Dose reduction factor

Dose reduction factor = [LD50 (30 days) treated /LD50 (30 days) untreated]. 

In this equation, the risk of cancer is assumed to be 100% for an effective equivalent dose of 20 Sv. The equation is based on the probabilities listed in Table 22.10. In order to take into account that a dose dehvered with a relatively low dose rate over a longer period of time has an appreciably smaller effect than a single dose, a dose reduction factor of 2 is recommended for smaller dose rates. However, in the report of the United Nations Scientific Committee on the Effects of Atomic Radiation... 

It is essential to establish certain criteria to evaluate the synthesized compounds, in particular their radioprotective effectiveness and their toxicity. For each of the molecules we synthesize, first we evaluate its acute (48 hours) and medium-term (2-30 days) toxicity in male Swiss CD1 mouse. The molecule is injected intraperitonally at different concentrations to determine the LD5o,ox/48h/ defined as the concentration which kills 50% ofthe animals at 48 hours. Then, radioprotective effectiveness is determined in the same animal model. In a preliminary study, the product is administered at the maximum tolerated dose (defined as 1/2 LD5otox/48h) 15 or 90 minutes before radiation exposure at doses LD,ooirr/3od nd LD,ooirr/3od + 2 Gy (LD,ooirr/3od is defined as the irradiation dose which kills 100% of the animals 30 days after exposure). Survival is observed for 30 days. In a second experiment we determine the Dose Reduction Factor (DRF) for the most radioprotective compounds. DRF is the ratio between the LDsoirr/sod of treated mice and that of non treated mice. 

Most of these phosphorated derivatives present still an interesting radioprotective activity even when mice have been exposed to LD,Qoi /3oj + 2 Gy. Compounds derived from naphthylethylimidazoline are less toxic and sometimes more active. Compounds (30, 31) are less toxic than compounds 28 and 29. However, in derivative 23, the most active of the series, the substitution of an hydrogen atom by a methyl group, giving compound 29, induces a great decrease in the activity, and even a total decrease of radioprotective activity at 10 Gy. In contrast, in the case of phosphorothioate 30, the presence ofa methyl group greatly improves radioprotective properties in comparison with compound 24 which is the less active derivative. The Dose Reduction Factor has been determined as previously described for compounds 27, 28 and 31. Their values are 1.6, 1.8 and 1.6, respectively (Tab. 4). 

Several other radiation protection agents are known. These compounds are typically amino thiols, similar to the natural amino acid cysteamine. They probably function as scavengers for the products of water radiolysis. Their effectiveness is evaluated by determination of the dose reduction factor (DRF), which is the ratio of LD5Q/3Q for protected and unprotected animals. Because of their chemical toxicity, many can o y be administered in small doses. 

In 18.6.1, it was stated that the lethal dose for instantaneous low-LET radiation is 10 Sv. The value 5%/Sv is half as large, which is a concession to the fact that biological harm d ) ds on dose-rates as described in 18.5. In ICRP terminology, the dose reduction factor is chosen to be 2, although UNSCEAR 1993 (p.688) notes that it is more likely 2 - 10. 

The dose reduction factor for dimethylsulfoxide (DMSO) absorbed through the tails of mice was found to be 1.35 - significant protection was provided to mice against 900 r by the vapors of lAlSO when present during or... 

Adrenochrome monoguanylhydrazone methanesulfonate ("S-adchnon"), said to have a dose reduction factor In mice of 1.32 at about 5 mg/kg. °... 

The use of mixtures of drugs to obtain greater protection than can be obtained by single components has continued to make progress. Malsln and his collaborators have used mixtures of well-known antlradlatlon drugs (MEA) AET, cysteine, reduced glutathione, serotonin creatinine sulfate) in mice to obtain dose reduction factors of 2.8, with decreased toxicity. 

Field and his associates prepared a variety of novel disulfides and observed "good" protection in mice with 2-acetamidoethyl acetyl disul-fide (< 50 mg/kg), with p-cyanobenzyl 2-(n-decylamino)ethyl disulfide (p-CHo, p-CHO and p-Cl analogs were Inactive) and with. 3-acetamidopropyl 2-(n-decylamino)ethyl disulfide l (30-50 mg/kg). The 2-acetamido isomer of the last-named compound was much less protective. Thiamine tetrahydro-furfuryl disulfide (40 mg/kg, i.p., post-irradiation) protected mice against 600-700r with a dose reduction factor of 1.34. ... 

A dose reduction factor of 3,8 in mice was achieved by combining a variety of drugs and factors.These included MEA (200 mg/kg, 15 min. pre-irradiation), hypoxia (nitrogen atmosphere during irradiation), syngeneic bone marrow (22 hrs. post-irradiation), sodium penicillin G (50,000 I. U., 30 days) and streptomycin (50 mg/kg, 30 days). 

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

This corresponds to a dose reduction in the house of more than a factor of 2. It also shows that more than half of the household radon is caused by the radon from water. The 0.76 pCi/1 is the radon caused by soil gas and building materials. These results are summarized in Table IV. 

After a meticulous review of the biomedical literature, the panel concluded that routine use of colony-stimulating factors for primary prophylaxis of febrile neutropenia in previously untreated patients is not justified by existing data. There is evidence, however, that colony-stimulation factor administration can decrease the probability of febrile neutropenia in subsequent cycles of chemotherapy after a documented occurrence in an earlier cycle. However, dose reduction after a severe episode, rather than administration of colony-stimulating factors, should be considered as a primary therapeutic option. In the absence of clinical evidence or other compelling reasons to maintain chemotherapy dose intensity, physicians should consider chemotherapy dose reduction... 

Sensitization of anoxic cells is also brought about by non-toxic concentrations of transition metal ions (< some 10-4 mol dm-3) such as Cu(I). A dose-modifying factor of 1.5 (at 6.6 x 10-5 mol dm-3 Cu(I)) has been observed for mammalian cells (Hesslewood et al. 1978), but no sensitizing effects were observed for oxygenated cells. Under anoxic conditions, reduction of Cu(II) to Cu(I) occurs within the cells without an added reductant (see also Cramp 1967). It would be premature to come up with detailled mechanistic concepts, but some aspects of the actions of transition-metal ions have been discussed in Chapter 2.5. 

Dose-related toxicities of azathioprine or 6-mercaptopurine include nausea, vomiting, bone marrow depression (leading to leukopenia, macrocytosis, anemia, or thrombocytopenia), and hepatic toxicity. Routine laboratory monitoring with complete blood count and liver function tests is required. Leukopenia or elevations in liver chemistries usually respond to medication dose reduction. Severe leukopenia may predispose to opportunistic infections leukopenia may respond to therapy with granulocyte stimulating factor. Hypersensitivity reactions to azathioprine or 6-mercaptopurine occur in 5% of patients. These include fever, rash, pancreatitis, diarrhea, and hepatitis. 

The most often used unit to quantify the activity of any radioactive material is the curie (Ci). For most level detection applications, source strengths of 100 millicuries (mCi) or less are satisfactory. A 1 Ci source will produce a dose of 1 roentgen (r) at a receiver placed 1 m (3 ft) away from the source for 1 h. Radiation is attenuated when it penetrates liquids or solids, and the rate of attenuation is a function of the density of the material. The higher the density, the more attenuation the shielding material will provide. Figure 3.122 shows how various thicknesses of different materials will attenuate (reduction factor—NB) the intensity of radiation and result in different degrees of attenuation. 

During treatment with extremely high doses of factor IX concentrate, to induce immune tolerance, nephrotic sjm-drome has been described (6,7). Withdrawal or dosage reduction is of crucial importance for the resolution of nephrosis (6). Renal biopsy in one of these patients showed peripheral capUlary wall thickening and deposits throughout the basement membrane (7). In addition minimal interstitial fibrosis and tubular atrophy were present. There were no deposits of factor IX in the glomeruli, which the authors attributed to absence of free factor IX epitope in the tissue (7). 

There is no antidote for azathioprine toxicity. Treatment for an overdose entails ipecac within 30 min or lavage within 1 h, followed by activated charcoal. Side effects may be minimized with adequate monitoring of peripheral blood count and liver enzymes. Asymptomatic leucopenia, as well as most other side effects, may be treated with dose reduction or drug cessation (and changing to 6-MP) however, a life-threatening leucopenic episode may require administration of granulocyte colony-stimulating factor as well as other supportive care. 

Theophylline is a classic example. Its bronchodi-lator effects are related to plasma concentrations in the range of 5-20 mg l-1, while higher concentrations are associated with tachyarrythmias and other serious adverse effects. This is a drug with a narrow therapeutic window . Elderly patients commonly have several risk factors that can lead to unexpectedly high serum concentrations after administration of standard doses reductions in renal clearance, reduced volume of distribution and an increased probability of concomitant disease and other therapies (Ohnishi et al., 2003). Monitoring plasma levels is thus helpful in avoiding the adverse effects of theophylline. 

---