Severe toxic dose

STD10 - the severely toxic dose with 10% mortality (rodent)... 

Monomethylmercury (MMM) is the most toxico-logically prominent of organic mercury compounds due to its environmental ubiquity and high potential for bioconcentration. Although DMM is less frequently encountered, it exhibits a far more toxic profile. Based on the lethality of only a few drops of the substance, DMM has been classified as a supertoxic chemical. Absorption of 100 pi of the colorless liquid is equivalent to a severely toxic dose of 100-200 mg of mercury per 100 ml of whole blood. Its synthesis, transportation, and use should be minimized and exercised with only extreme care. 

The dosage of flucytosine is 150—200 mg/kg orally in four portions every six hours. A 1% flucytosine solution has been developed for intravenous adrninistration. In some countries, a 10% ointment is also available. In patients with normal renal function, flucytosine is seldom toxic, but occasionally severe toxicity may be observed (leukopenia and thrombocytopenia). Plasma levels should be determined and the dose in patients with impaired renal function should be checked. Liver function tests (transaininases and alkaline phosphatase) should be performed regularly. In some patients with high flucytosine plasma levels, hepatic disorders have been observed (24). 

Usual dose schedules of streptozotocin involve 500 mg/m2 i.v. during five consecutive days. The major toxicity is renal tubular damage. Treatment of metastatic insulinomas may result in the release of insulin from the tumor and subsequent hypoglycemic coma. Less severe toxicities include diarrhea, anemia, and mild alterations in glucose tolerance or liver function tests. 

Toxicity and Hazards. The odor cf ozone can be detected in concn as low as several parts per hundred million by vol (pphm). The threshold limit value (TLV) is O.lppmor 0.2mg/m3 its toxic dose level (TDL), 50% kill concn is 2ppm (Ref 6) Pure 100% liq ozone may be kept safely at 90°K (cooled by liq oxygen) for indefinite periods of time, but the smallest provocation, such as a spark or fast warming, even only up to bp (161°K), causes detonation. The evapn of liq ozone, for example, in the process of the prepn of pure gaseous ozone is, therefore, a dangerous procedure (Ref 3, p 224)... 

Merkord J, Weber H, Kroning G, Henningshausen G (2001) Repeated administration of a mild acute toxic dose of di-n-butyltin dichioride at intervals of 3 weeks induces severe lesions in pancreas and liver of rats. Human and Experimental Toxicology, 20(8) 386-392. 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Similar to 5-FU, there is a polymorphism associated with irinotecan toxicity. UDP-glucuronosyltransferase (UGT1A1) is an enzyme responsible for the glucuronidation of SN-38 to inactive metabolites, and reduced or deficient levels of this enzyme correlate with irinotecan-induced diarrhea and neutropenia.39 Recently the FDA approved a blood test that detects variations in this gene. This test will assist health care providers in predicting which patients may develop severe toxicities from normal doses of irinotecan and can be ordered prior to patients receiving irinotecan. binotecan is administered as an IV bolus over 60 to 90 minutes in a variety dosing schedules. 

Propranolol doses required to relieve adrenergic symptoms vary, but an initial dose of 20 to 40 mg four times daily is effective for most patients (heart rate less than 90 beats/min). Younger or more severely toxic patients may require as much as 240 to 480 mg/day. 

Decreasing doses in standard regimens should be avoided unless necessitated by severe toxicity. 

Recent studies have examined the separation of APP and Notch processing effects in vivo. Dibenzazepinone 29 (LY-411,575) demonstrates significant reductions in plasma, CSF, and brain A (3 in transgenic mice [80-83]. Several toxicities attributed to inhibition of Notch processing, including effects on the intestine, thymus, and spleen, have also been characterized. Doses associated with partial inhibition of cortical A (340 levels by 29 in mice did not cause intestinal changes... 

The number of drugs susceptible to S-methylation is still limited but greater than the number turned over by COMT. Thiopurine methyl transferase (TPMT) is an important enzyme responsible for detoxifying mercaptopurine—a drug used to treat leukemia— as well as azathioprine —a prodrug that is metabolized to mercaptopurine (Fig. 7.12). This enzyme is polymorphic and patients who are homozygous for the deficient enzyme experience severe toxicity when given usual doses of mercaptopurine (19). Similar aromatic and heterocyclic sulfhydryls can also be substrates for TPMT. The similar thiol... 

Patients who are treated with standard doses of chemotherapy exhibit large inter-and intraindividnal variability in the development of severe toxicities. In addition, there is a wide variation between patients with the same tnmor type and stage in the likelihood of response after standard chemotherapy. 

Death. Information regarding death in humans following exposure to 1,2-diphenylhydrazine by any route was not found. Some information is available on lethality of orally-administered 1,2-diphenylhydrazine in animals. This information, consisting of a gavage LDso value in fats (Marhold et al. 1968) and an unreliable 3-day dietary lethal dose in mice (Schafer and Bowles 1985), indicates that single or several oral doses of about 1000 mg/kg/day may be lethal for rodents. Based on these data, 1,2-diphenylhydrazine does not appear to be highly acutely toxic to humans he oral route. 

It was recommended that excursions above the TDI/PTWI should be considered in the way as for substances where an ADI has been set. It was emphasized that contaminants having very long half-lives accumulate in the body and the chronic toxicity is most often manifested when critical concentrations are achieved in target tissues. Furthermore, there are usually large differences between the acute or shorter-term toxic doses and the chronic LOAELs. In such cases, peak excursions of several times the PTWIs for short periods (days, weeks, or even months) or lower peak intakes for even longer periods (months to years) may be of no consequence provided that the integrated exposure over longer periods does not lead to critical steady-state tissue concentrations. 

Barium ion is a muscle poison causing stimulation and then paralysis. Initial symptoms are gastrointestinal, including nausea, vomiting, colic, and diarrhea, followed by myocardial and general muscular stimulation with tingling in the extremities. Severe cases continue to loss of tendon reflexes, general muscular paralysis, and death from respiratory arrest or ventricular fibrillation. Threshold of a toxic dose in humans is reported to be about 0.2-0.5 g Ba absorbed from the gut the lethal dose is 3 g Ba. 

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