phtalimidoethanesulfonamide derivatives with phenyl groups attached to the sulphonamide moiety The preliminary screening results indicated that the exchange of the N-isopropyl moiety for an N-phenyl ring in the taltrimide molecule abolished the anticonvulsant activity. However, introducing certain substituents, such as nitro, methyl, and chloro, into the N-phenyl ring lead to more active compounds in the MES test in comparison to the unsubstituted derivatives (Table 1). In the rotarod test for neurotoxicity effects were observed with a methyl substituent in the N-phenyl ring [36].

Time of the test after administration of the drug
0.5 h4 h
Best activity in MES test(I) R = 3-NO2(III) R = 2-CH3
(II) R = 2-Cl  (IV) R = 2-CH(CH3)2
(V) R = 4-NO2
Higher neurotoxicity(VI) R = 3-CH3(VII) R = 2-CH3

Oja and co-workers obtained 23 taurine derivatives substituted at the amine and sulfonic acid group. Figure 3 shows nine of the active compounds: piperidino (VIII) benzamido (IX-XIII), phthalimido (XIV) and phenylsuccinimido (XV-XVI) derivatives. Compound VIII showed the best activity when tested in rotarod method (used to assess motor coordination and balance in rodents) than other compounds and greater than valproate and diazepam when its effects were calculated from both the MES and PST test and compound I showed toxicity [37].

Figure 3. Structures of the compounds with anticonvulsant activity [37].

Figure 3. Structures of the compounds with anticonvulsant activity [37].

Table 1. Best phenyl phtalimidoethanesulfonamide derivatives in MES test after 0.5 and 4 h of administration and the compounds’ neurotoxicity [36].

Taurolidine is an antimicrobial that is used to try 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]

It is derived from the endogenous amino acidtaurine. Taurolidine’s putative mechanism of action is based on a chemical reaction. During the metabolism of taurolidine to taurinamide and ultimately taurine and water, methylol groups are liberated that chemically react with the mureins in the bacterial cell wall and with the amino and hydroxyl groups of endotoxins and exotoxins. This results in denaturing of the complex polysaccharide and lipopolysaccharide components of the bacterial cell wall and of the endotoxin and in the inactivation of susceptible exotoxins.[3]

Medical uses[edit]

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.[4]

  • Catheter lock solution in home parenteral nutrition (HPN) / total parenteral nutrition (TPN): CRBSI remains the most common serious complication associated with long-term parenteral nutrition HPN/TPN. The use of taurolidine as a catheter lock solution shows a reduction of CRBSI.[1][5] The overall quality of the evidence however is not strong enough to justify routine use.[1][5]
  • Catheter lock solution: Taurolidine decreases the adherence of bacteria and fungi to host cells by destructing the fimbriae and flagella and thus prevent the biofilm formation.[6][7] Taurolidine is the active ingredient of anti-microbial catheter lock solutions for the prevention and treatment of catheter related blood stream infections (CRBSIs) and is suitable for use in all catheter based vascular access devices.[8][9] Bacterial resistance against taurolidine has never been observed in various studies.[10][11]
  • The use of a taurolidine lock solution may decrease the risk of catheter infection in children with cancer but the evidence is tentative.[12]

[edit]

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 [13]

Toxicology[edit]

Taurolidine has a relatively low acute and subacute toxicity.[1] 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.[13] 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.[13][14][15][16][17]

Pharmacology[edit]

  • Metabolism: Taurolidine and taurultam are quickly metabolized to taurinamide, taurine, carbon dioxide (CO2) and water (Fig 1). Taurolidine exists in equilibrium with taurultam and N-methylol- taurultam in aqueous solution.[18]
  • Pharmacokinetic (elimination): The half-life of the terminal elimination phase of taurultam is about 1.5 hours, and of the taurinamide metabolite about 6 hours. 25% of the taurolidine dose applied is renally eliminated as taurinamide and/or taurine.[14][15][19]

Mechanism of action[edit]

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.[20]

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.[15]

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).[21] 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.[22]

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).[16][17][23]

  • Gram positive bacteria minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC 1 – 2 mg/mL): Staphylococci (including multiple-antibiotic resistant coagulase negative strains, Methicillin-resistant Staph. aureus), streptococci, enterococci, pneumococci.
  • Gram negative bacteria (MIC/MBC 0.5 – 5 mg/mL): Aerobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Proteus species (indole negative), Proteus mirabilis, Pseudomonas species (including Ps. aeruginosa), Salmonella species, Serratia marcescans, Klebsiella species.
  • Anaerobes (MIC/MBC 0.03 - 0.3 mg/mL): Bacteroides species (including Bact. fragilis), Fusobacteria, Clostridium species, Peptostreptococcus anaerobius.
  • Fungi (MIC 0.3 – 5 mg/mL): Candida albicans, Cryptococcus neoformans, Aspergillus species, Trichophyton rubrum, Epidermophyton floccosum, Pitosporom ovale [11][18][23]

Chemical properties[edit]

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[edit]

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[edit]

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.[24] 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.[25][26][27] 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.[22][28]

References[edit]

  1. ^ abcdeLiu, 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. ^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. 
  3. ^Waser, P.G.; Sibler, E. (1986). "Taurolidine: A new concept in antimicrobial chemotherapy". In A.F. Harms. 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; Lipsett, PA; Masur, H; Mermel, LA; Pearson, ML; Raad, II; Randolph, AG; Rupp, ME; Saint, S; Healthcare Infection Control Practices Advisory Committee, (HICPAC) (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. ^ abBradshaw, Joanne H.; Puntis, John W. L. (2008-08-01). "Taurolidine and catheter-related bloodstream infection: a systematic review of the literature". Journal of Pediatric Gastroenterology and Nutrition. 47 (2): 179–186. doi:10.1097/MPG.0b013e318162c428. ISSN 1536-4801. PMID 18664870. 
  6. ^ abGorman, S.P.; McCafferty; et al. (1987). "Reduced adherence of micro-organisms to human mucosal epithelial cells following treatment with Taurolin, a novel antimicrobial agent". J Appl Bacteriol. 62 (4): 315–20. doi:10.1111/j.1365-2672.1987.tb04926.x. PMID 3298185. 
  7. ^ abBlenkharn, J.I. (1989). "Anti-adherence properties of taurolidine and noxythiolin". J Chemother. 1 (Suppl 4): 233–4. 
  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 Purif. 37: 179–187. doi:10.1159/000360271. 
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  10. ^Olthof, D.; Rentenaar, R.J.; Rijs, A.J.M.M.; Wanten, G.J.A. (2013). "Absence of microbial adaption to taurolidine in patients on home parenteral nutrition who develop catheter related bloodstream infections and use taurolidine lock". Clin Nutr. 32: 538–542. doi:10.1016/j.clnu.2012.11.014. 
  11. ^ abTorres-Viera, C.; Thauvin-Eliopoulos, C.; Souli, M.; DeGirolami, P.; Farris, M.G.; Wennersten, C.B.; Sofia, R.D.; Eliopoulos, G.M. (2000). "Aktivities of Taurolidine In Vitro and in Experimental Enterococcal Endocarditis". Antimicrobial Agents and Chemotherapy. 44 (6): 1720–1724. doi:10.1128/aac.44.6.1720-1724.2000. PMC 89943. PMID 10817739. 
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  13. ^ abcGong, L.; Greenberg, H.E.; et al. (2007). "The pharmacokinetics of taurolidine metabolites in healthy volunteers". J Clin Pharmacol. 47 (6): 697–703. doi:10.1177/0091270007299929. PMID 17395893. 
  14. ^ abKnight, B.I.; Skellern, G.G.; et al. (1981). "Peritoneal absorption of the antibacterial and antiendotoxin taurolin in peritonitis". Br J Clin Pharmacol. 12 (5): 695–9. doi:10.1111/j.1365-2125.1981.tb01292.x. PMC 1401955. PMID 7332737. 
  15. ^ abcStendel, R.; Scheurer, L.; 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". Clin Pharmacokinet. 46 (6): 513–24. doi:10.2165/00003088-200746060-00005. PMID 17518510. 
  16. ^ abBrowne, M.K.; MacKenzie, M.; et al. (1978). "A controlled trial of taurolin in established bacterial peritonitis". Surg Gynecol Obstet. 146 (5): 721–4. PMID 347606. 
  17. ^ abBrowne, M.K. (1981). "The treatment of peritonitis by an antiseptic - taurolin". Pharmatherapeutica. 2 (8): 517–22. PMID 7255507. 
  18. ^ abKnight, B.I.; Skellern; et al. (1981). "The characterisation and quantitation by high-performance liquid chromatography of the metabolites of taurolin". Br J Clin Pharmacol. 12 (3): 439–40. doi:10.1111/j.1365-2125.1981.tb01245.x. PMC 1401804. PMID 7295478. 
  19. ^Browne, M.K.; Leslie, G.B.; et al. (1976). "Taurolin, a new chemotherapeutic agent". J Appl Bacteriol. 41 (3): 363–8. doi:10.1111/j.1365-2672.1976.tb00647.x. PMID 828157. 
  20. ^Braumann, C.; Pfirrman, R.W.; et al. (2013). "Taurolidine, an Effective Multimodal Antimicrobial Drug Versus Traditional Antiseptics and Antibiotics". In C. Willy. Antiseptics in Surgery - Update 2013. Lindqvist Book Publishing. pp. 119–125. 
  21. ^Bedrosian, I.; Sofia, R.D.; et al. (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. 
  22. ^ abJacobi, CA; Menenakos, C.; Braumann, C. (October 2005). "Taurolidine--a new drug with anti-tumor and anti-angiogenic effects". Anticancer Drugs. 16 (9): 917–21. doi:10.1097/01.cad.0000176502.40810.b0. PMID 16162968. 
  23. ^ abNösner, 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. 
  24. ^Stendel, Ruediger; Picht, Thomas; Schilling, Andreas; Heidenreich, Jens; Loddenkemper, Christoph; Jänisch, Werner; Brock, Mario (2004-04-01). "Treatment of glioblastoma with intravenous taurolidine. First clinical experience". Anticancer Research. 24 (2C): 1143–1147. ISSN 0250-7005. PMID 15154639. 
  25. ^Calabresi, P.; Goulette, F. A.; Darnowski, J. W. (2001-09-15). "Taurolidine: cytotoxic and mechanistic evaluation of a novel antineoplastic agent". Cancer Research. 61 (18): 6816–6821. ISSN 0008-5472. PMID 11559556. 
  26. ^Clarke, N.W.D.; Wang, J.H.; et al. (2005). "Taurolidine inhibits colorectal adenocarcinoma metastases in vivo and in vitro by inducing apoptosis". Ir J Med Sci. 174 (Supplement 3): 1. 
  27. ^Stendel, Ruediger; Scheurer, Louis; Stoltenburg-Didinger, Gisela; Brock, Mario; Möhler, Hanns (2003-06-01). "Enhancement of Fas-ligand-mediated programmed cell death by taurolidine". Anticancer Research. 23 (3B): 2309–2314. ISSN 0250-7005. PMID 12894508. 
  28. ^Neary, Peter M.; Hallihan, Patrick; Wang, Jiang H.; Pfirrmann, Rolf W.; Bouchier-Hayes, David J.; Redmond, Henry P. (2010-04-01). "The evolving role of taurolidine in cancer therapy". Annals of Surgical Oncology. 17 (4): 1135–1143. doi:10.1245/s10434-009-0867-9. ISSN 1534-4681. PMID 20039217. 

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