taurolidine and taurultam , its intermediate and active metabolite , are methylol transfer agents . they act by transferring methylol groups at the site of action . both substances have low toxicity and are not cytotoxic against normal cells . this invention provides for treatment and / or prophylaxis of tumors and / or suppressing of primary and secondary tumors of the central nervous system in mammalian subjects wherein an effective dose of a methylol transfer agent such as taurolidine and / or taurultam is administered to a mammalian subject suffering from or at risk of central nervous system tumor growth . furthermore the invention includes special methods for local application of taurolidine and / or taurultam in solution using microdialysis methods , irrigation methods , implantation methods , and angiographic methods . the terms taurolidine and / or taurultam as used herein are intended to refer to the compounds taurolidine , taurultam , taurultam - glucose ( as described below ), and their substantial bioequivalents or agents which act in a substantially similar manner . for example , an aminoglycan derived from taurultam and any other suitable derivate of taurolidine and / or taurultam , or agents which act in a substantially similar manner , can be utilized like taurolidine and / or taurultam according to the invention . the term “ treatment ” as used herein is intended to refer to treatment , prophylaxis and / or suppression of cns tumors . the present invention is applicable to treatment of cns tumors , which may include : treatment takes place primarily in connection with surgical intervention , such as surgical removal of a cns tumor , as well as postoperative local application of taurolidine and / or taurultam solution while using , for example , a microdialysis method or an irrigation method . since the blood / brain barrier is passed by taurolidine and / or taurultam , it also may be appropriate to administer 2 % taurolidine solutions or 3 % taurultam solutions intravenously through a central catheter . here , in addition to the antineoplastic action , prevention of infection is also of great advantage for the patient . in this connection , dosage appropriately may be 15 - 20 g of taurolidine as a 2 % solution through a central catheter daily for 7 - 8 days , or alternatively as 3 % taurultam solution , 20 - 30 g taurultam daily , for 7 - 8 days with adults . this is intended to preserve or improve neurological function and health - related quality of life . for local application in connection with operations in the brain , glucose - based solutions , with or without electrolytes , and which additionally contain 0 . 2 - 1 % taurolidine , taurultam or taurultam - glucose , are preferred . basic treatment solutions preferably are modeled after cerebrospinal solution , contain glucose and electrolytes , are substantially isotonic to the extent possible and have a slightly alkaline ph value of about 7 . 3 - 7 . 35 . the following ingredients may be included in a basic solution : taurolidine , taurultam , taurultam - glucose or the like are added to a basic solution . a basic solution may , for example , be comprised of cerebrospinal fluid ( csf ) components as shown in the following table . 13 . 6 g taurultam and 18 g of anhydrous glucose were weighed out into a 250 ml serum bottle , and 200 ml of distilled water were added . the solution obtained was heated to 100 ° c . for 30 minutes . the clear solution was evaporated in a vacuum until dry . the residue was absorbed in 96 % alcohol and placed in an erlenmeyer flask overnight for forming crystals . amino - sugar / taurultam - glucose crystallized out , and the crystals were suction filtered with a raw yield of 5 . 3 g . from alcohol mixed with a few drops of water , white crystals were recrystallized : the ir spectrum corresponded nmr in dmso 6 200 mhz . sulfonamide nh coupling to its adjacent ch 2 , one oh coupling to ch 2 and three oh &# 39 ; s couplings to ch indicated internal loss of water and that the chain had cyclised to form a sugar . the solutions 1 and 2 are filtered in an appropriately sterile manner with a 0 . 1 micron sterile filter and aseptically deposited in sterile infusion bottles . the ph is set at 7 . 3 . the solution is filtered in a sterile manner and aseptically deposited in 100 ml infusion bottles . the solution is set at a ph of 7 . 5 prior to sterilization and subsequently filtered in a sterile manner , deposited in 250 ml infusion bottles and sterilized with steam for 15 minutes at 121 ° c . taurolidine and / or taurultam may be administered by injection or infusion , or by local application . isotonic glucose solution and / or artificial cerebrospinal fluid solution as described above may be used containing taurolidine and / or taurultam , or a substantial bioequivalent thereof . the local administration can be performed via ( a ) microdialysis using a probe tube , and ( b ) direct irrigation and / or implantation of a catheter , and single or repeated irrigation . a microdialysis - method can be utilized in nonextirpated tumors or reoccurrences as well as in inoperable tumors , e . g ., diffuse brain stem gliomas . an irrigation / catheter method may be utilized following complete or incomplete tumor extirpation . an isotonic solution as described above , is stored at body temperature in a tank . a small pump ( subcutaneous or outside the body ) forces the taurolidine and / or taurultam solution via tubular microprobe to the tumor and / or its surrounding . the microprobe may be formed of plastic material with a small lumen . the tip of the probe may have a semipermeable membrane so that an osmotic fluid exchange can occur . in this way , the taurolidine and / or taurultam can diffuse inside the tumor and its surroundings . different types of probes can include a probe with a small tip to terminate directly inside the tumor . with large tumors , a large membrane can be provided at the end of the probe to lie inside the tumor cavity or on the surface of the tumor . in some cases with large tumors , it may be necessary to implant more than one probe . following removal of a tumor , or with cystic tumors , direct single or repeated irrigation of the tumor cavity or area may be performed . furthermore , a catheter can be implanted in the tumor cavity for repeated local administration with taurolidine and / or taurultam . another method for regional application of taurolidine and / or taurultam may be provided for tumors with blood supply by one or a few dominant feeder arteries . taurolidine and / or taurultam may be administered by an angiographic catheter , which may be introduced supraselectively into the feeders . the taurolidine and / or taurultam then may be administered once or repeatedly . following complete or incomplete removal of a tumor , direct single or repeated implantion of a matrix containing taurolidine and / or taurultam into the tumor cavity may be performed . taurolidine and / or taurultam have been found to inhibit directly the growth of cns tumor cell lines , including neuronal ( ht22 ) as well as glial ( c6 ) tumor cell lines . furthermore , this action was shown to be selective in that the growth of primary cell lines of a fetal rat central nervous system required significantly higher concentrations and a significantly longer contact time for inhibition , as compared to tumor cells ( taking into account a very high general sensitivity of primary cell lines of the fetal rat central nervous system ). the effect was concentration - dependent . antineoplastic effects of concentrations of 0 . 1 to 4 mg / ml taurolidine and / or taurultam in pvp and glucose solution was demonstrated . the tumor cells were inhibited starting after 10 minutes . following about 1 to 2 hours 90 % of the tumor cells were inhibited . the tumor - inhibiting agents of the present invention , including taurolidine and / or taurultam , may be administered by injection or infusion . agents in accordance with the present invention may be administered locally using microdialysis utilizing probes , as well as regionally using superselective angiographic catheters with continuous or sequential administration of an agent in accordance with the present invention . probes for practicing a microdialysis method in accordance with the invention can be placed using neuronavigation , mri guidance and / or ultrasound guidance . a diagnostic biopsy can be taken from the tumor to make a histological diagnosis during the same surgical procedure in which treatment utilizing a microdialysis method in accordance with the invention is utilized . alternatively , during a microdialysis method in accordance with the present invention , fluid can be obtained from the tumor or its surroundings so as to maintain a desired fluid level in the area of the tumor . an agent in accordance with the present invention can be administered by a permanently or temporarily implanted catheter for continuous or repeated local irrigation of a tumor or its surroundings . the treatment agent can be administered locally by irrigation of the surroundings of a totally or partially extirpated tumor . in preferred embodiments , taurolidine and / or taurultam is administered intravenously in a dosage range of about 50 - 500 mg / kg per day , sequentially or by continuous administration . separately or simultaneously with administration of a methylol transfer agent in accordance with the present invention , other agents can be administered to the patient , including cytotoxic , antineoplastic agents ( including alkylating agents , and / or agents involved in tumor metabolism ). alternatively or additionally , if desired , other tumor treating agents may be administered , such as interleukin - 1 , interleukin - 2 , interferon , or other immunomodulating agents . 1 ) synergic effects may be realized from employment of a combination therapy with regard to achievement of tumor control and survival improvement . 2 ) dosage reduction in administration of antineoplastic medicaments will lead to amelioration of the considerable side effects , such as hair loss , nausea , vomiting , diarrhea , etc . 3 ) combination therapy allows for different ways of application of the medicaments , e . g ., local taurolidine / taurultam administration , systemic general chemotherapy , etc . taurolidine and / or taurultam can be administered by intraperitoneal application in combination with local inthratecal or intravenous general chemotherapy . this combined administration facilitates prevention of development of metastates and dissemination thereof into the liquor and into the brain during laparotomy or laparoscopic tumor surgery . taurolidine and taurultam have been found to inhibit directly the growth of neuronal ( ht22 , mouse ), glial ( c6 , rat ), and mixed neuronaland glial ( u373 , human ) tumor cell lines . for the latter cell line , however , the experiments are not complete as yet . furthermore , this action was shown to be selective in that the growth of normal central nervous system cells was not significantly inhibited . the effect was concentration - dependent . antineoplastic effects of concentrations of 0 . 1 to 4 mg / ml taurolidine and / or taurultam was demonstrated . the tumor cells were inhibited selectively beginning after 30 minutes . following 1 to 3 hours about 90 % of the tumor cells were inhibited . for the cell culture , cells were used in rpm1 1640 medium and plated in falcon flasks . following incubation with 0 . 1 - 4 mg / ml taurolidine and taurultam , cytological changes were recorded after 10 , 30 , 60 , 120 , 180 , 300 minutes , and after 24 and 48 hours . beginning following 30 minutes , cytological changes were observed , including : ( a ) development of vacuoles , and ( b ) condensation of nuclei , shrinking of cytoplasm , and cell death . ultrastructural changes include : swelling of mitochondria , swelling of nuclei , swelling of cytoplasm , and rupture of cell membrane . the first changes occurred after 10 minutes , increasing with time and concentration . the effect of taurolidine / taurultam on primary cns - cells was investigated using the brain cells of rat fetuses in a cell culture . we found no significant cytological effect following 48 hours . for treatment of glioma patients , taurolidine and / or taurultam may be administered by injection or infusion , or by local application . the local administration can be performed via ( a ) microdialysis using tubular probes , and ( b ) direct irrigation and / or implantation of a temporary or permanent catheter , and single or repeated irrigation . the microdialysis - method can be utilized in nonextirpated tumors or reoccurrences as well as in inoperable tumors , e . g ., diffuse brain stem gliomas . the irrigation / catheter method may be utilize following complete or incomplete tumor extirpation . combined therapy with taurolidine and additionally antineoplasatic agents in patients with glioblastoma , gliosarcoma , anaplasatic glioma and astrocytoma the combination of taurolidine / taurultam with antineoplastic agents for treatment of brain tumors such as glioblastoma , astrocytoma and gliosarcoma offers a number of advantages . the combination of , for example , alkylated agents and taurolidine and / or taurultam avoids or reduces side effects such as nausea , vomiting , diarrhea , etc ., induced by use of antineoplastic medicaments . the dosage of these antineoplastic medicaments can be reduced by up to half or more and still increase the overall response rate ( disease stabilization rate ) by synergic effects . radiotherapy with its strong side effects can also be avoided or reduced in many cases . the recurrency rate of dissemination of tumors in primary brain tumors in glioblastoma miltiforma and astrocytoma can also be reduced by a combined therapy . of various antineoplastic agents , those medicaments should be chosen which , due to their molecular structure , are unlikely to interact with taurolidine and / or taurultam . it is also preferable to direct the combined chemotherapy at the tumor in different ways , e . g ., locally to the brain tumor via direct irrigation of taurolidine and / or taurultam , or by implantation of a permanent catheter , or via microcialysis in using tubes , and by established chemotherapy i . v . or orally , e . g . by administration of temozolamide 100 mg / m 2 once daily for 5 days . alternatively , after surgical resection of glioblastoma , localized and sustained delivery of 5 - fluorouracil ( f - fu ) can be provided in combination with taurolidine and / or taurultam via central catheter as drop infusion for several days . in cases of laparoscopic emergency surgery of tumors , laparoscopic cholecystectomy , cholecystitis , laparoscopic cholorectal surgery , etc . in tumor patients as well as in general laparotomy , the intraperitoneal administration of 2 % taurolidine as lavage or instillation in combination with regular i . v . chemotherapy for combating tumors , prevention of metastases and dissemination in the brain , is posssible . in leptomeningeal dissemination of malignant glioma ( meningeal gliomatosis ) associated with poor survival intrathecal ( it ) chemotherapeutic agents used in combination with local or systemic administration of taurolidine and / or taurultam solutions to achieve tumor control and improve survival , may be helpful . the following antineoplastic agents may be compatible for combination with taurolidine and / or tarultam : the nitrosourea medicaments such as acnu / bcnu / ccnu are generally applied in lower concentration , e . g ., 30 - 50 mg / m 2 i . v . once per week of 6 weeks . temozolamide is given orally in a dosage of 50 - 100 mg / m 2 for 5 days . mx - 2 - hydrochlorid is given as antra venous bolus at 20 mg / m 2 every 28th day for several months until progression occurs . cytosinarabinosides ( ara - c ), thiotriethylene - phosphoramide ( thio - tepa ), and neocarzinostatis can be administered in low doses in it - chemotherapy in various combinations with taurolidine and / or taurultam for improvement of survival and achievement of tumor control and prevention of dissemination , respectively . the solution for delivery to a patient should contain an effective dosage of taurolidine and / or taurultam and / or taurultam - glucose in the tissue - culture of glioblastoma multiform - tumor cells : as little as 0 . 1 - 4 mg / ml taurolidine inhibits or kills tumor cells in tissue - culture . taurultam so far has been shown to be almost twice as effective as taurolidine , the explanation of which may be found in the equilibrium of taurolidine in aqueous solution between methylol - taurultam and taurultam . taurultam - glucose , on the other hand , has to be dosaged about twice as high as taurultam , as the molecular weight from taurultam increases from 136 to 298 . when administered to patients utilizing the irrigation / catheter method described above , a concentration of at least about 4 mg / ml taurolidine , taurultam or taurultam - glucose , respectively , should be utilized .
reaction products of taurultam and glucose are useful as antineoplastic agents . they are produced by reacting an aqueous solution of taurultam and glucose at about 100 degrees celsius for about 30 minutes , yielding a reaction product which has a melting point of 168 to 170 degrees celsius .