Effect of a number of sulfur-containing radioprotective agents on the evacuatory function of the stomach in mice

Tests staged on mongrel albino mice demonstrated that sulphur-containing radioprotectors used in doses two orders below those exercising a radioprotective action with their peroral administration are apt to significantly modify the evacuative function of the stomach. This properties of the sulphur-containing radioprotectors depends upon their chemical structure. A particularly strong influence on the evacuative function of the stomach in mice exerts cystamine dichlorohydrate, aminoalkylamino-alkylthiophosphates and mercaptoamidines. This property is less pronounced in cystaphos and cysteamine chlorhydrate. The least effect on the delayed evacuation was found in cysteamine bitartrate and in the disodium salt-4, 4(1)-trithiobis (butane-sulphonate). These data allow it to explain the specificity of the toxic and radioprotective action produced by diverse drugs with their peroral administration.     

Coloplasty for congenital short colon

The radioprotective properties of 12 compounds of 9a-homo-13-thiaprostanoid series were investigated under gamma irradiation using the molecular model of beta-carotene radio-oxidation in oleic acid in vitro, erythrocyte radiomimetic model in ex vivo-in vitro system as well as in vivo radiation damage in mice. Most of these compounds stimulated the radio-oxidation of beta-carotene, however in this model two prostanoids with natural alpha-chain displayed radioprotective properties. Expressed membrane stabilizing effect of two 9a-homo-13-thiaprostanoid nor-analogues was revealed in radiomimetic model experiments. Two 10, 10-dimethyl-13-thiaprostanoids raised animal radioresistance during in vivo experiments.     

Radioprotective effects of basic copper carboxylate complexes

The radioprotective activity of eight selected copper (II) carboxylates--Cu (RCOO)2.nL (R = alkyl, aryl, 2-furyl and 2-thienyl; L usually represents water)--was assayed in a model of lethally gamma-irradiated (9 Gy, 0.97 Gy/min) mice. The compounds tested were applied (as solutions in saline) s.c. in three single doses of 20 mumol/kg 48.24 and 6 h before irradiation. The highest radioprotective effects were measured by survival of mice achieved after premedication of animals with copper (II) 2-thenoate monohydrate (77%), copper (II) acetylsalicylate (64%), copper (II) 2-methoxybenzoate monohydrate (62%) and copper (II) acetate monohydrate (54%). On the other hand, survival of vehicle-pretreated mice was only 10%. The observed biological properties of complexes are discussed in relation to their structures.     

Effects of combination of immunomodulators and an adrenochrome derivative on survival of irradiated mice

PURPOSE: The combined effects of immunomodulators (lithium or OK432) and an adrenochrome derivative (AMM), an agent found to activate granulocyte-macrophage colony stimulating activity, on the survival of irradiated ddY mice is described. METHODS AND MATERIALS: ddY mice at 4-5 weeks old were whole body irradiated with X rays at 8.5 Gy. Sole injection and combined injection of AMM and/or one of the immunomodulators were performed before or after irradiation. Then, survival was monitored daily for 30 days after irradiation. RESULTS: Lithium at 60 mg/kg had no radioprotective effect; rather it accelerated radiation induced death. Sole treatment with AMM (100 mg/kg) had no effect on survival of irradiated mice. However, combination of both drugs caused a slight radioprotection. OK432 (25 KE/kg), which activates a variety of cellular effector cells had radioprotective effect. When combined with AMM, however, it totally lost radioprotective effect. CONCLUSION: Lithium chloride cannot be used as a radioprotector because of its adverse effect. Combination with AMM showed slight radioprotection, but the extent thereof may not be clinically useful. OK432 was proved to be a potent radioprotector. However, combination with AMM should be avoided, since the radioprotection was totally eliminated.     

Might intrinsic radioresistance of human tumour cells be induced by radiation?

Survival measurements were made on six human tumour cell lines in vitro after irradiation with single doses of X rays. Doses up to 5 Gy were used giving surviving fractions down to 20%, but the majority of the measurements were made at doses < 1 Gy. These six cell lines have very different intrinsic radiosensitivities: HT29, Be11, and RT112 are radioresistant with surviving fractions at 2 Gy (SF2) between 60 and 74%, while MeWo, SW48, and HX142 are radiosensitive (SF2 = 3-29%). For all the cell lines, response over the dose range 2-5 Gy showed a good fit to a Linear-Quadratic (LQ) model. However, HT29, Be11, and RT112 cells showed a significant increase in X-ray radiosensitivity at doses below < 1 Gy compared with the prediction extrapolated from a LQ model fitted to the data at higher doses. The LQ model also slightly underpredicted the effect of low-dose X rays in MeWo cells, but the response of SW48 and HX142 cells was well described by the LQ model at all doses, with no evidence of increased low-dose effectiveness. The most plausible explanation for this phenomenon is that it reflects an induced radioresistance so that low doses of X-rays in vitro are more effective per Gy than higher doses, because only at higher doses is there sufficient damage to trigger repair systems or other radioprotective mechanisms. It follows that variation in the amount of inducible radioresistance might explain, in part, differences in intrinsic radiosensitivity above > 1 Gy between cell lines: cells would be intrinsically radiosensitive because they have a diminished inducible response.     

Hypersensitivity following low one-time irradiation dosage and induced radio resistance

There is now little doubt of the existence of radioprotective mechanisms, or stress responses, that are upregulated in response to exposure with small doses of ionizing radiation and other DNA-damaging agents. Phenomenologically, there are two ways in which these induced mechanisms operate. First, a small conditioning dose (generally below 30 cGy) may protect against a subsequent, separate irradiation. This has been termed the adaptive response. Second, the response to single doses may itself be dose-dependent so that small acute radiation exposures are more effective per unit dose than larger exposures above the threshold where the induced radioprotection is triggered. This combination has been termed low dose hypersensitivity (HRS) and induced radioresistance (IRR) as the dose increases. Both the adaptive response and HRS/IRR have been well documented in studies with yeast, bacteria, protozoa, algae, higher plant cells, insect cells, mammalian and human cells in vitro, and in studies on animal models in vivo. There is indirect evidence that the adaptive response and the IRR phenomenon in response to single doses is a manifestation of the same underlying mechanisms, namely an increase of the amount and rate of DNA repair induced by low radiation doses.     

In vivo protective effects of tetrapeptide AcSDKP, with or without granulocyte colony-stimulation factor, on murine progenitor cells after sublethal irradiation

Acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) demonstrated hemato-protective activity in mice after sublethal irradiation (7 GY). Bone marrow interleukin-3 (IL-3)-responsive colony-forming cells (CFC and high proliferative potential colony-forming cells (HPP-CFC) were significantly (p < 0.05) increased by day 10 after irradiation in mice receiving a continuous infusion of 1000 ng/day of AcSDKP compared to irradiated control mice. The maximum protective effect for bone marrow progenitors was achieved when AcSDKP was administered for 3 days beginning 24 hours before irradiation. Other dosages and schedules in relationship to irradiation were less active. Further, when granulocyte colony-stimulating factor (G-CSF) was administered for 10 days beginning 24 hours before irradiation. Other dosages and schedules in relationship to irradiation were less active. Further, when granulocyte colony-stimulating factor (G-CSF) was administered for 10 days after AcSDKP infusion in irradiated mice, significantly increased numbers of IL-3 responsive CSF-only control mice. In addition, platelets were significantly (p < 0.05) increased in mice receiving AcSDKP and G-CSF on days 18 and 21 after irradiation compared with mice receiving G-CSF alone. We conclude that ACSDKP has a radioprotective effect in vivo for progenitor cells, and that time of initiation and duration of AcSDKP administration relative to irradiation are crucial for these effects. Further, AcSDKP has a significant additive protective effect not only for progenitor cells but also for platelets when given in combination with G-CSF. We suggest that these in vivo observations provide a basis on which to design optimal clinical hypothesis and protocols.     

Toxicity and side effects of antibiotics in radiation sickness and during the use of aminothiol group radioprotective agents

It was shown in experiments on mice, rats and rabbits that resistance of animals in the state of acute radiation sickness to severe intoxication by aminoglycoside antibiotics, such as streptomycin, dihydrostreptomycin and monomycin did not significantly change. The exception was kanamycin the toxicity of which during the period of the acute state of radiation sickness increased by 30 per cent. The use of cystamine and merkamine before irradiation or their administration to non-irradiated animals resulted in lowering of the antibiotic tolerance by 1.5--2 times. The above aftereffects of the radioprotectors was observed within 3--12 days after their use and was most pronounced for the combination of cystamine and streptomycin. The acute toxicity of tetracyclines did not significantly differ at various stages of radiation disease and at the background of cystamine use. No significant cumulation of the toxicity of aminoglycoside antibiotics and tetracyclines or signs of adaptation in the healthy and irradiated animals was observed on prolong treatment with therapeutic doses. Cystamine had no effect on the tolerance of the antibiotics on their prolonged use.     

Ergot alkaloids. Current status and review of clinical pharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology

Ergot alkaloids are well known preparations. Ergot alkaloids used in obstetrics and gynaecology are ergometrine (ergonovine; EM), methylergometrine (methergine; ME) and bromocriptine. The pharmaceutical properties of ME EM) are critical. To guarantee stability, ME and EM ampoules should be stored in a cool, dark place. ME and EM tablets are unstable in all conditions and they show an unpredictable bioavailability, which prevents oral use of the drugs for any purpose. ME and EM are known for their strong uterotonic effect and, compared with other ergot alkaloids, for their relatively slight vasoconstrictive abilities. ME and EM do have a place in the management of the third stage of labour as they are strong uterotonics. They act differently from oxytocin and prostaglandins, and have different adverse effects. Oxytocin should be used as prophylaxis or a the drug of first choice; next, ME or EM should be used, and if none of these drugs produce the desired effects, prostaglandins should be used to control bleeding. Ergot alkaloid use in gynaecology has been limited and today is discouraged even in essential menorrhagia. It is suggested that EM and ME be used (parenterally) only in first trimester abortion curettage, to reduce blood loss. Bromocriptine has been used for lactation suppression. However, alternatives such as cabergoline, which possess fewer adverse effects, are now available and therefore preferred for this indication. In sum, there is no place for the prophylactic use of ME and EM in obstetrics or gynaecology. They can be used for therapeutic purposes in the third stage of labour. During use, the practitioner must be alert for adverse effects.     

Effect of hyperthermia on the radiosensitivity of normal and malignant cells in mice

The effect of systemic hyperthermia on the in vivo radiation response of normal and malignant mouse cells was evaluated. X-irradiation of L1210 cells and Ehrlich ascites cells at body temperatures above 41 degrees C resulted in strongly enhanced tumor cell death. The magnitude of this thermal effect increased with increasing temperatures. Hypoxic tumor cells were particularly sensitive to combined heat-radiation treatment. L1210 leukemia cells did not become resistant to the sensitizing effects of hyperthermia even after repeated heat exposures over several transplant generations. The sensitizing action of hyperthermia varied with different heating strategies. Heating before or during irradiation did not materially alter the radiation response of tumor cells. Maximal potentiation of radiation damage was achieved only when the tumorous mice were subjected to at least 20 minutes heat incubation after irradiation. LD studies on ICR mice revealed that moderate hyperthermia (41.5 degrees C) does not alter the radiation response of normal body tissues. These findings indicate that it is possible to devise hyperthermic treatment regimens that drastically enhance radiation-induced tumor cell death in vivo without reducing the radioresistance of normal tissues.     

Nociceptors and the peripheral nervous system''s role in pain

The main trends of contemporary pharmacology of hypolipidemic and hypocholesterolemic agents were analysed. A list of drugs capable of correcting lipid metabolism disorders is given: cholesterol absorption inhibitors, stimulators of bile acid synthesis, inhibitors of cholesterol synthesis, analogs of fibroic acid and other inhibitors and correctors of hypertriglyceridemias, stimulators of reverse cholesterol transport and synthesis of high-density lipoproteins, etc. The latest theoretical and experimental elaborations of gene therapy of dyslipoproteinemias in atherosclerosis are discussed.     

Mice's rectum radioprotection: comparative efficacy of a series of aminothiols and aminothiol precursors

In mice, in a test of rectal gamma irradiation, cysteamine and cysteine are poor radioprotectors relative to thiazolanes or WR 2721. Among the tested prodrugs, 2-isopropyl 1,3-thiazolane was nearly as efficient as WR 2721 as soon as 15 minutes after its administration. The guarantee of radioprotection is the effective presence of the active aminothiols in the intracellular room during the irradiation. In this study, enterocytes of the rectal mucous membrane were not sufficiently permeable to exogenous cysteine or cysteamine. The cell imperviousness to these straight active aminothiols was compensated by the diffusion of their precursors across the membrane.     

Effects of low radiation doses on Chinese hamster cells

The induction of cytogenetic damages after irradiation with single dose of gamma-rays (0.1-2 Gy) have been studied. It is shown non-linear curve for the induction of chromosome aberrations, detected by anaphase method. After irradiation in S-stage of the cell cycle at dose below 0.2 Gy the cells were more radiosensitive than after irradiation with doses 0.3-2 Gy. Between the phases of high radiosensitivity and radioresistance the reversal dose-effect relation was observed. This phenomenon was not marked for the cells after irradiation in G2-stage of the cell cycle. It is possible, this results could reflect an induced radioresistance at low dose of irradiation.     

Histological study of colonic ischaemia after aortic surgery

We examined the radioprotective effect of aminothiol 2-N-propylamine-cyclo-hexanethiol (20-PRA) on a human leukemic cell line (K562) following various radiation doses (5, 7.5 and 20 Gy) using a source of 60Co gamma-rays. At 5 Gy and 1 nM 20-PRA, a substantial protective effect (58%) was seen 24 h after irradiation, followed by a decrease at 48 h (11%). At the high radiation dose (20 Gy) a low protective effect was also seen (35%). In addition, the antitumorigenic potential of 10 nM 20-PRA was shown by the inhibition of crown gall formation induced by Agrobacterium tumefaciens. The radioprotective potency of 20-PRA is 10(5)-10(6) times higher than that of the aminothiol WR-1065 (N-(2-mercaptoethyl)-1,3-diaminopropane) whose protective effect is in the 0.1 to 1.0 mM range.     

Pancreatic steatorrhea, malabsorption, and nutrition biochemistry: a comparison of Japanese, European, and American patients with chronic pancreatitis

Neuroleptic and anticonvulsant drugs are used to reduce the occurrence of aberrant behaviors, seizures, or both in individuals with mental retardation. However, their use may disrupt the learning of desired skills, and the extent to which anatomical (e.g., microencephaly) or biochemical abnormalities or both in such individuals alter the effects of drugs on learning is not known. In this study, the effects of neuroleptics and anticonvulsants on learning and performance in a repeated acquisition task in methylazoxymethanol-induced microencephalic and saline control rats were assessed. Thioridazine was more potent in microencephalic rats than in control rats in increasing errors and decreasing response rates. Clozapine was equally potent in both microencephalic and control rats in increasing errors and decreasing response rates. The effect of carbamazepine was biphasic in both rat groups: Low doses decreased errors and increased response rates, whereas higher doses did the opposite.     

Metals for Human Implants

Precision alloys are being developed at Bardin Central Research Institute of Ferrous Metals for use in medical instruments and for insertion in the human organism (stents, stimulators, joint prostheses, etc.). Long-term implantation in the body (for practically a human lifetime) is now within the bounds of possibility.     

Tempace and troxyl-novel synthesized 2,2,6,6-tetramethylpiperidine derivatives as antioxidants and radioprotectors

Two novel 2,2,6,6-tetramethylpiperidine derivatives (Tempace and Troxyl) were synthesized and their capacity to act as scavengers of superoxide, inhibitors of iron and ascorbate-driven Fenton reaction and radioprotectors was tested. The possibility for one-electron oxidation of novel compounds by heme-ferryl species was also examined. The results clearly indicate that Tempace and Troxyl are acting as promising antioxidants and radioprotectors thus providing a base for further investigations and pharmacological applications.     

Glucan as stimulator of hematopoiesis in normal and gamma-irradiated mice. A survey of the authors' results

Glucan, a beta-1,3-linked polyglucose derived from the yeast Saccharomyces cerevisiae, is a broad spectrum enhancer of host defense mechanisms stimulating humoral and cell-mediated immunity. On the basis of these features, glucan has been tested by the authors' research group in experiments on gamma-irradiated mice. Two glucan forms, particulate and soluble, have been studied. Attention has been focused on various application regimens in relation to the time of irradiation (pre- or postirradiation application), the possibilities of using glucan in various radiation regimens (single or repeated irradiation), combined pharmacological therapy (joint administration of glucan with cystamine or inhibitors of prostaglandin synthesis), and on the negative side effects of therapy with glucan. Some studies included also experiments on unirradiated mice. The results have demonstrated the ability of glucan to influence positively the course of the acute radiation disease. Stimulation of hematopoiesis has been found to be the most important mechanism of glucan's radioprotective effects. In this communication, the results of 11 full-length articles are summarized and discussed.     

Mechanism of radioprotection conferred by the immunomodulator AS101

AS101 [ammonium trichloro (dioxyethylene-0-0') tellurate] is a new synthetic compound previously described by us as having immunomodulating properties and minimal toxicity. Clinical trials are currently in progress with AS101 in AIDS and cancer patients. AS101 has recently been found to have radioprotective effects on hemopoiesis in irradiated mice when administered prior to irradiation. Since the early progenitors, spleen colony-forming units (CFU-S), are the critical cells needed for the reconstitution of the hemopoietic system, the mechanisms of action of AS101 were explored in this study by examining the compound's effect on the recovery of CFU-S, its protective effect on endogenous CFU-S and its effect on self-renewal of CFU-S. We also studied the effect of AS101 on the induction of progenitor cells into the radioresistant S-phase of the cell cycle. On days 1 and 5 after irradiation, the number of CFU-S in the bone marrow and spleen of AS101-treated mice was significantly higher than that of PBS-injected mice. Nine days after sublethal doses of irradiation, the number of endogenous spleen colonies was highest in mice given AS101 every 24 hours or every other day for 1 week prior to irradiation. AS101 administered immediately after irradiation, however, also resulted in an increase in the endogenous CFU-S. The higher number of CFU-S found in each 9-day endogenous spleen colony suggests increased self-renewal of CFU-S in AS101-treated mice. Moreover, we found that AS101 induced a higher number of progenitor cells in the S-phase of the cell cycle. These findings suggest that the radioprotection conferred by AS101 results from induction of progenitor cells in DNA synthesis (S-phase) and from the enhanced stimulation of CFU-S, not only toward proliferation but also toward CFU-S self-renewal.     

Primary hemochromatosis and dietary iron

Primary haemochromatosis is characterized by an unusually high degree of iron absorption resulting in the accumulation of excessive amounts of tissue iron. Excess stores of iron are removed by repeated phlebotomy. Health personnel and a number of patients with primary haemochromatosis have expressed their desire for advice on special diets to try and reduce the number of phlebotomies per year. This article gives advice on how patients with primary haemochromatosis can decrease their dietary iron intake and how they can put together meals to obtain low bioavailability, and therefore a lower iron absorption. The diet should be varied and be rich in bread and cereals, and fruit and vegetables. The amount of meat, Norwegian brown whey cheese (iron supplemented) and alcohol should be limited. Tea or coffee with meals will reduce iron absorption. Food rich in ascorbic acid (fruit and fruit juice) should be avoided with meals. Ascorbic acid supplements are not recommended.