Myocardial protection by antioxidant during permanent and temporary coronary occlusion in dogs.

In an ischaemic heart model the lipid peroxidation, scavenger state and ultrastructure were studied, to determine the action of a new antioxidant of dihydroquinoline type (MTDQ-DA). In dog experiments, the left descending coronary artery (LAD) was ligated permanently (30 minutes, 1, 2 or 3 hours) or temporarily (30 minutes, 1 or 2 hours of ischaemia followed by 1 hour of recirculation). The experimental protocol involved two groups: control animals without antioxidant treatment and animals treated with antioxidant infusion during the ischaemic and reperfusion period. In both groups, the thiobarbituric acid reactive product, the malondialdehyde (MDA), reduced glutathione (GSH) and superoxide dismutase (SOD) were measured, to illustrate the injured or scavenged state of the membrane system. In nontreated animals the permanent and temporary LAD increased the MDA content, decreased GSH concentration (mainly during reperfusion) and reduced SOD activity. Treatment with MTDQ-DA diminishes the characteristic biochemical changes. According to ultrastructural investigations, irreversible alterations (Ca deposits in the mitochondria, disruption of intramitochondrial membranes, hypercontraction bands) occurred only in the control group. Anti-oxidant therapy is able to reduce the myocardial damages both quantitatively and qualitatively.

Promising reduction of ventricular fibrillation in experimentally induced heart infarction by antioxidant therapy.

Studies were undertaken using a synthetic free radical scavenger (MTDQ-DA) on regional ischaemic dog hearts; it was found that the rate of malignant ventricular arrhythmias and fibrillation after coronary ligature unexpectedly decreased. According to experiments on 22 dogs, the intravenous MTDQ-DA therapy decreases the unfavourable ECG consequences of left anterior descending branch ligature: already 5 to 10 minutes after drug administration the ST segment elevation, the QT interval lengthening and the occurrence of ventricular extrasystoles and salvos are diminishing. The so-called epicardial ST map ameliorates rapidly. MTDQ-DA as a blocking agent of free radicals is able to prevent the irritative stimuli around and in the border zone of an infarct, has a vigorous anti-arrhythmogenous effect and greatly reduces the electric heterogeneity. These unexpected results may lead to a promising therapy for the acute heart infarction.

Effects of antioxidant therapy in experimentally induced heart infarcts.

Experiments were performed on dog hearts following coronary ligation and treatment with synthetic antioxidant of dihydroquinoline type. Experimental groups were: control dogs, dogs with ligation of descendens anterior coronary branch, coronary ligated dogs with antioxidant pretreatment and dogs with coronary ligation and simultaneous antioxidant infusion therapy. The heart infarction per se is accompanied by the disintegration of membrane polyunsaturated fatty acids expressed by increase of malondialdehyde (MDA) concentration and the impairment of natural scavenging characterized by the decrease of superoxide dismutase (SOD) and reduced glutathione (GSH) content. The oral pretreatment with antioxidant for 8 days prevented or decreased the unfavourable pathobiochemical responses. The acute infusion therapy exerted no immediate protection, nonetheless, it could decrease the severity of pathological signs.

[Clinical experiences with the radiation sensitizer MTDQ (Sensorad) in advanced malignancies of the head and neck region and in uterine cancer]. / Klinische Erfahrungen mit dem Radiosensitizer MTDQ (Sensorad) bei fortgeschrittenen Malignomen des Kopf-Hals-Bereiches und bei Gebärmutterkrebs.

33 patients with malignancies of the head and neck and 9 patients with carcinoma uteri received Sensorad combined with megavolt-therapy in a placebo controlled trial. 35% of the Sensorad treated patients with head and neck cancer showed an early radiomucositis. A full regression was achieved in 15 patients and a partial regression in 18 patients thus the drug helped in 79% of the patients treated. No regression was noted in 6 patients and a progression in 3, that means in 21% of patients no benefit was detected. In the placebo control group a benefit was proved for 35% of the patients whereas 65% of the patients showed no benefit. The proportion of benefit to no benefit was 3.66 in the Sensorad group compared to 0.54 in the placebo group. The patients with carcinoma uteri all showed a benefit from the treatment with Sensorad. The number of adverse reactions was small. 4 patients had nausea and gastrointestinal symptoms, 2 allergic reactions and 3 elevated SGOT (21.4%).

Experimental models for the study of hepatoprotection.

In the therapy of chronic liver diseases several drugs are currently used. This review summarizes the results of the authors in the therapy of chronic liver diseases with cyanidanol-3, as well as the beneficial effects of the new dihydroquinoline-type antioxidants in acute carbon tetrachloride induced and galactosamine induced liver lesions. In addition, the immunostimulant effects of Aicaphosphate is demonstrated in chronic active hepatitis.

Liver lipid peroxidation induced by cholesterol and its treatment with a dihydroquinoline type free radical scavenger in rabbits.

Lipid peroxidation has been induced by means of an atherogenic diet causing hypercholesterolaemia, hypertriglyceridaemia, increased LDL and decreased HDL serum fractions in addition to the fatty degeneration, vacuolization of the liver cells and accumulation of malondialdehyde in the liver. Increased release of acid phosphatase and N-beta-glucuronidase was also observed pointing to cholesterol-induced lysosomal membrane damage. In response to pretreatment with, and simultaneous administration of, 6,6'-methylene bis (2,2-dimethyl-4-methane sulphonic acid sodium salt-1,2-dihydroquinoline) the signs and symptoms of fatty liver degeneration, the tissue, plasma and platelet malondialdehyde concentrations and the LDL serum fraction significantly decreased and HDL serum fraction increased. Lisosomal membrane stability was restored, resulting in physiological acid phosphatase and N-beta-glucuronidase activities. The pathological and clinical aspects of lipid peroxidation in several diseases of the digestive organs and the suggested therapeutic uses of non-toxic radical scavengers have been outlined.

Biochemical markers in carbon-tetrachloride-and galactosamine-induced acute liver injuries: the effects of dihydroquinoline-type antioxidants.

The pharmacological action and possible therapeutic uses of some recently developed synthetic, non-toxic dihydroquinoline-type antioxidants were studied. The effect of the lipid-soluble 6,6-methylene-bis (2,2,4-trimethyl-1,2-dihydroquinoline) (n = 1, 2 or 3) (MTDQ) on carbon-tetrachloride-induced acute liver injuries was investigated, and that of the water-soluble 6,6-methylene-bis (2,2-dimethyl-4-methansulphonic acid sodium-1,2-dihydroquinoline) (MDS) on galactosamine-induced acute liver injuries in CFLP mice (Lati, Hungary). MTDQ was found suitable for the prevention of acute CCl4-induced liver injuries and MDS for that of acute galactosamine-induced liver injuries. Disappearance or significant diminution of the morphological signs and lesions of lipid degeneration and centro-lobular liver necrosis, decrease of serum GOT activities, and also inflammatory changes induced by galactosamine were observed.

Acute carbon tetrachloride induced lysosomal membrane damage and the membrane protecting effect of a new dihydroquinoline-type antioxidant.

The authors examined the damage of lysosomal membrane caused by acute CCl4 intoxication by in vitro methods. They measured the acid phosphatase as well as beta-glucuronidase enzyme levels and determined the rate of release of these two enzymes. The in vivo changes in enzyme activity were extrapolated from the in vitro results. The CCl4 causes a significant increase in the permeability and rigidity of the lysosomal membrane. By oral and/or intraperitoneal administration of MTDQ the state of permeability can be improved or even corrected. On the basis of their results, the authors conclude that the lysosomal damage caused by CCl4 is mediated by peroxidation of lipids and the lysosomal membrane can be stabilised by MTDQ.

Clinical trials with MTDQ /6,6'-methylene-bis (2,2,4-trimethyl-1,2-dihydroquinoline)/ an antioxidant with radiation sensitizing effect.

Daily doses of 1320 mg MTDQ have been administered orally to 7 patients for 100 subsequent days. Biological half-life and serum concentration measurements were performed. Function of vital organs, as well as routine laboratory findings revealed that MTDQ did not induce any toxic changes. The effect of MTDQ on the radiosensitivity of hypoxic tumor cells was studied in a combined treatment modality including 12 patients. The action on tumor regression was found encouraging. It has been found remarkable, too, that due to the effect of MTDQ and radiotherapy some of the nonspecific and general symptoms (e. g. pruritus) also disappeared.

Basal cell carcinoma treated with MTDQ and irradiation.

Patients with basal cell carcinoma of the skin were treated with combined MTDQ (6,6'-methylene-bis-(2,2,4-trimethyl-1,2-dihydroquinoline)) administration and irradiation. Significantly better results were obtained with a skin exposure of 2 000 R combined with MTDQ than with the same dose alone. The results were comparable to those obtained with an exposure of 4 000 R. MTDQ administration induced decrease of tissular malonaldehyde concentration and suggested the peroxide-decomposing action of the radiation sensitizer.

[Study of the biochemical and radiochemical effects of the agent MTDQ (author's transl]. / Beitrag zu den bio- und radiochemischen Wirkungen der Verbindung MTDQ.

The antioxidant MTDQ exhibits a radiosensitizing effect and was used in pretreatment of radiation-resistant human tumors, e.g. synoviomas, sarcomas, von Recklinghausen disease. After this premedication and fractionated radiation therapy of different kinds a permanent regression of the tumors was observed. The radiosensitizing compound is non-toxic and selectively accumulates in tumorous tissues. The chemical structure (three functional groups) and in vitro tests make probable that the main factors in the mechanism of action are peroxide decomposition, hydrol formation, polymerization and, in the course of those reactions, the in situ release of oxygen.

Biopharmacological investigation of 6,6'methylene-bis/2,2,4-trimethyl-1,2-dihydroquinoline (MTDQ) a radical binding antioxidant of secondary amine type.

The evidence of free radicals in tumor tissue and the possibility of their experimental influencing by means of antioxidants justifies the search for new pharmacological groups of tumor inhibiting agents. The authors synthesized a sterically inhibited, heterocyclic, bifunctional, non-toxic radical binding antioxidant of secondary amine type. The structural change is interpreted with the possibility of recombination characteristic for secondary amine groups and the double chain closing effect. The conjugation effect secures mobility of the hydrogen atom. The compound contains 10 to 12 per cent dimer-trimer of higher biological activity than monomers, due to higher molecular weight. An additional pharmacodynamic advantage compared to hitherto known antioxidants consists in its lower vapour volutility and the biradicality.

[Investigation on radiosensitizing and tumor inhibiting actions of the antioxidant MTDQ (6,6'-methylen-bis/2,2,4-trimethyl-1-1,2-dihydroquinolin) (author's transl)]. / Untersuchung der radiosensibilisierenden und tumorhemmenden Wirkung des als MTDQ (6,6' methylen bis/2,2,4-trimethyl-1,2-dihydroquinolin) bezeichneten antioxidans

Unlike the hitherto known antioxidants, MTDQ is not a radiation protective-but a radiation sensitizing agent. According to autoradiographic findings accumulation of 14C-labelled MTDQ occurs in tumor tissue. The compound was found to be suitable in the combined treatment (MTDQ and 300 R x-ray therapy). In these instances tumor weight of solid Ehrlich- and Yoshida-tumors will be reduced even by doses ineffective as monotherapy. The MTDQ pretreatment of NKLy ascites tumorbearing rats raised survival rat by 60 to 90 per cent (controls 20%) and inhibited growth of solid Yoshida-tumors. No side-effects have been observed. In contrast to other antineoplastic agents MTDQ does not induce granulocytopenia.