Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo.

BACKGROUND: Former studies already revealed the anti-neoplastic properties of the anti-infective agent Taurolidine (TRD) against many tumor species in vitro and in vivo. Its anti-proliferative and cell death inducing capacity is largely due to its main derivative Taurultam (TRLT). In this study it could be demonstrated, that substance 2250 - a newly defined innovative structural analogue of TRLT - exhibits an anti-neoplastic effect on malignant pancreatic carcinoma in vitro and in vivo. METHODS: The anti-neoplastic potential of substance 2250 as well as its mode of action was demonstrated in extensive in vitro analysis, followed by successful and effective in vivo testings, using xenograft models derived from established pancreatic cancer cell lines as well as patient derived tissue. RESULTS: Our functional analysis regarding the role of oxidative stress (ROS) and caspase activated apoptosis showed, that ROS driven programmed cell death (PCD) is the major mechanisms induced by substance 2250 in pancreatic carcinoma. What is strongly relevant towards clinical practice is especially the observed inhibition of patient derived pancreatic cancer tumor growth in mice treated with this new substance in combination with its sharply higher metabolic stability. CONCLUSION: These encouraging results provide new therapeutical opportunities in pancreatic cancer treatment and build the basis for further functional analysis as well as first clinical studies for this promising agent.

Wound healing is not impaired in rats undergoing perioperative treatment with the antineoplastic agent taurolidine.

BACKGROUND/AIM: The aim of this study was to determine whether an intravenous or an intraperitoneal application of the antineoplastic agent taurolidine (TRD) impairs wound healing in the absence of tumor load in rats. METHODS: Eighty rats were randomized into eight groups (n = 10). Median laparotomy was performed in all animals. Three groups were treated by intravenous injection and three groups by local administration using a central port catheter system. For each group, 1 ml was applied: isotone sodium chloride solution (control groups), 1% TRD, 2% TRD, and 3% TRD. Fascia and skin were closed using a standardized running suture technique with 4-0 Vicryl. Wounds were evaluated once a day. Animals were treated every 8 h for 7 days (ports were then removed) and wounds were evaluated at day 28. Macroscopic and histopathologic examinations of scar tissue biopsies (hemalaun-eosin stain) were performed at the end of the experiment. RESULTS: No animal died. No relevant impairment of wound healing was observed independent of the different treatment strategies. CONCLUSION: Our results suggest that wound healing does not seem to be impaired by TRD in rats.

Leukopoiesis is not affected after intravenous treatment with the novel antineoplastic agent taurolidine. Results of an experimental study in rats.

BACKGROUND/AIM: Chemotherapy can induce serious leukopenia. The aim of our study was to investigate the effects on leukopoiesis when the antineoplastic agent taurolidine (TRD) is administered by a bolus injection or during repetitive treatment (21 cycles) over 7 days in rats. METHODS: Rats were intravenously treated with a single injection (A) or by a 7-day treatment (B) with increasing doses of TRD versus control (isotone sodium) in a standardized animal model. Hematological adverse effects on leukopoiesis were analyzed in peripheral blood. RESULTS: (A) Neither the highest TRD concentration (3%) nor 1 or 2% caused a significant difference between the control and TRD groups (p > 0.085) in the perioperative course after bolus administration. (B) The administration of TRD 3% led to a slight change of granulocyte and monocyte counts compared to the control group particularly on postoperative day 7, but this difference was not significant. In both protocols a slight postoperative increase in leukocytes was observed. CONCLUSION: We report that TRD administered intravenously in an antitumor dose does not affect leukopoiesis in rats. Thus, the agent offers a promising and safe means in cancer treatment. The effects are currently investigated in incurable cancer patients.

Studies of the thiadiazine, taurolidine-I. Identification of the molecular species present in aqueous solutions by (1)H- and (13)C-NMR spectroscopy.

The equilibria in deuterium oxide solutions of the diamine, 4,4'-methylenebis(tetrahydro-1,2,4-thiadiazine-1,1-dioxide), were studied using highfield (1)H- and (13)C-NMR with the aid of solutions of tetrahydro-2H-1,2,4-thiadiazine-1,1-dioxide (taurultam), its two N-methyl detivatives and methylene glycol. Comparison of the (1)H-NMR spectrum of taurolidine with the one obtained from a mixture of taurultam and methylene glycol indicated that the same equilibria exists in both these solutions. It was concluded that taurolidine, taurultam and its 4-hydroxymethyl adduct and methylene glycol are the major components present. To facilitate the interpretation of the (13)C-spectra, (13)C-enriched methylene glycol was added to solutions of taurultam. The (13)C-studies confirmed the (1)H-NMR study.

[Hydroxyapatite-coated total hip prosthesis. 3d-generation hip prostheses]. / Die Hydroxylapatit-beschichtete Totalprothese der Hüfte. III. Generation Hüftprothesen.

Since 1987, 80 hydroxyapatite-coated (HA) cementless total hip prostheses have been implanted. Thirty patients were examined 21 months post-operatively and the results compared with data for uncoated prosthesis. Earlier mobilisation and freedom from pain, together with evidence of bone ingrowth without connective tissue membrane formation, confirmed the benefits of HA-coated prostheses.

NMR studies and GC analysis of the antibacterial agent taurolidine.

The NMR spectrum of taurolidine in deuterium oxide was compared with spectra obtained from model experiments with amines and formaldehyde. Head-space analysis combined with capillary GC showed that there was less than 0.004% free formaldehyde present in 2% solutions of taurolidine. This value is comparable to the concentration of formaldehyde found when the taurolidine solutions were injected directly onto GC columns.

Peritoneal absorption of the antibacterial and antiendotoxin taurolin in peritonitis.

1 Taurolin metabolite plasma concentrations were measured in two groups of patient undergoing abdominal surgery, one group with peritonitis and the other without peritonitis, each group receiving taurolin by intraperitoneal instillation. 2 There was no significant difference in the area under the curves, for the two groups, for one of the metabolites. This would suggest that the absorption of taurolin was not modified in inflammatory conditions such as bacterial peritonitis.

[Focalized irrigation-lavage and sequential use of a new antiseptic by local and general route. Preliminary report apropos of 2 cases of suppurative pancreatic necrosis]. / Irrigation-lavage focalisée et utilisation séquentielle d'un nouvel anti-septique par voies locale et générale. Note préliminaire à propos de deux cas de nécrose pancréatique suppurée.

In view of the severe course seen in the presence of any suppurated pancreatic necrosis, it was felt to be of value to treat two patients by the adjuvant use of a new antiseptic tauroline, administered locally and, where appropriate, systemically. After surgical excision of pancreatic and peripancreatic necrotic tissue, the authors prefer to avoid active suction drainage of the residual pocket, replacing it by continuous and prolonged post-operative irrigation-lavage, together with the sequential, twice-daily use of a solution of 2 p. 100 tauroline. In view of the presence of a Gram negative septicemia (organisms identical to those of the suppurated area), the same substance was given by intravenous infusion in a 0.5 p. 100 solution, this being the only systemic, anti-infectious therapy. The effectiveness, good tolerance and originality of this new substance, active against Gram negative, Gram positive, aerobic and anaerobic organisms as well as yeast, have led the authors to immediately report their initial experience with its use.

[Development of new antiepileptics. IV. Anticonvulsant activity of some derivatives of 1-(p-sulfamoyl-phenyl)-pyrrolidin-2-one (author's transl)]. / Die Entwicklung neuer Antiepileptika. IV. Antikonvulsive Wirkung einiger 1-(p-Sulfamoyl-phenyl)-pyrrolidin-2-on-Derivate).

A series of derivatives of 1-(p-sulfamoyl-phenyl)-pyrrolidin-2-one were tested for anticonvulsant properties in rats and mice. The substance 1-(o-chloro-p-sulfamoyl-phenyl)-4-phenyl-pyrrolidin-2-one (1725) was found to have potent anticonvulsant activities in rats and mice against seizures induced by electroshock or pentylenetetrazol. The unsubstituted phenyl ring has to be in position 4, otherwise the activity of the product is weakened. The ortho position of the halogen atom on the N-phenyl is also important for the anticonvulsant effect; chlorine acts better than fluorine. The anticonvulsants tested also potentiate the sleeping time induced by pentobarbitone and attenuate the motor activity of mice. 1-(o-Chloro-p-sulfamoyl-phenyl)-4-phenyl-pyrrolidin-2-one (1725) has a LD50 of 1000 mg/kg p.o.; the lesser active substances generally have a LD50 greater than 5000 mg/kg p.o. Toxic effects of large doses were manifested by sedation and diarrhoea.

[Development of new antiepileptics. V. Pharmacological activity of some derivatives of sulfanilamide (author's transl)]. / Die Entwicklung neuer Antiepileptika. V. Mitteilung: Pharmakologische Wirkungen einiger Sulfanilamidderivate.

9 derivatives of sulfanilamide were tested for anticonvulsant properties against electroconvulsive shock in mice and rats and against pentylenetetrazole shock in mice. Reference standard in these tests was sulfanilamide. Their toxic, analgesic and sedative activities were also examined. The anticonvulsive activity of sulfanilamide could be enhanced by substitution of the phenyl ring with a halogen atom. Substitution of the sulfonamide group diminishes the anticonvulsant and increases the sedative activity of sulfanilamide. Detoxication of the basic substance by substitution of the aromatic amino group only little influences the anticonvulsant activity and may even enhance it. Of the tested substances, 1742 (3-chloro-4-phenacetamido-benzene-sulfonamide) exhibited the best anticonvulsant activity; slightly weaker was PB 311 (3-chloro-4-amino-benzene-sulfonamide). The ED50 for the activity against electroconvulsive shock of both substances was about 30 mg/kg p.o. in mice. The relationship between anticonvulsant activity and inhibition of the renal and cerebral carbonic anhydrase is discussed.

[Anticovulsant activity of N-(p-sulfamoyl-phenyl)-succinimide derivatives (author's transl)]. / Die Entwicklung neuer Antiepileptika. I: Antikonvulsive Wirkung von N-(p-Sulfamoylphenyl)-succinimid--Derivaten.

A series of newly synthesized N-phenyl-substituted derivatives of succinimide were screened for anticonvulsant activity. Addition of a sulfonamide group in the p-position was of great consequence for the anticonvulsant effect. Substitution of a halogen in the m- or o-position improved activity against electroshock induced seizures. Pentylenetetrazole convulsions could only be prevented by few of these substances in smaller than 200 mg/kg oral doses. Activity could be further enhanced by adding more aliphatic or aromatic groups to the succinimide ring. The lethal doses of most of the active succinimides were higher than 5000 mg/kg p.o. With sublethal doses mice sometimes become drowsy and had myoclonic seizures and/or diarrhoea. At therapeutic dose levels kinetic disturbances, potentiation of pentobarbitone hypnosis or analgesia were rarely observed.

[Development of new antiepileptics. II. Anticonvulsant effect of hydantoin derivatives]. / Die Entwicklungen neuer Antiepileptika. Teil II: Antikonvulsive Wirkung einiger Hydantoin-Derivate.

From a series of N-substituted hydantoin derivatives, 1-phenyl-3-(o-chloro-p-sulfonamide-phenyl)-hydantoin was found to exhibit the best anticonvulsant activity against electroshock seizures. This substance showed also a weak activity against pentylenetetrazole seizures, as well as minor analgesic and sedative effects. The toxic effects are negligible; the lethal dose in mice was higher than 5000 mg/kg p.o. The other tested hydantoin derivatives showed much weaker anticonvulsant activities.

[Development of new antiepileptic agents. III. Anticonvulsant activity of some derivatives of 1-(p-sulfamoylphenyl)-imidazolidinone-5 (author's transl)]. / Die Entwicklung neuer Antiepileptika. III. Antikonvulsive Wirkung einiger 1-(p-Sulfamoylphenyl)-imidazolidinon-5-Derivate).

A series of derivatives of 1-(p-sulfamoylphenyl)imidazolidinone-5 were tested for anticonvulsant properties against electroshock and pentylenetetrazole seizures. They were also screened for analgesic, sedative and toxic effects. The substances that had the best anticonvulsant activities were those with halogen substitution in the ortho position of the 1-phenylring of 1-(p-sulfamoylphenyl)-3-phenylimidazolidinone-5. Additional substitutions on the basic structure (imidazolidinone-5) or on the 3-phenylring diminished the anticonvulsant activity. The anticonvulsants are less toxic than diphenylhydantoin. Some of the substances exhibited feeble analgesic and sedative properties.